RAF/MAP kinase cascade (Homo sapiens)

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Description

The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011). View original pathway at:Reactome.

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114761	view	16:25, 25 January 2021	ReactomeTeam	Reactome version 75
113205	view	11:27, 2 November 2020	ReactomeTeam	Reactome version 74
112429	view	15:37, 9 October 2020	ReactomeTeam	Reactome version 73
101333	view	11:22, 1 November 2018	ReactomeTeam	reactome version 66
100871	view	20:55, 31 October 2018	ReactomeTeam	reactome version 65
100412	view	19:28, 31 October 2018	ReactomeTeam	reactome version 64
99961	view	16:13, 31 October 2018	ReactomeTeam	reactome version 63
99516	view	14:46, 31 October 2018	ReactomeTeam	reactome version 62 (2nd attempt)
99158	view	12:41, 31 October 2018	ReactomeTeam	reactome version 62
93933	view	13:46, 16 August 2017	ReactomeTeam	reactome version 61
93520	view	11:25, 9 August 2017	ReactomeTeam	reactome version 61
88127	view	10:15, 26 July 2016	Ryanmiller	Ontology Term : 'kinase mediated signaling pathway' added !
88126	view	10:15, 26 July 2016	Ryanmiller	Ontology Term : 'signaling pathway' added !
86618	view	09:22, 11 July 2016	ReactomeTeam	reactome version 56
83142	view	10:09, 18 November 2015	ReactomeTeam	Version54
81486	view	13:01, 21 August 2015	ReactomeTeam	Version53
76963	view	08:24, 17 July 2014	ReactomeTeam	Fixed remaining interactions
76668	view	12:03, 16 July 2014	ReactomeTeam	Fixed remaining interactions
75998	view	10:05, 11 June 2014	ReactomeTeam	Re-fixing comment source
75701	view	11:04, 10 June 2014	ReactomeTeam	Reactome 48 Update
75057	view	13:56, 8 May 2014	Anwesha	Fixing comment source for displaying WikiPathways description
74701	view	08:46, 30 April 2014	ReactomeTeam	New pathway

External references

DataNodes

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Name	Type	Database reference	Comment
'activator' RAF:YWHAB dimer	Complex	R-HSA-5672710 (Reactome)
26S proteasome	Complex	R-HSA-68819 (Reactome)
ACTN2	Protein	P35609 (Uniprot-TrEMBL)
ADP	Metabolite	CHEBI:16761 (ChEBI)
AKAP9	Protein	Q99996 (Uniprot-TrEMBL)
ANGPT1	Protein	Q15389 (Uniprot-TrEMBL)
APBB1IP	Protein	Q7Z5R6 (Uniprot-TrEMBL)
ARRB1	Protein	P49407 (Uniprot-TrEMBL)
ARRB2	Protein	P32121 (Uniprot-TrEMBL)
ATP	Metabolite	CHEBI:15422 (ChEBI)
Activated FGFR2b homodimer bound to FGF		R-HSA-192606 (Reactome)
Activated FGFR2c homodimer bound to FGF		R-HSA-192616 (Reactome)
BRAP	Protein	Q7Z569 (Uniprot-TrEMBL)
BRAP:KSR1:MARK3	Complex	R-HSA-5674011 (Reactome)
BRAP	Protein	Q7Z569 (Uniprot-TrEMBL)
CALM1	Protein	P62158 (Uniprot-TrEMBL)
CNKSR1	Protein	Q969H4 (Uniprot-TrEMBL)
CNKSR2	Protein	Q8WXI2 (Uniprot-TrEMBL)
CSK	Protein	P41240 (Uniprot-TrEMBL)
CUL3	Protein	Q13618 (Uniprot-TrEMBL)
Ca2+	Metabolite	CHEBI:29108 (ChEBI)
Cell surface interactions at the vascular wall	Pathway	R-HSA-202733 (Reactome)	Leukocyte extravasation is a rigorously controlled process that guides white cell movement from the vascular lumen to sites of tissue inflammation. The powerful adhesive interactions that are required for leukocytes to withstand local flow at the vessel wall is a multistep process mediated by different adhesion molecules. Platelets adhered to injured vessel walls form strong adhesive substrates for leukocytes. For instance, the initial tethering and rolling of leukocytes over the site of injury are mediated by reversible binding of selectins to their cognate cell-surface glycoconjugates. Endothelial cells are tightly connected through various proteins, which regulate the organization of the junctional complex and bind to cytoskeletal proteins or cytoplasmic interaction partners that allow the transfer of intracellular signals. An important role for these junctional proteins in governing the transendothelial migration of leukocytes under normal or inflammatory conditions has been established. This pathway describes some of the key interactions that assist in the process of platelet and leukocyte interaction with the endothelium, in response to injury.
DAB2IP	Protein	Q5VWQ8 (Uniprot-TrEMBL)
DAG	Metabolite	CHEBI:17815 (ChEBI)
DAP12 interactions	Pathway	R-HSA-2172127 (Reactome)	DNAX activation protein of 12kDa (DAP12) is an immunoreceptor tyrosine-based activation motif (ITAM)-bearing adapter molecule that transduces activating signals in natural killer (NK) and myeloid cells. It mediates signalling for multiple cell-surface receptors expressed by these cells, associating with receptor chains through complementary charged transmembrane amino acids that form a salt-bridge in the context of the hydrophobic lipid bilayer (Lanier et al. 1998). DAP12 homodimers associate with a variety of receptors expressed by macrophages, monocytes and myeloid cells including TREM2, Siglec H and SIRP-beta, as well as activating KIR, LY49 and the NKG2C proteins expressed by NK cells. DAP12 is expressed at the cell surface, with most of the protein lying on the cytoplasmic side of the membrane (Turnbull & Colonna 2007, Tessarz & Cerwenka 2008).
DLG4	Protein	P78352 (Uniprot-TrEMBL)
DUSP1	Protein	P28562 (Uniprot-TrEMBL)
DUSP10	Protein	Q9Y6W6 (Uniprot-TrEMBL)
DUSP16	Protein	Q9BY84 (Uniprot-TrEMBL)
DUSP2	Protein	Q05923 (Uniprot-TrEMBL)
DUSP4	Protein	Q13115 (Uniprot-TrEMBL)
DUSP5	Protein	Q16690 (Uniprot-TrEMBL)
DUSP6	Protein	Q16828 (Uniprot-TrEMBL)
DUSP7	Protein	Q16829 (Uniprot-TrEMBL)
DUSP8	Protein	Q13202 (Uniprot-TrEMBL)
DUSP9	Protein	Q99956 (Uniprot-TrEMBL)
EGF	Protein	P01133 (Uniprot-TrEMBL)
EGF-like ligands		R-HSA-1233230 (Reactome)
F-actin		R-HSA-196015 (Reactome)
FGA	Protein	P02671 (Uniprot-TrEMBL)
FGB	Protein	P02675 (Uniprot-TrEMBL)
FGF1	Protein	P05230 (Uniprot-TrEMBL)
FGF10	Protein	O15520 (Uniprot-TrEMBL)
FGF16	Protein	O43320 (Uniprot-TrEMBL)
FGF17-1	Protein	O60258-1 (Uniprot-TrEMBL)
FGF18	Protein	O76093 (Uniprot-TrEMBL)
FGF19	Protein	O95750 (Uniprot-TrEMBL)
FGF2(10-155)	Protein	P09038 (Uniprot-TrEMBL)
FGF20	Protein	Q9NP95 (Uniprot-TrEMBL)
FGF22	Protein	Q9HCT0 (Uniprot-TrEMBL)
FGF23(25-251)	Protein	Q9GZV9 (Uniprot-TrEMBL)
FGF3	Protein	P11487 (Uniprot-TrEMBL)
FGF4	Protein	P08620 (Uniprot-TrEMBL)
FGF5-1	Protein	P12034-1 (Uniprot-TrEMBL)
FGF6	Protein	P10767 (Uniprot-TrEMBL)
FGF8-1	Protein	P55075-1 (Uniprot-TrEMBL)
FGF9	Protein	P31371 (Uniprot-TrEMBL)
FGG	Protein	P02679 (Uniprot-TrEMBL)
FN1(32-2386)	Protein	P02751 (Uniprot-TrEMBL)
Fc epsilon receptor (FCERI) signaling	Pathway	R-HSA-2454202 (Reactome)	Mast cells (MC) are distributed in tissues throughout the human body and have long been recognized as key cells of type I hypersensitivity reactions. They also play important roles in inflammatory and immediate allergic reactions. Activation through FCERI-bound antigen-specific IgE causes release of potent inflammatory mediators, such as histamine, proteases, chemotactic factors, cytokines and metabolites of arachidonic acid that act on the vasculature, smooth muscle, connective tissue, mucous glands and inflammatory cells (Borish & Joseph 1992, Amin 2012, Metcalfe et al. 1993). FCERI is a multimeric cell-surface receptor that binds the Fc fragment of IgE with high affinity. On mast cells and basophils FCERI exists as a tetrameric complex consisting of one alpha-chain, one beta-chain, and two disulfide-bonded gamma-chains, and on dendritic cells, Langerhans cells, macrophages, and eosinophils it exists as a trimeric complex with one alpha-chain and two disulfide-bonded gamma-chains (Wu 2011, Kraft & Kinet 2007). FCERI signaling in mast cells includes a network of signaling molecules and adaptor proteins. These molecules coordinate ultimately leading to effects on degranulation, eicosanoid production, and cytokine and chemokine production and cell migration and adhesion, growth and survival. The first step in FCERI signaling is the phosphorylation of the tyrosine residues in the ITAM of both the beta and the gamma subunits of the FCERI by LYN, which is bound to the FCERI beta-chain. The phosphorylated ITAM then recruits the protein tyrosine kinase SYK (spleen tyrosine kinase) which then phosphorylates the adaptor protein LAT. Phosphorylated LAT (linker for activation of T cells) acts as a scaffolding protein and recruits other cytosolic adaptor molecules GRB2 (growth-factor-receptor-bound protein 2), GADS (GRB2-related adaptor protein), SHC (SRC homology 2 (SH2)-domain-containing transforming protein C) and SLP76 (SH2-domain-containing leukocyte protein of 76 kDa), as well as the exchange factors and adaptor molecules VAV and SOS (son of sevenless homologue), and the signalling enzyme phospholipase C gamma1 (PLC-gamma1). Tyrosoine phosphorylation of enzymes and adaptors, including VAV, SHC GRB2 and SOS stimulate small GTPases such as RAC, RAS and RAF. These pathways lead to activation of the ERK, JNK and p38 MAP kinases, histamine release and cytokine production. FCERI activation also triggers the phosphorylation of PLC-gamma which upon membrane localisation hydrolyse PIP2 to form IP3 and 1,2-diacylglycerol (DAG) - second messengers that release Ca2+ from internal stores and activate PKC, respectively. Degranulation or histamine release follows the activation of PLC-gamma and protein kinase C (PKC) and the increased mobilization of calcium (Ca2+). Receptor aggregation also results in the phosphorylation of adaptor protein NTAL/LAT2 which then recruits GAB2. PI3K associates with phosphorylated GAB2 and catalyses the formation of PIP3 in the membrane, which attracts many PH domain proteins like BTK, PLC-gamma, AKT and PDK. PI3K mediated activation of AKT then regulate the mast cell proliferation, development and survival (Gu et al. 2001).
GDP	Metabolite	CHEBI:17552 (ChEBI)
GDP	Metabolite	CHEBI:17552 (ChEBI)
GRB2-1	Protein	P62993-1 (Uniprot-TrEMBL)
GRIN1	Protein	Q05586 (Uniprot-TrEMBL)
GRIN2A	Protein	Q12879 (Uniprot-TrEMBL)
GRIN2B	Protein	Q13224 (Uniprot-TrEMBL)
GRIN2C	Protein	Q14957 (Uniprot-TrEMBL)
GRIN2D	Protein	O15399 (Uniprot-TrEMBL)
GTP	Metabolite	CHEBI:15996 (ChEBI)
GTP	Metabolite	CHEBI:15996 (ChEBI)
Gly	Metabolite	CHEBI:15428 (ChEBI)
H2O	Metabolite	CHEBI:15377 (ChEBI)
HBEGF(63-148)	Protein	Q99075 (Uniprot-TrEMBL)
HRAS	Protein	P01112 (Uniprot-TrEMBL)
HS	Metabolite	CHEBI:28815 (ChEBI)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-(Y593,628)-Bc:p(427,349,350)-SHC1		R-HSA-913439 (Reactome)
IL17RD	Protein	Q8NFM7 (Uniprot-TrEMBL)
IL17RD:p-2S MAP2Ks:MAPKs	Complex	R-HSA-5674360 (Reactome)
IL17RD:p-2S MAP2Ks:p-T,Y MAPKs	Complex	R-HSA-5674362 (Reactome)
IL17RD	Protein	Q8NFM7 (Uniprot-TrEMBL)
IL2	Protein	P60568 (Uniprot-TrEMBL)
IL2RA	Protein	P01589 (Uniprot-TrEMBL)
IL2RG	Protein	P31785 (Uniprot-TrEMBL)
IQGAP1	Protein	P46940 (Uniprot-TrEMBL)
ITGA2B(32-1039)	Protein	P08514 (Uniprot-TrEMBL)
ITGB3	Protein	P05106 (Uniprot-TrEMBL)
Interleukin-2 signaling	Pathway	R-HSA-451927 (Reactome)	Interleukin-2 (IL-2) is a cytokine that is produced by T cells in response to antigen stimulation. Originally, IL-2 was discovered because of its potent growth factor activity on activated T cells in vitro and was therefore named 'T cell growth factor' (TCGF). However, the generation of IL-2- and IL-2 receptor-deficient mice revealed that IL-2 also plays a regulatory role in the immune system by suppressing autoimmune responses. Two main mechanisms have been identified that explain this suppressive function: (1) IL-2 sensitizes activated T cells for activation-induced cell death (AICD) and (2) IL-2 is critical for the survival and function of regulatory T cells (Tregs), which possess potent immunosuppressive properties. IL-2 signaling occurs when IL-2 binds to the heterotrimeric high-affinity IL-2 receptor (IL-2R), which consists of alpha, beta and gamma chains. The IL-2R was identified in 1981 via radiolabeled ligand binding (Robb et al. 1981). The IL-2R alpha chain was identified in 1982 (Leonard et al.), the beta chain in 1986/7 (Sharon et al. 1986, Teshigawara et al. 1987) and the IL-2R gamma chain in 1992 (Takeshita et al.). The high affinity of IL-2 binding to the IL-2R is created by a very rapid association rate to the IL-2R alpha chain, combined with a much slower dissociation rate contributed by the combination of the IL-2R beta and gamma chains (Wang & Smith 1987). After antigen stimulation, T cells upregulate the high-affinity IL-2R alpha chain; IL-2R alpha captures IL-2 and this complex then associates with the constitutively expressed IL-2R beta and gamma chains. The IL-2R gamma chain is shared by several other members of the cytokine receptor superfamily including IL-4, IL-7, IL-9, IL-15 and IL-21 receptors, and consequently is often referred to as the Common gamma chain (Gamma-c). The tyrosine kinases Jak1 and Jak3, which are constitutively associated with IL-2R beta and Gamma-c respectively, are activated resulting in phosphorylation of three critical tyrosine residues in the IL-2R beta cytoplasmic tail. These phosphorylated residues enable recruitment of the adaptor molecule Shc, activating the MAPK and PI3K pathways, and the transcription factor STAT5. After phosphorylation, STAT5 forms dimers that translocate to the nucleus and initiate gene expression. While STAT5 activation is critical for IL-2 function in most cell types, the contribution of the PI3K/Akt pathway differs between distinct T cell subsets. In Tregs for example, PI3K/Akt is not involved in IL-2 signaling and this may explain some of the different functional outcomes of IL-2 signaling in Tregs vs. effector T cells.
Interleukin-3, 5 and GM-CSF signaling	Pathway	R-HSA-512988 (Reactome)	The Interleukin-3 (IL-3), IL-5 and Granulocyte-macrophage colony stimulating factor (GM-CSF) receptors form a family of heterodimeric receptors that have specific alpha chains but share a common beta subunit, often referred to as the common beta (Bc). Both subunits contain extracellular conserved motifs typical of the cytokine receptor superfamily. The cytoplasmic domains have limited similarity with other cytokine receptors and lack detectable catalytic domains such as tyrosine kinase domains. IL-3 is a 20-26 kDa product of CD4+ T cells that acts on the most immature marrow progenitors. IL-3 is capable of inducing the growth and differentiation of multi-potential hematopoietic stem cells, neutrophils, eosinophils, megakaryocytes, macrophages, lymphoid and erythroid cells. IL-3 has been used to support the proliferation of murine cell lines with properties of multi-potential progenitors, immature myeloid as well as T and pre-B lymphoid cells (Miyajima et al. 1992). IL-5 is a hematopoietic growth factor responsible for the maturation and differentiation of eosinophils. It was originally defined as a T-cell-derived cytokine that triggers activated B cells for terminal differentiation into antibody-secreting plasma cells. It also promotes the generation of cytotoxic T-cells from thymocytes. IL-5 induces the expression of IL-2 receptors (Kouro & Takatsu 2009). GM-CSF is produced by cells (T-lymphocytes, tissue macrophages, endothelial cells, mast cells) found at sites of inflammatory responses. It stimulates the growth and development of progenitors of granulocytes and macrophages, and the production and maturation of dendritic cells. It stimulates myeloblast and monoblast differentiation, synergises with Epo in the proliferation of erythroid and megakaryocytic progenitor cells, acts as an autocrine mediator of growth for some types of acute myeloid leukemia, is a strong chemoattractant for neutrophils and eosinophils. It enhances the activity of neutrophils and macrophages. Under steady-state conditions GM-CSF is not essential for the production of myeloid cells, but it is required for the proper development of alveolar macrophages, otherwise, pulmonary alvelolar proteinosis (PAP) develops. A growing body of evidence suggests that GM-CSF plays a key role in emergency hematopoiesis (predominantly myelopoiesis) in response to infection, including the production of granulocytes and macrophages in the bone marrow and their maintenance, survival, and functional activation at sites of injury or insult (Hercus et al. 2009). All three receptors have alpha chains that bind their specific ligands with low affinity (de Groot et al. 1998). Bc then associates with the alpha chain forming a high affinity receptor (Geijsen et al. 2001), though the in vivo receptor is likely be a higher order multimer as recently demonstrated for the GM-CSF receptor (Hansen et al. 2008). The receptor chains lack intrinsic kinase activity, instead they interact with and activate signaling kinases, notably Janus Kinase 2 (JAK2). These phosphorylate the common beta subunit, allowing recruitment of signaling molecules such as Shc, the phosphatidylinositol 3-kinases (PI3Ks), and the Signal Transducers and Activators of Transcription (STATs). The cytoplasmic domain of Bc has two distinct functional domains: the membrane proximal region mediates the induction of proliferation-associated genes such as c-myc, pim-1 and oncostatin M. This region binds multiple signal-transducing proteins including JAK2 (Quelle et al. 1994), STATs, c-Src and PI3 kinase (Rao and Mufson, 1995). The membrane distal domain is required for cytokine-induced growth inhibition and is necessary for the viability of hematopoietic cells (Inhorn et al. 1995). This region interacts with signal-transducing proteins such as Shc (Inhorn et al. 1995) and SHP and mediates the transcriptional activation of c-fos, c-jun, c-Raf and p70S6K (Reddy et al. 2000). Figure reproduced by permission from Macmillan Publishers Ltd: Leukemia, WL Blalock et al. 13:1109-1166, copyright 1999. Note that residue numbering in this diagram refers to the mature Common beta chain with signal peptide removed.
JAK2	Protein	O60674 (Uniprot-TrEMBL)
JAK3	Protein	P52333 (Uniprot-TrEMBL)
KBTBD7	Protein	Q8WVZ9 (Uniprot-TrEMBL)
KBTBD7:CUL3:RBX1	Complex	R-HSA-5658416 (Reactome)
KITLG-1(26-190)	Protein	P21583-1 (Uniprot-TrEMBL)
KL-1	Protein	Q9UEF7-1 (Uniprot-TrEMBL)
KL-2	Protein	Q9UEF7-2 (Uniprot-TrEMBL)
KLB	Protein	Q86Z14 (Uniprot-TrEMBL)
KRAS	Protein	P01116 (Uniprot-TrEMBL)
KSR1	Protein	Q8IVT5 (Uniprot-TrEMBL)
KSR1:MARK3	Complex	R-HSA-5672689 (Reactome)
KSR2	Protein	Q6VAB6 (Uniprot-TrEMBL)
L-Glu	Metabolite	CHEBI:16015 (ChEBI)
LAMTOR2	Protein	Q9Y2Q5 (Uniprot-TrEMBL)
LAMTOR3	Protein	Q9UHA4 (Uniprot-TrEMBL)
MAP2K homo/heterodimers	Complex	R-HSA-5672716 (Reactome)
MAP2K1	Protein	Q02750 (Uniprot-TrEMBL)
MAP2K2	Protein	P36507 (Uniprot-TrEMBL)
MAP3K11	Protein	Q16584 (Uniprot-TrEMBL)
MAPK monomers and dimers	Complex	R-HSA-5675361 (Reactome)
MAPK monomers and dimers	Complex	R-HSA-5675363 (Reactome)
MAPK1	Protein	P28482 (Uniprot-TrEMBL)
MAPK3	Protein	P27361 (Uniprot-TrEMBL)
MAPKs		R-HSA-169291 (Reactome)
MAPKs	Complex	R-HSA-169291 (Reactome)
MARK3	Protein	P27448 (Uniprot-TrEMBL)
Mg2+	Metabolite	CHEBI:18420 (ChEBI)
Mn2+	Metabolite	CHEBI:29035 (ChEBI)
NCAM signaling for neurite out-growth	Pathway	R-HSA-375165 (Reactome)	The neural cell adhesion molecule, NCAM, is a member of the immunoglobulin (Ig) superfamily and is involved in a variety of cellular processes of importance for the formation and maintenance of the nervous system. The role of NCAM in neural differentiation and synaptic plasticity is presumed to depend on the modulation of intracellular signal transduction cascades. NCAM based signaling complexes can initiate downstream intracellular signals by at least two mechanisms: (1) activation of FGFR and (2) formation of intracellular signaling complexes by direct interaction with cytoplasmic interaction partners such as Fyn and FAK. Tyrosine kinases Fyn and FAK interact with NCAM and undergo phosphorylation and this transiently activates the MAPK, ERK 1 and 2, cAMP response element binding protein (CREB) and transcription factors ELK and NFkB. CREB activates transcription of genes which are important for axonal growth, survival, and synaptic plasticity in neurons. NCAM1 mediated intracellular signal transduction is represented in the figure below. The Ig domains in NCAM1 are represented in orange ovals and Fn domains in green squares. The tyrosine residues susceptible to phosphorylation are represented in red circles and their positions are numbered. Phosphorylation is represented by red arrows and dephosphorylation by yellow. Ig, Immunoglobulin domain; Fn, Fibronectin domain; Fyn, Proto-oncogene tyrosine-protein kinase Fyn; FAK, focal adhesion kinase; RPTPalpha, Receptor-type tyrosine-protein phosphatase; Grb2, Growth factor receptor-bound protein 2; SOS, Son of sevenless homolog; Raf, RAF proto-oncogene serine/threonine-protein kinase; MEK, MAPK and ERK kinase; ERK, Extracellular signal-regulated kinase; MSK1, Mitogen and stress activated protein kinase 1; CREB, Cyclic AMP-responsive element-binding protein; CRE, cAMP response elements.
NCAM1	Protein	P13591 (Uniprot-TrEMBL)
NEFL	Protein	P07196 (Uniprot-TrEMBL)
NF1(2-2839)	Protein	P21359 (Uniprot-TrEMBL)
NF1(2-2839)	Protein	P21359 (Uniprot-TrEMBL)
NGF signalling via TRKA from the plasma membrane	Pathway	R-HSA-187037 (Reactome)	Trk receptors signal from the plasma membrane and from intracellular membranes, particularly from early endosomes. Signalling from the plasma membrane is fast but transient; signalling from endosomes is slower but long lasting. Signalling from the plasma membrane is annotated here. TRK signalling leads to proliferation in some cell types and neuronal differentiation in others. Proliferation is the likely outcome of short term signalling, as observed following stimulation of EGFR (EGF receptor). Long term signalling via TRK receptors, instead, was clearly shown to be required for neuronal differentiation in response to neurotrophins.
NRAS	Protein	P01111 (Uniprot-TrEMBL)
Neuregulins		R-HSA-1227957 (Reactome)
Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell	Pathway	R-HSA-112314 (Reactome)	The neurotransmitter in the synaptic cleft released by the pre-synaptic neuron binds specific receptors located on the post-synaptic terminal. These receptors are either ion channels or G protein coupled receptors that function to transmit the signals from the post-synaptic membrane to the cell body.
PAQR3	Protein	Q6TCH7 (Uniprot-TrEMBL)
PAQR3:inactive RAFs	Complex	R-HSA-5674139 (Reactome)
PAQR3	Protein	Q6TCH7 (Uniprot-TrEMBL)
PDGFA-1	Protein	P04085-1 (Uniprot-TrEMBL)
PDGFA-2	Protein	P04085-2 (Uniprot-TrEMBL)
PDGFB	Protein	P01127 (Uniprot-TrEMBL)
PDGFB(82-241)	Protein	P01127 (Uniprot-TrEMBL)
PEA15	Protein	Q15121 (Uniprot-TrEMBL)
PEA15	Protein	Q15121 (Uniprot-TrEMBL)
PEBP1	Protein	P30086 (Uniprot-TrEMBL)
PEBP1	Protein	P30086 (Uniprot-TrEMBL)
PHB	Protein	P35232 (Uniprot-TrEMBL)
PI(4,5)P2	Metabolite	CHEBI:18348 (ChEBI)
PP2A	Complex	R-HSA-196206 (Reactome)
PPP2CA	Protein	P67775 (Uniprot-TrEMBL)
PPP2CB	Protein	P62714 (Uniprot-TrEMBL)
PPP2R1A	Protein	P30153 (Uniprot-TrEMBL)
PPP2R1B	Protein	P30154 (Uniprot-TrEMBL)
PPP2R5A	Protein	Q15172 (Uniprot-TrEMBL)
PPP2R5B	Protein	Q15173 (Uniprot-TrEMBL)
PPP2R5C	Protein	Q13362 (Uniprot-TrEMBL)
PPP2R5D	Protein	Q14738 (Uniprot-TrEMBL)
PPP2R5E	Protein	Q16537 (Uniprot-TrEMBL)
PPP5C	Protein	P53041 (Uniprot-TrEMBL)
PSMA1	Protein	P25786 (Uniprot-TrEMBL)
PSMA2	Protein	P25787 (Uniprot-TrEMBL)
PSMA3	Protein	P25788 (Uniprot-TrEMBL)
PSMA4	Protein	P25789 (Uniprot-TrEMBL)
PSMA5	Protein	P28066 (Uniprot-TrEMBL)
PSMA6	Protein	P60900 (Uniprot-TrEMBL)
PSMA7	Protein	O14818 (Uniprot-TrEMBL)
PSMA8	Protein	Q8TAA3 (Uniprot-TrEMBL)
PSMB1	Protein	P20618 (Uniprot-TrEMBL)
PSMB10	Protein	P40306 (Uniprot-TrEMBL)
PSMB11	Protein	A5LHX3 (Uniprot-TrEMBL)
PSMB2	Protein	P49721 (Uniprot-TrEMBL)
PSMB3	Protein	P49720 (Uniprot-TrEMBL)
PSMB4	Protein	P28070 (Uniprot-TrEMBL)
PSMB5	Protein	P28074 (Uniprot-TrEMBL)
PSMB6	Protein	P28072 (Uniprot-TrEMBL)
PSMB7	Protein	Q99436 (Uniprot-TrEMBL)
PSMB8	Protein	P28062 (Uniprot-TrEMBL)
PSMB9	Protein	P28065 (Uniprot-TrEMBL)
PSMC1	Protein	P62191 (Uniprot-TrEMBL)
PSMC2	Protein	P35998 (Uniprot-TrEMBL)
PSMC3	Protein	P17980 (Uniprot-TrEMBL)
PSMC4	Protein	P43686 (Uniprot-TrEMBL)
PSMC5	Protein	P62195 (Uniprot-TrEMBL)
PSMC6	Protein	P62333 (Uniprot-TrEMBL)
PSMD1	Protein	Q99460 (Uniprot-TrEMBL)
PSMD10	Protein	O75832 (Uniprot-TrEMBL)
PSMD11	Protein	O00231 (Uniprot-TrEMBL)
PSMD12	Protein	O00232 (Uniprot-TrEMBL)
PSMD13	Protein	Q9UNM6 (Uniprot-TrEMBL)
PSMD14	Protein	O00487 (Uniprot-TrEMBL)
PSMD2	Protein	Q13200 (Uniprot-TrEMBL)
PSMD3	Protein	O43242 (Uniprot-TrEMBL)
PSMD4	Protein	P55036 (Uniprot-TrEMBL)
PSMD5	Protein	Q16401 (Uniprot-TrEMBL)
PSMD6	Protein	Q15008 (Uniprot-TrEMBL)
PSMD7	Protein	P51665 (Uniprot-TrEMBL)
PSMD8	Protein	P48556 (Uniprot-TrEMBL)
PSMD9	Protein	O00233 (Uniprot-TrEMBL)
PSME1	Protein	Q06323 (Uniprot-TrEMBL)
PSME2	Protein	Q9UL46 (Uniprot-TrEMBL)
PSME3	Protein	P61289 (Uniprot-TrEMBL)
PSME4	Protein	Q14997 (Uniprot-TrEMBL)
PSMF1	Protein	Q92530 (Uniprot-TrEMBL)
PTPRA	Protein	P18433 (Uniprot-TrEMBL)
Phosphorylated ERBB2:ERBB4cyt1 heterodimers		R-HSA-1963568 (Reactome)
Phosphorylated ERBB2:ERBB4cyt2 heterodimers		R-HSA-1963591 (Reactome)
Phosphorylated p-6Y-ERBB2 heterodimers		R-HSA-1963585 (Reactome)
Phosphorylated p-Y877-ERBB2 heterodimers		R-HSA-1963580 (Reactome)
Pi	Metabolite	CHEBI:18367 (ChEBI)
RAF activating kinases	Complex	R-HSA-5672734 (Reactome)
RAF/MAPK scaffolds	Complex	R-HSA-5672717 (Reactome)
RAP1A	Protein	P62834 (Uniprot-TrEMBL)
RAP1B	Protein	P61224 (Uniprot-TrEMBL)
RAPGEF2	Protein	Q9Y4G8 (Uniprot-TrEMBL)
RAS GAPs	Complex	R-HSA-5658216 (Reactome)
RAS GEFs	Complex	R-HSA-5672601 (Reactome)
RASA1	Protein	P20936 (Uniprot-TrEMBL)
RASA2	Protein	Q15283 (Uniprot-TrEMBL)
RASA3	Protein	Q14644 (Uniprot-TrEMBL)
RASA4	Protein	O43374 (Uniprot-TrEMBL)
RASAL1	Protein	O95294 (Uniprot-TrEMBL)
RASAL2	Protein	Q9UJF2 (Uniprot-TrEMBL)
RASAL3	Protein	Q86YV0 (Uniprot-TrEMBL)
RASGEF1A	Protein	Q8N9B8 (Uniprot-TrEMBL)
RASGRF1	Protein	Q13972 (Uniprot-TrEMBL)
RASGRF2	Protein	O14827 (Uniprot-TrEMBL)
RASGRP1	Protein	O95267 (Uniprot-TrEMBL)
RASGRP4	Protein	Q8TDF6 (Uniprot-TrEMBL)
RBX1	Protein	P62877 (Uniprot-TrEMBL)
RPS27A(1-76)	Protein	P62979 (Uniprot-TrEMBL)
SOS1	Protein	Q07889 (Uniprot-TrEMBL)
SPRED dimer:NF1	Complex	R-HSA-5658232 (Reactome)
SPRED dimer:ub-NF1	Complex	R-HSA-5658420 (Reactome)
SPRED dimer	Complex	R-HSA-5658219 (Reactome)
SPRED1	Protein	Q7Z699 (Uniprot-TrEMBL)
SPRED2	Protein	Q7Z698 (Uniprot-TrEMBL)
SPRED3	Protein	Q2MJR0 (Uniprot-TrEMBL)
SPTA1	Protein	P02549 (Uniprot-TrEMBL)
SPTAN1	Protein	Q13813 (Uniprot-TrEMBL)
SPTB	Protein	P11277 (Uniprot-TrEMBL)
SPTBN1	Protein	Q01082 (Uniprot-TrEMBL)
SPTBN2	Protein	O15020 (Uniprot-TrEMBL)
SPTBN4	Protein	Q9H254 (Uniprot-TrEMBL)
SPTBN5	Protein	Q9NRC6 (Uniprot-TrEMBL)
SYNGAP1	Protein	Q96PV0 (Uniprot-TrEMBL)
Signaling by EGFR	Pathway	R-HSA-177929 (Reactome)	The epidermal growth factor receptor (EGFR) is one member of the ERBB family of transmembrane glycoprotein tyrosine receptor kinases (RTK). Binding of EGFR to its ligands induces conformational change that unmasks the dimerization interface in the extracellular domain of EGFR, leading to receptor homo- or heterodimerization at the cell surface. Dimerization of the extracellular regions of EGFR triggers additional conformational change of the cytoplasmic EGFR regions, enabling the kinase domains of two EGFR molecules to achieve the catalytically active conformation. Ligand activated EGFR dimers trans-autophosphorylate on tyrosine residues in the cytoplasmic tail of the receptor. Phosphorylated tyrosines serve as binding sites for the recruitment of signal transducers and activators of intracellular substrates, which then stimulate intracellular signal transduction cascades that are involved in regulating cellular proliferation, differentiation, and survival. Recruitment of complexes containing GRB2 and SOS1 to phosphorylated EGFR dimers either directly, through phosphotyrosine residues that serve as GRB2 docking sites, or indirectly, through SHC1 recruitment, promotes GDP to GTP exchange on RAS, resulting in the activation of RAF/MAP kinase cascade. Binding of complexes of GRB2 and GAB1 to phosphorylated EGFR dimers leads to formation of the active PI3K complex, conversion of PIP2 into PIP3, and activation of AKT signaling. Phospholipase C-gamma1 (PLCG1) can also be recruited directly, through EGFR phosphotyrosine residues that serve as PLCG1 docking sites, which leads to PLCG1 phosphorylation by EGFR and activation of DAG and IP3 signaling. EGFR signaling is downregulated by the action of ubiquitin ligase CBL. CBL binds directly to the phosphorylated EGFR dimer through the phosphotyrosine Y1045 in the C-tail of EGFR, and after CBL is phosphorylated by EGFR, it becomes active and ubiquitinates phosphorylated EGFR dimers, targeting them for degradation. For a recent review of EGFR signaling, please refer to Avraham and Yarden, 2011.
Signaling by ERBB2	Pathway	R-HSA-1227986 (Reactome)	ERBB2, also known as HER2 or NEU, is a receptor tyrosine kinase (RTK) belonging to the EGFR family. ERBB2 possesses an extracellular domain that does not bind any known ligand, contrary to other EGFR family members, a single transmembrane domain, and an intracellular domain consisting of an active kinase and a C-tail with multiple tyrosine phosphorylation sites. Inactive ERBB2 is associated with a chaperone heat shock protein 90 (HSP90) and its co-chaperone CDC37 (Xu et al. 2001, Citri et al. 2004, Xu et al. 2005). In addition, ERBB2 is associated with ERBB2IP (also known as ERBIN or LAP2), a protein responsible for proper localization of ERBB2. In epithelial cells, ERBB2IP restricts expression of ERBB2 to basolateral plasma membrane regions (Borg et al. 2000). ERBB2 becomes activated by forming a heterodimer with another ligand-activated EGFR family member, either EGFR, ERBB3 or ERBB4, which is accompanied by dissociation of chaperoning proteins HSP90 and CDC37 (Citri et al. 2004), as well as ERBB2IP (Borg et al. 2000) from ERBB2. ERBB2 heterodimers function to promote cell proliferation, cell survival and differentiation, depending on the cellular context. ERBB2 can also be activated by homodimerization when it is overexpressed, in cancer for example. In cells expressing both ERBB2 and EGFR, EGF stimulation of EGFR leads to formation of both ERBB2:EGFR heterodimers (Wada et al. 1990, Karunagaran et al. 1996) and EGFR homodimers. Heterodimers of ERBB2 and EGFR trans-autophosphorylate on twelve tyrosine residues, six in the C-tail of EGFR and six in the C-tail of ERBB2 - Y1023, Y1139, Y1196, Y1221, Y1222 and Y1248 (Margolis et al. 1989, Hazan et al. 1990,Walton et al. 1990, Helin et al. 1991, Ricci et al. 1995, Pinkas-Kramarski 1996). Phosphorylated tyrosine residues in the C-tail of EGFR and ERBB2 serve as docking sites for downstream signaling molecules. Three key signaling pathways activated by ERBB2:EGFR heterodimers are RAF/MAP kinase cascade, PI3K-induced AKT signaling, and signaling by phospholipase C gamma (PLCG1). Downregulation of EGFR signaling is mediated by ubiquitin ligase CBL, and is shown under Signaling by EGFR. In cells expressing ERBB2 and ERBB3, ERBB3 activated by neuregulin NRG1 or NRG2 binding (Tzahar et al. 1994) forms a heterodimer with ERBB2 (Pinkas-Kramarski et al. 1996, Citri et al. 2004). ERBB3 is the only EGFR family member with no kinase activity, and can only function in heterodimers, with ERBB2 being its preferred heterodimerization partner. After heterodimerization, ERBB2 phosphorylates ten tyrosine residues in the C-tail of ERBB3, Y1054, Y1197, Y1199, Y1222, Y1224, Y1260, Y1262, Y1276, Y1289 and Y1328 (Prigent et al. 1994, Pinkas-Kramarski et al. 1996, Vijapurkar et al. 2003, Li et al. 2007) that subsequently serve as docking sites for downstream signaling molecules, resulting in activation of PI3K-induced AKT signaling and RAF/MAP kinase cascade. Signaling by ERBB3 is downregulated by the action of RNF41 ubiquitin ligase, also known as NRDP1. In cells expressing ERBB2 and ERBB4, ligand stimulated ERBB4 can either homodimerize or form heterodimers with ERBB2 (Li et al. 2007), resulting in trans-autophosphorylation of ERBB2 and ERBB4 on C-tail tyrosine residues that will subsequently serve as docking sites for downstream signaling molecules, leading to activation of RAF/MAP kinase cascade and, in the case of ERBB4 CYT1 isoforms, PI3K-induced AKT signaling (Hazan et al. 1990, Cohen et al. 1996, Li et al. 2007, Kaushansky et al. 2008). Signaling by ERBB4 is downregulated by the action of WWP1 and ITCH ubiquitin ligases, and is shown under Signaling by ERBB4.
Signaling by ERBB4	Pathway	R-HSA-1236394 (Reactome)	ERBB4, also known as HER4, belongs to the ERBB family of receptors, which also includes ERBB1 (EGFR i.e. HER1), ERBB2 (HER2 i.e. NEU) and ERBB3 (HER3). Similar to EGFR, ERBB4 has an extracellular ligand binding domain, a single transmembrane domain and a cytoplasmic domain which contains an active tyrosine kinase and a C-tail with multiple phosphorylation sites. At least three and possibly four splicing isoforms of ERBB4 exist that differ in their C-tail and/or the extracellular juxtamembrane regions: ERBB4 JM-A CYT1, ERBB4 JM-A CYT2 and ERBB4 JM-B CYT1 (the existence of ERBB4 JM-B CYT2 has not been confirmed). ERBB4 becomes activated by binding one of its seven ligands, three of which, HB-EGF, epiregulin EPR and betacellulin BTC, are EGF-like (Elenius et al. 1997, Riese et al. 1998), while four, NRG1, NRG2, NRG3 and NRG4, belong to the neuregulin family (Tzahar et al. 1994, Carraway et al. 1997, Zhang et al. 1997, Hayes et al. 2007). Upon ligand binding, ERBB4 forms homodimers (Sweeney et al. 2000) or it heterodimerizes with ERBB2 (Li et al. 2007). Dimers of ERBB4 undergo trans-autophosphorylation on tyrosine residues in the C-tail (Cohen et al. 1996, Kaushansky et al. 2008, Hazan et al. 1990, Li et al. 2007), triggering downstream signaling cascades. The pathway Signaling by ERBB4 only shows signaling by ERBB4 homodimers. Signaling by heterodimers of ERBB4 and ERBB2 is shown in the pathway Signaling by ERBB2. Ligand-stimulated ERBB4 is also able to form heterodimers with ligand-stimulated EGFR (Cohen et al. 1996) and ligand-stimulated ERBB3 (Riese et al. 1995). Dimers of ERBB4 with EGFR and dimers of ERBB4 with ERBB3 were demonstrated in mouse cell lines in which human ERBB4 and EGFR or ERBB3 were exogenously expressed. These heterodimers undergo trans-autophosphorylation, but their downstream signaling and physiological significance have not been studied. All splicing isoforms of ERBB4 possess two tyrosine residues in the C-tail that serve as docking sites for SHC1 (Kaushansky et al. 2008, Pinkas-Kramarski et al. 1996, Cohen et al. 1996). Once bound to ERBB4, SHC1 becomes phosphorylated on tyrosine residues by the tyrosine kinase activity of ERBB4, which enables it to recruit the complex of GRB2 and SOS1, resulting in the guanyl-nucleotide exchange on RAS and activation of RAF and MAP kinase cascade (Kainulainen et al. 2000). The CYT1 isoforms of ERBB4 also possess a C-tail tyrosine residue that, upon trans-autophosphorylation, serves as a docking site for the p85 alpha subunit of PI3K (Kaushansky et al. 2008, Cohen et al. 1996), leading to assembly of an active PI3K complex that converts PIP2 to PIP3 and activates AKT signaling (Kainulainen et al. 2000). Besides signaling as a transmembrane receptor, ligand activated homodimers of ERBB4 JM-A isoforms (ERBB4 JM-A CYT1 and ERBB4 JM-A CYT2) undergo proteolytic cleavage by ADAM17 (TACE) in the juxtamembrane region, resulting in shedding of the extracellular domain and formation of an 80 kDa membrane bound ERBB4 fragment known as ERBB4 m80 (Rio et al. 2000, Cheng et al. 2003). ERBB4 m80 undergoes further proteolytic cleavage, mediated by the gamma-secretase complex, which releases the soluble 80 kDa ERBB4 intracellular domain, known as ERBB4 s80 or E4ICD, into the cytosol (Ni et al. 2001). ERBB4 s80 is able to translocate to the nucleus, promote nuclear translocation of various transcription factors, and act as a transcription co-factor. In neuronal precursors, ERBB4 s80 binds the complex of TAB and NCOR1, helps to move the complex into the nucleus, and is a co-factor of TAB:NCOR1-mediated inhibition of expression of astrocyte differentiation genes GFAP and S100B (Sardi et al. 2006). In mammary cells, ERBB4 s80 recruits STAT5A transcription factor in the cytosol, shuttles it to the nucleus, and acts as the STAT5A co-factor in binding to and promoting transcription from the beta-casein (CSN2) promoter, and may be involved in the regulation of other lactation-related genes (Williams et al. 2004, Muraoka-Cook et al. 2008). ERBB4 s80 was also shown to bind activated estrogen receptor in the nucleus and act as its transcriptional co-factor in promoting transcription of some estrogen-regulated genes, such as progesterone receptor gene NR3C3 and CXCL12 i.e. SDF1 (Zhu et al. 2006). The C-tail of ERBB4 possesses several WW-domain binding motifs (three in CYT1 isoform and two in CYT2 isoform), which enable interaction of ERBB4 with WW-domain containing proteins. ERBB4 s80, through WW-domain binding motifs, interacts with YAP1 transcription factor, a known proto-oncogene, and may be a co-regulator of YAP1-mediated transcription (Komuro et al. 2003, Omerovic et al. 2004). The tumor suppressor WWOX, another WW-domain containing protein, competes with YAP1 in binding to ERBB4 s80 and prevents translocation of ERBB4 s80 to the nucleus (Aqeilan et al. 2005). ERBB4 s80 is also able to translocate to the mitochondrial matrix, presumably when its nuclear translocation is inhibited. Once in the mitochondrion, the BH3 domain of ERBB4, characteristic of BCL2 family members, may enable it to act as a pro-apoptotic factor (Naresh et al. 2006). Activation of ERBB4 in breast cancer cell lines leads to JNK-dependent increase in BRCA1 mRNA level and mitotic cell cycle delay, but the exact mechanism has not been elucidated (Muraoka-Cook et al. 2006). WW-domain binding motifs in the C-tail of ERBB4 play an important role in the downregulation of ERBB4 receptor signaling, enabling the interaction of intact ERBB4, ERBB4 m80 and ERBB4 s80 with NEDD4 family of E3 ubiquitin ligases WWP1 and ITCH. The interaction of WWP1 and ITCH with intact ERBB4 is independent of receptor activation and autophosphorylation. Binding of WWP1 and ITCH ubiquitin ligases leads to ubiquitination of ERBB4 and its cleavage products, and subsequent degradation through both proteasomal and lysosomal routes (Omerovic et al. 2007, Feng et al. 2009). In addition, the s80 cleavage product of ERBB4 JM-A CYT-1 isoform is the target of NEDD4 ubiquitin ligase. NEDD4 binds ERBB4 JM-A CYT-1 s80 (ERBB4jmAcyt1s80) through its PIK3R1 interaction site and mediates ERBB4jmAcyt1s80 ubiquitination, thereby decreasing the amount of ERBB4jmAcyt1s80 that reaches the nucleus (Zeng et al. 2009).
Signaling by FGFR1	Pathway	R-HSA-5654736 (Reactome)	The 22 members of the fibroblast growth factor (FGF) family of growth factors mediate their cellular responses by binding to and activating the different isoforms encoded by the four receptor tyrosine kinases (RTKs) designated FGFR1, FGFR2, FGFR3 and FGFR4. These receptors are key regulators of several developmental processes in which cell fate and differentiation to various tissue lineages are determined. Unlike other growth factors, FGFs act in concert with heparin or heparan sulfate proteoglycan (HSPG) to activate FGFRs and to induce the pleiotropic responses that lead to the variety of cellular responses induced by this large family of growth factors. An alternative, FGF-independent, source of FGFR activation originates from the interaction with cell adhesion molecules, typically in the context of interactions on neural cell membranes and is crucial for neuronal survival and development. Upon ligand binding, receptor dimers are formed and their intrinsic tyrosine kinase is activated causing phosphorylation of multiple tyrosine residues on the receptors. These then serve as docking sites for the recruitment of SH2 (src homology-2) or PTB (phosphotyrosine binding) domains of adaptors, docking proteins or signaling enzymes. Signaling complexes are assembled and recruited to the active receptors resulting in a cascade of phosphorylation events. This leads to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape, depending on the cell type or stage of maturation.
Signaling by FGFR2	Pathway	R-HSA-5654738 (Reactome)	The 22 members of the fibroblast growth factor (FGF) family of growth factors mediate their cellular responses by binding to and activating the different isoforms encoded by the four receptor tyrosine kinases (RTKs) designated FGFR1, FGFR2, FGFR3 and FGFR4. These receptors are key regulators of several developmental processes in which cell fate and differentiation to various tissue lineages are determined. Unlike other growth factors, FGFs act in concert with heparin or heparan sulfate proteoglycan (HSPG) to activate FGFRs and to induce the pleiotropic responses that lead to the variety of cellular responses induced by this large family of growth factors. An alternative, FGF-independent, source of FGFR activation originates from the interaction with cell adhesion molecules, typically in the context of interactions on neural cell membranes and is crucial for neuronal survival and development. Upon ligand binding, receptor dimers are formed and their intrinsic tyrosine kinase is activated causing phosphorylation of multiple tyrosine residues on the receptors. These then serve as docking sites for the recruitment of SH2 (src homology-2) or PTB (phosphotyrosine binding) domains of adaptors, docking proteins or signaling enzymes. Signaling complexes are assembled and recruited to the active receptors resulting in a cascade of phosphorylation events. This leads to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape, depending on the cell type or stage of maturation.
Signaling by FGFR3	Pathway	R-HSA-5654741 (Reactome)	The 22 members of the fibroblast growth factor (FGF) family of growth factors mediate their cellular responses by binding to and activating the different isoforms encoded by the four receptor tyrosine kinases (RTKs) designated FGFR1, FGFR2, FGFR3 and FGFR4. These receptors are key regulators of several developmental processes in which cell fate and differentiation to various tissue lineages are determined. Unlike other growth factors, FGFs act in concert with heparin or heparan sulfate proteoglycan (HSPG) to activate FGFRs and to induce the pleiotropic responses that lead to the variety of cellular responses induced by this large family of growth factors. An alternative, FGF-independent, source of FGFR activation originates from the interaction with cell adhesion molecules, typically in the context of interactions on neural cell membranes and is crucial for neuronal survival and development. Upon ligand binding, receptor dimers are formed and their intrinsic tyrosine kinase is activated causing phosphorylation of multiple tyrosine residues on the receptors. These then serve as docking sites for the recruitment of SH2 (src homology-2) or PTB (phosphotyrosine binding) domains of adaptors, docking proteins or signaling enzymes. Signaling complexes are assembled and recruited to the active receptors resulting in a cascade of phosphorylation events. This leads to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape, depending on the cell type or stage of maturation.
Signaling by FGFR4	Pathway	R-HSA-5654743 (Reactome)	The 22 members of the fibroblast growth factor (FGF) family of growth factors mediate their cellular responses by binding to and activating the different isoforms encoded by the four receptor tyrosine kinases (RTKs) designated FGFR1, FGFR2, FGFR3 and FGFR4. These receptors are key regulators of several developmental processes in which cell fate and differentiation to various tissue lineages are determined. Unlike other growth factors, FGFs act in concert with heparin or heparan sulfate proteoglycan (HSPG) to activate FGFRs and to induce the pleiotropic responses that lead to the variety of cellular responses induced by this large family of growth factors. An alternative, FGF-independent, source of FGFR activation originates from the interaction with cell adhesion molecules, typically in the context of interactions on neural cell membranes and is crucial for neuronal survival and development. Upon ligand binding, receptor dimers are formed and their intrinsic tyrosine kinase is activated causing phosphorylation of multiple tyrosine residues on the receptors. These then serve as docking sites for the recruitment of SH2 (src homology-2) or PTB (phosphotyrosine binding) domains of adaptors, docking proteins or signaling enzymes. Signaling complexes are assembled and recruited to the active receptors resulting in a cascade of phosphorylation events. This leads to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape, depending on the cell type or stage of maturation.
Signaling by Insulin receptor	Pathway	R-HSA-74752 (Reactome)	Insulin binding to its receptor results in receptor autophosphorylation on tyrosine residues and the tyrosine phosphorylation of insulin receptor substrates (e.g. IRS and Shc) by the insulin receptor tyrosine kinase. This allows association of IRSs with downstream effectors such as PI-3K via its Src homology 2 (SH2) domains leading to end point events such as Glut4 (Slc2a4) translocation. Shc when tyrosine phosphorylated associates with Grb2 and can thus activate the Ras/MAPK pathway independent of the IRSs. Signal transduction by the insulin receptor is not limited to its activation at the cell surface. The activated ligand-receptor complex initially at the cell surface, is internalised into endosomes itself a process which is dependent on tyrosine autophosphorylation. Endocytosis of activated receptors has the dual effect of concentrating receptors within endosomes and allows the insulin receptor tyrosine kinase to phosphorylate substrates that are spatially distinct from those accessible at the plasma membrane. Acidification of the endosomal lumen, due to the presence of proton pumps, results in dissociation of insulin from its receptor. (The endosome constitutes the major site of insulin degradation). This loss of the ligand-receptor complex attenuates any further insulin-driven receptor re-phosphorylation events and leads to receptor dephosphorylation by extra-lumenal endosomally-associated protein tyrosine phosphatases (PTPs). The identity of these PTPs is not clearly established yet. A discussion of candidates will be added in the near future.
Signaling by PDGF	Pathway	R-HSA-186797 (Reactome)	Platelet-derived Growth Factor (PDGF) is a potent stimulator of growth and motility of connective tissue cells such as fibroblasts and smooth muscle cells as well as other cells such as capillary endothelial cells and neurons.The PDGF family of growth factors is composed of four different polypeptide chains encoded by four different genes. The classical PDGF chains, PDGF-A and PDGF-B, and more recently discovered PDGF-C and PDGF-D. The four PDGF chains assemble into disulphide-bonded dimers via homo- or heterodimerization, and five different dimeric isoforms have been described so far; PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC and PDGF-DD. It is notable that no heterodimers involving PDGF-C and PDGF-D chains have been described. PDGF exerts its effects by binding to, and activating, two protein tyrosine kinase (PTK) receptors, alpha and beta. These receptors dimerize and undergo autophosphorylation. The phosphorylation sites then attract downstream effectors to transduct the signal into the cell.
Signaling by SCF-KIT	Pathway	R-HSA-1433557 (Reactome)	Stem cell factor (SCF) is a growth factor with membrane bound and soluble forms. It is expressed by fibroblasts and endothelial cells throughout the body, promoting proliferation, migration, survival and differentiation of hematopoetic progenitors, melanocytes and germ cells.(Linnekin 1999, Ronnstrand 2004, Lennartsson and Ronnstrand 2006). The receptor for SCF is KIT, a tyrosine kinase receptor (RTK) closely related to the receptors for platelet derived growth factor receptor, colony stimulating factor 1 (Linnekin 1999) and Flt3 (Rosnet et al. 1991). Four isoforms of c-Kit have been identified in humans. Alternative splicing results in isoforms of KIT differing in the presence or absence of four residues (GNNK) in the extracellular region. This occurs due to the use of an alternate 5' splice donor site. These GNNK+ and GNNK- variants are co-expressed in most tissues; the GNNK- form predominates and was more strongly tyrosine-phosphorylated and more rapidly internalized (Ronnstrand 2004). There are also splice variants that arise from alternative usage of splice acceptor site resulting in the presence or absence of a serine residue (Crosier et al., 1993). Finally, there is an alternative shorter transcript of KIT expressed in postmeiotic germ cells in the testis which encodes a truncated KIT consisting only of the second part of the kinase domain and thus lackig the extracellular and transmembrane domains as well as the first part of the kinase domain (Rossi et al. 1991). Binding of SCF homodimers to KIT results in KIT homodimerization followed by activation of its intrinsic tyrosine kinase activity. KIT stimulation activates a wide array of signalling pathways including MAPK, PI3K and JAK/STAT (Reber et al. 2006, Ronnstrand 2004). Defects of KIT in humans are associated with different genetic diseases and also in several types of cancers like mast cell leukaemia, germ cell tumours, certain subtypes of malignant melanoma and gastrointestinal tumours.
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)	Pathway	R-HSA-2404192 (Reactome)	Binding of IGF1 (IGF-I) or IGF2 (IGF-II) to the extracellular alpha peptides of the type 1 insulin-like growth factor receptor (IGF1R) triggers the activation of two major signaling pathways: the SOS-RAS-RAF-MAPK (ERK) pathway and the PI3K-PKB (AKT) pathway (recently reviewed in Pavelic et al. 2007, Chitnis et al. 2008, Maki et al. 2010, Parella et al. 2010, Annunziata et al. 2011, Siddle et al. 2012, Holzenberger 2012).
Signaling by the B Cell Receptor (BCR)	Pathway	R-HSA-983705 (Reactome)	Mature B cells express IgM and IgD immunoglobulins which are complexed at the plasma membrane with Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) to form the B cell receptor (BCR) (Fu et al. 1974, Fu et al. 1975, Kunkel et al. 1975, Van Noesel et al. 1992, Sanchez et al. 1993, reviewed in Brezski and Monroe 2008). Binding of antigen to the immunoglobulin activates phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the cytoplasmic tails of Ig-alpha and Ig-beta by Src family tyrosine kinases, including LYN, FYN, and BLK (Nel et al. 1984, Yamanashi et al. 1991, Flaswinkel and Reth 1994, Saouaf et al. 1994, Hata et al. 1994, Saouaf et al. 1995, reviewed in Gauld and Cambier 2004, reviewed in Harwood and Batista 2010). The protein kinase SYK binds the phosphorylated immunoreceptor tyrosine-activated motifs (ITAMs) on the cytoplasmic tails of Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) (Wienands et al. 1995, Rowley et al. 1995, Tsang et al. 2008). The binding causes the activation and autophosphorylation of SYK (Law et al. 1994, Baldock et al. 2000, Irish et al. 2006, Tsang et al. 2008, reviewed in Bradshaw 2010). Activated SYK and other kinases phosphorylate BLNK (SLP-65), BCAP, and CD19 which serve as scaffolds for the assembly of large complexes, the signalosomes, by recruiting phosphoinositol 3-kinase (PI3K), phospholipase C gamma (predominantly PLC-gamma2 in B cells, Coggeshall et al. 1992), NCK, BAM32, BTK, VAV1, and SHC. The effectors are phosphorylated by SYK and other kinases. PLC-gamma associated with BLNK hydrolyzes phosphatidylinositol-4,5-bisphosphate to yield inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (Carter et al. 1991, Kim et al. 2004). IP3 binds receptors on the endoplasmic reticulum and causes release of calcium ions from the ER into the cytosol. The depletion of calcium from the ER in turn activates STIM1 to interact with ORAI and TRPC1 channels in the plasma membrane, resulting in an influx of extracellular calcium ions (Muik et al. 2008, Luik et al. 2008, Park et al. 2009, Mori et al. 2002). PI3K associated with BCAP and CD19 phosphorylates phosphatidylinositol 4,5-bisphosphate to yield phosphatidyinositol 3,4,5-trisphosphate. Second messengers (calcium, diacylglycerol, inositol 1,4,5-trisphosphate, and phosphatidylinositol 3,4,5-trisphosphate) trigger signaling pathways: NF-kappaB is activated via protein kinase C beta, RAS is activated via RasGRP proteins, NF-AT is activated via calcineurin, and AKT (PKB) is activated via PDK1 (reviewed in Shinohara and Kurosaki 2009, Stone 2006).
TLN1	Protein	Q9Y490 (Uniprot-TrEMBL)
UBA52(1-76)	Protein	P62987 (Uniprot-TrEMBL)
UBB(1-76)	Protein	P0CG47 (Uniprot-TrEMBL)
UBB(153-228)	Protein	P0CG47 (Uniprot-TrEMBL)
UBB(77-152)	Protein	P0CG47 (Uniprot-TrEMBL)
UBC(1-76)	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(153-228)	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(229-304)	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(305-380)	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(381-456)	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(457-532)	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(533-608)	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(609-684)	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(77-152)	Protein	P0CG48 (Uniprot-TrEMBL)
Ub	Complex	R-HSA-113595 (Reactome)
VCL	Protein	P18206 (Uniprot-TrEMBL)
VWF(23-763)	Protein	P04275 (Uniprot-TrEMBL)
WDR83	Protein	Q9BRX9 (Uniprot-TrEMBL)
WDR83:LAMTOR2:LAMTOR3:activated RAF:MAP2K:MAPK complex	Complex	R-HSA-5674138 (Reactome)
WDR83:LAMTOR2:LAMTOR3:activated RAF:p-2S MAP2K:p-T,Y MAPK complex	Complex	R-HSA-5674131 (Reactome)
WDR83:LAMTOR2:LAMTOR3	Complex	R-HSA-5674133 (Reactome)
YWHAB	Protein	P31946 (Uniprot-TrEMBL)
YWHAB dimer	Complex	R-HSA-2028645 (Reactome)
activated RAF:scaffold:MAP2K:MAPK complex	Complex	R-HSA-5672720 (Reactome)
activated RAF:scaffold:p-2S MAP2K:MAPK complex	Complex	R-HSA-5672723 (Reactome)
activated RAF:scaffold:p-2S MAP2K:p-2T MAPK complex	Complex	R-HSA-5672724 (Reactome)
activated RAF homo/heterodimer	Complex	R-HSA-5674136 (Reactome)
cytosolic MAPK DUSPs	Complex	R-HSA-5675365 (Reactome)
dephosphorylated "receiver" RAF/KSR1	Complex	R-HSA-5672731 (Reactome)
dephosphorylated inactive RAFS:YWHAB dimer	Complex	R-HSA-5672728 (Reactome)
dephosphorylated inactive RAFs	Complex	R-HSA-5672726 (Reactome)
hyperphosphorylated BRAF	Protein	P15056 (Uniprot-TrEMBL)
hyperphosphorylated RAF1	Protein	P04049 (Uniprot-TrEMBL)
inactive RAFs:YWHAB dimer	Complex	R-HSA-5672707 (Reactome)
inactive RAFs	Complex	R-HSA-5672708 (Reactome)
nuclear MAPK DUSPs	Complex	R-HSA-5675368 (Reactome)
p-11Y-PDGFRA	Protein	P16234 (Uniprot-TrEMBL)
p-12Y-PDGFRB	Protein	P09619 (Uniprot-TrEMBL)
p-2S MAP2K homo/heterodimers	Complex	R-HSA-5672721 (Reactome)
p-2S MAP2K homo/heterodimers		R-HSA-5672721 (Reactome)
p-2S MAP2K1:p-2S MAPK2K2 heterodimer	Complex	R-HSA-5672705 (Reactome)
p-2S,T MAP2K1:p-2S MAPK2K2 heterodimer	Complex	R-HSA-5674489 (Reactome)
p-5Y,S1119-TEK	Protein	Q02763 (Uniprot-TrEMBL)
p-5Y-FGFR4	Protein	P22455 (Uniprot-TrEMBL)
p-5Y-FRS3	Protein	O43559 (Uniprot-TrEMBL)	The phospho-tyrosine positions for FRS2-beta were inferred by similarity to the analogous positions in FRS2-alpha. Five out of six tyrosine positions in alpha are present in beta.
p-5Y-LAT-2	Protein	O43561-2 (Uniprot-TrEMBL)
p-6Y-EGFR	Protein	P00533 (Uniprot-TrEMBL)
p-6Y-ERBB2	Protein	P04626 (Uniprot-TrEMBL)
p-6Y-FGFR3b	Protein	P22607-2 (Uniprot-TrEMBL)
p-6Y-FGFR3c	Protein	P22607-1 (Uniprot-TrEMBL)
p-6Y-FRS2	Protein	Q8WU20 (Uniprot-TrEMBL)
p-6Y-PTK2	Protein	Q05397 (Uniprot-TrEMBL)
p-7Y-ERBB2	Protein	P04626 (Uniprot-TrEMBL)
p-7Y-KIT	Protein	P10721 (Uniprot-TrEMBL)
p-8Y-FGFR1b	Protein	P11362-19 (Uniprot-TrEMBL)	While the existence of a "b" isoform of fibroblast growth factor receptor 1 is well established and its biochemical and functional properties have been extensively characterized (e.g., Mohammadi et al. 2005; Zhang et al. 2006), its amino acid sequence is not represented in reference protein sequence databases, except as the 47-residue polypeptide (deposited in GenBank as accession AAB19502) first used by Johnson et al. (1991) to distinguish the "b" and "c" isoforms of the receptor.
p-8Y-FGFR1c	Protein	P11362-1 (Uniprot-TrEMBL)
p-ERBB4cyt1 homodimers		R-HSA-1250351 (Reactome)
p-S,218, S222,T292 MAP2K1	Protein	Q02750 (Uniprot-TrEMBL)
p-S214,S576 ARAF	Protein	P10398 (Uniprot-TrEMBL)
p-S218,S222-MAP2K1	Protein	Q02750 (Uniprot-TrEMBL)
p-S222,S226-MAP2K2	Protein	P36507 (Uniprot-TrEMBL)
p-S259,S621-RAF1	Protein	P04049 (Uniprot-TrEMBL)
p-S299,S302,T452,T455,S576 ARAF	Protein	P10398 (Uniprot-TrEMBL)
p-S311 KSR1:MARK3:YWHAB dimer	Complex	R-HSA-5672692 (Reactome)
p-S311 KSR1	Protein	Q8IVT5 (Uniprot-TrEMBL)
p-S311 KSR1:MARK3	Complex	R-HSA-5672691 (Reactome)
p-S311,S406 KSR1:MARK3:YWHAB dimer	Complex	R-HSA-5672696 (Reactome)
p-S311,S406 KSR1:MARK3	Complex	R-HSA-5672695 (Reactome)
p-S311,S406 KSR1	Protein	Q8IVT5 (Uniprot-TrEMBL)
p-S311,Y552 KSR1	Protein	Q8IVT5 (Uniprot-TrEMBL)
p-S338,Y341,T491,S494,S621 RAF1	Protein	P04049 (Uniprot-TrEMBL)
p-S338,Y341,T491,S494,S621 RAF1	Protein	P04049 (Uniprot-TrEMBL)
p-S365,S445,S729 BRAF	Protein	P15056 (Uniprot-TrEMBL)
p-S445,S729-BRAF	Protein	P15056 (Uniprot-TrEMBL)
p-S445,T599,S602,S729 BRAF	Protein	P15056 (Uniprot-TrEMBL)
p-S445,T599,S602,S729 BRAF	Protein	P15056 (Uniprot-TrEMBL)
p-S576 ARAF	Protein	P10398 (Uniprot-TrEMBL)
p-S621-RAF1	Protein	P04049 (Uniprot-TrEMBL)
p-T,Y MAPK dimers		R-HSA-1268261 (Reactome)
p-T,Y MAPK dimers		R-HSA-198701 (Reactome)
p-T,Y MAPK dimers	Complex	R-HSA-1268261 (Reactome)
p-T,Y MAPK monomers and dimers:PEA15	Complex	R-HSA-5675205 (Reactome)
p-T,Y MAPK monomers and dimers	Complex	R-HSA-5674340 (Reactome)
p-T,Y MAPK monomers and dimers	Complex	R-HSA-5674341 (Reactome)
p-T,Y MAPKs		R-HSA-169289 (Reactome)
p-T,Y MAPKs		R-HSA-5674338 (Reactome)
p-T,Y MAPKs	Complex	R-HSA-169289 (Reactome)
p-T133-RASGRP3	Protein	Q8IV61 (Uniprot-TrEMBL)
p-T184-RASGRP1	Protein	O95267 (Uniprot-TrEMBL)
p-T185,Y187-MAPK1	Protein	P28482 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3	Protein	P27361 (Uniprot-TrEMBL)
p-T286-CAMK2A	Protein	Q9UQM7 (Uniprot-TrEMBL)
p-T287-CAMK2B	Protein	Q13554 (Uniprot-TrEMBL)
p-T287-CAMK2D	Protein	Q13557 (Uniprot-TrEMBL)
p-T287-CAMK2G	Protein	Q13555 (Uniprot-TrEMBL)
p-Y-IRS1	Protein	P35568 (Uniprot-TrEMBL)
p-Y-IRS2	Protein	Q9Y4H2 (Uniprot-TrEMBL)
p-Y-JAK1	Protein	P23458 (Uniprot-TrEMBL)
p-Y-SHC1	Protein	P29353 (Uniprot-TrEMBL)
p-Y-SHC2	Protein	P98077 (Uniprot-TrEMBL)
p-Y-SHC3	Protein	Q92529 (Uniprot-TrEMBL)
p-Y1172,Y1226-ERBB4 JM-A CYT-2 isoform	Protein	Q15303-3 (Uniprot-TrEMBL)
p-Y194,Y195,Y272-SHC1-1(156-583)	Protein	P29353-3 (Uniprot-TrEMBL)
p-Y239,Y240,Y317-SHC1-2	Protein	P29353-2 (Uniprot-TrEMBL)
p-Y341,T491,S494,S621 RAF1	Protein	P04049 (Uniprot-TrEMBL)
p-Y349,Y350-SHC1	Protein	P29353 (Uniprot-TrEMBL)
p-Y364,Y418,Y536-IL2RB	Protein	P14784 (Uniprot-TrEMBL)
p-Y419-SRC	Protein	P12931-1 (Uniprot-TrEMBL)
p-Y420-FYN	Protein	P06241 (Uniprot-TrEMBL)
p-Y427-SHC1	Protein	P29353 (Uniprot-TrEMBL)
p-Y530-SRC	Protein	P12931-1 (Uniprot-TrEMBL)
p21 RAS:GTP:'activator' RAF:YWHAB dimer	Complex	R-HSA-5672729 (Reactome)
p21 RAS:GTP:activated RAF homo/heterodimer complexes	Complex	R-HSA-5672718 (Reactome)
p21 RAS:GTP:activated RAF1 homo/heterodimer:PEBP1	Complex	R-HSA-5675413 (Reactome)
p21 RAS:GTP:homo/heterodimerized RAF complex	Complex	R-HSA-5672733 (Reactome)
p21 RAS:GDP	Complex	R-HSA-109796 (Reactome)
p21 RAS:GTP:BRAP	Complex	R-HSA-5674003 (Reactome)
p21 RAS:GTP:RAS GAPs	Complex	R-HSA-5658227 (Reactome)
p21 RAS:GTP:ub-BRAP	Complex	R-HSA-5674005 (Reactome)
p21 RAS:GTP	Complex	R-HSA-109783 (Reactome)
p21RAS:GTP:activated RAF homo/heterodimers	Complex	R-HSA-5672712 (Reactome)
p21RAS:GTP:activated RAF1 homo/heterodimer	Complex	R-HSA-5675414 (Reactome)
p21RAS:GTP:dephosphorylated RAF1 homo/heterodimer	Complex	R-HSA-5675430 (Reactome)
p21RAS:GTP:p-S621 RAF1 homo/heterodimer	Complex	R-HSA-5675412 (Reactome)
ub-BRAP	Protein	Q7Z569 (Uniprot-TrEMBL)
ub-NF1(2-2839)	Protein	P21359 (Uniprot-TrEMBL)

Annotated Interactions

View all...

Source	Target	Type	Database reference	Comment
'activator' RAF:YWHAB dimer			R-HSA-5672950 (Reactome)
26S proteasome		mim-catalysis	R-HSA-5658430 (Reactome)
	ADP	Arrow	R-HSA-5672948 (Reactome)
	ADP	Arrow	R-HSA-5672969 (Reactome)
	ADP	Arrow	R-HSA-5672973 (Reactome)
	ADP	Arrow	R-HSA-5672978 (Reactome)
	ADP	Arrow	R-HSA-5674130 (Reactome)
	ADP	Arrow	R-HSA-5674373 (Reactome)
	ADP	Arrow	R-HSA-5674496 (Reactome)
	ADP	Arrow	R-HSA-5675194 (Reactome)
	ADP	Arrow	R-HSA-5675198 (Reactome)
ATP			R-HSA-5672948 (Reactome)
ATP			R-HSA-5672969 (Reactome)
ATP			R-HSA-5672973 (Reactome)
ATP			R-HSA-5672978 (Reactome)
ATP			R-HSA-5674130 (Reactome)
ATP			R-HSA-5674373 (Reactome)
ATP			R-HSA-5674496 (Reactome)
ATP			R-HSA-5675194 (Reactome)
ATP			R-HSA-5675198 (Reactome)
	BRAP:KSR1:MARK3	Arrow	R-HSA-5674019 (Reactome)
BRAP:KSR1:MARK3		TBar	R-HSA-5672966 (Reactome)
BRAP			R-HSA-5674018 (Reactome)
BRAP			R-HSA-5674019 (Reactome)
	GDP	Arrow	R-HSA-5672965 (Reactome)
GTP			R-HSA-5672965 (Reactome)
H2O			R-HSA-5672957 (Reactome)
H2O			R-HSA-5672961 (Reactome)
H2O			R-HSA-5675373 (Reactome)
H2O			R-HSA-5675376 (Reactome)
H2O			R-HSA-5675431 (Reactome)
H2O			R-HSA-5675433 (Reactome)
	IL17RD:p-2S MAP2Ks:MAPKs	Arrow	R-HSA-5674366 (Reactome)
IL17RD:p-2S MAP2Ks:MAPKs			R-HSA-5674373 (Reactome)
IL17RD:p-2S MAP2Ks:MAPKs		mim-catalysis	R-HSA-5674373 (Reactome)
	IL17RD:p-2S MAP2Ks:p-T,Y MAPKs	Arrow	R-HSA-5674373 (Reactome)
IL17RD			R-HSA-5674366 (Reactome)
KBTBD7:CUL3:RBX1		mim-catalysis	R-HSA-5658424 (Reactome)
KSR1:MARK3			R-HSA-5672948 (Reactome)
KSR1:MARK3			R-HSA-5674019 (Reactome)
KSR1:MARK3		mim-catalysis	R-HSA-5672948 (Reactome)
MAP2K homo/heterodimers			R-HSA-5672972 (Reactome)
MAP2K homo/heterodimers			R-HSA-5674132 (Reactome)
MAP3K11		Arrow	R-HSA-5672966 (Reactome)
	MAPK monomers and dimers	Arrow	R-HSA-5675373 (Reactome)
	MAPK monomers and dimers	Arrow	R-HSA-5675376 (Reactome)
MAPKs			R-HSA-5672972 (Reactome)
MAPKs			R-HSA-5674132 (Reactome)
MAPKs			R-HSA-5674366 (Reactome)
NF1(2-2839)			R-HSA-5658438 (Reactome)
	PAQR3:inactive RAFs	Arrow	R-HSA-5674140 (Reactome)
PAQR3			R-HSA-5674140 (Reactome)
PEA15			R-HSA-5675206 (Reactome)
PEBP1			R-HSA-5675417 (Reactome)
PHB		Arrow	R-HSA-5672950 (Reactome)
PP2A		mim-catalysis	R-HSA-5672957 (Reactome)
PP2A		mim-catalysis	R-HSA-5672961 (Reactome)
PP2A		mim-catalysis	R-HSA-5675431 (Reactome)
PPP5C		mim-catalysis	R-HSA-5675433 (Reactome)
	Pi	Arrow	R-HSA-5672957 (Reactome)
	Pi	Arrow	R-HSA-5672961 (Reactome)
	Pi	Arrow	R-HSA-5675373 (Reactome)
	Pi	Arrow	R-HSA-5675376 (Reactome)
	Pi	Arrow	R-HSA-5675431 (Reactome)
	Pi	Arrow	R-HSA-5675433 (Reactome)
			R-HSA-5658231 (Reactome)	The intrinsic GTPase activity of RAS proteins is stimulated by the GAP proteins, of which there are at least 10 in the human genome (reviewed in King et al, 2013).
			R-HSA-5658424 (Reactome)	NF1 levels are controlled by proteasomal degradation in response to stimulation by some growth factors (Cichowski et al, 2003). Ubiquitination is mediated by the CUL3:RBX1 RING E3 ligase complex in conjunction with the BTB adaptor protein KBTBD7 (Hollstein et al, 2013). After its initial rapid degradation, NF1 protein levels are re-established shortly after growth factor treatment, allowing appropriate termination of RAS MAPK signaling (Cichowski et al, 2003). Aberrant destabilization of NF1 by CUL3:KBTBD7-mediated proteasomal degradation has been identified in cases of glioblastoma and depends on activation of PKC alpha (Cichowski et al, 2003; McGillicuddy et al, 2009; Hollstein et al, 2013).
			R-HSA-5658430 (Reactome)	After ubiquitination by the CUL3:KBTBD7 E3 RING ligase complex, NF1 is degraded by the proteasome (Cichowski et al, 2003; McGillicuddy et al, 2009; Hollstein et al, 2013).
			R-HSA-5658435 (Reactome)	The human genome encodes at least 10 proteins that bind RAS and activate its intrinsic GTPase activity, resulting in the formation of inactive RAS:GDP and attenuating RAS signaling (reviewed in King et al, 2013). These identified RAS GAP proteins are RASA1 (also known as p120 GAP), NF1, the GAP1 family (RASA2, RASA3, RASA4 and RASAL1) and the SYNGAP family (SYNGAP1, DAB2IP, RASAL2 and RASAL3). GAP proteins stimulate RAS GTPase activity by inserting a conserved arginine residue into the RAS active site, promoting a conformational change in the active site to allow GTP hydrolysis (Ahamdian et al, 2003; Scheffzek et al, 1997; Ahamdian et al, 1997). In addition to the GAP domain, most RAS GAP proteins also contain membrane targeting domains that facilitate interaction with the plasma membrane where RAS is tethered. In some cases, such as RASA3, membrane localization is constitutive, whereas in others, the GAP proteins are targeted to the membrane in response to cellular signaling. In addition to binding RAS, a number of GAP proteins also mediate other protein-protein interactions and act as scaffolds to integrate signaling; some GAPs are also known to bind and activate other small GTPases such as RAP (reviewed in King et al, 2013). Loss-of-functions mutations in RAS GAP proteins have been identified in a number of cancers (reviewed in Maertens and Cichowski, 2014).
			R-HSA-5658438 (Reactome)	Sprouty-related proteins (SPRED) 1, 2 and 3 are negative regulators of the MAPK pathway that act at least in part by recruiting the RAS GAP protein neurofibromin 1 (NF1) to the plasma membrane (Kato et al, 2003; King et al, 2006; Stowe et al, 2012). NF1, a negative regulator of RAS is a tumor suppressor that is mutated in the familial cancer syndrome neurofibromatosis I as well as in sporadic cases of glioblastoma, non-small cell lung cancers, neuroblastoma and melanoma (Martin et al, 1990; Bollag et al, 1996; reviewed in Bollag and McCormick, 1992; Maertens and Cichowski, 2014). Plasma membrane-association of the SPRED proteins themselves depends on the C-terminal SPR domain. Mutations in this region abrogate membrane localization of the protein (King et al, 2005; Stowe et al, 2012). Membrane association may also be promoted by interaction of the SPRED proteins with RAS (Wakioka et al, 2001). Interaction with NF1 is mediated by the SPRED EVH1 domain, and mutations in this region affect both NF1 recruitment and the ability of SPRED and NF1 proteins to negatively regulate RAS pathway activity (Stowe et al, 2012; reviewed in McClatchey and Cichowski, 2012).
			R-HSA-5672948 (Reactome)	KSR1 (Kinase suppressor of RAS 1) was originally identified in Drosophila and C. elegans as a suppressor of activated RAS, and is one of a number of scaffolding proteins that bring RAS-RAF-MAPK members together to promote pathway activation (Therrien et al, 1995; Kornfeld et al, 1995; Sundaram et al, 1995; reviewed in Zhang et al, 2013). Consistent with its role as a scaffolding protein, KSR1 interacts with all of the kinases of the MAPK pathway. Interaction with the MEK proteins MAP2K1 and MAP2K2 is constitutive, while pathway activation promotes heterodimerization with activated RAF proteins and subsequent interaction with ERK/MAPK proteins (Rajakulendran et al, 2009; Therrien et al, 1996; McKay et al, 2009; Hu et al, 2011; Hu et al, 2013; Brennan et al, 2011; note, however, that for simplicity MAP2K/MEK proteins are not depicted as part of this reaction). Like the RAF proteins, KSR1 is maintained in an inactive state in quiescent cells by interaction with 14-3-3 dimers; this interaction is promoted by phosphorylation of KSR1 residues S311 and S406 by the MAP/microtubule affinity-regulating kinase 3 (MARK3), which is constitutively bound to KSR1 (Muller et al, 2001).
			R-HSA-5672950 (Reactome)	Activation of RAS downstream of extracellular signals allows RAS:GTP to recruit BRAF to the plasma membrane, disrupting the inactivating interaction between BRAF and the 14-3-3 protein YWHAB (Marais et al, 1997; Yamamori et al, 1995; reviewed in Cseh et al, 2014). BRAF, unique of the three mammalian RAF isoforms, is constitutively phosphorylated on the conserved serine residue (445 in BRAF) in the N-terminal acidic motif (NtA). Constitutive negative charge in this region is critical for BRAF to function as an activator of other RAF molecules, allowing signal amplification (Marais et al, 1997; Mason et al, 1999; Wan et al, 2004; Garnett et al, 2005; Hu et al, 2013; reviewed in Cseh et al, 2014). RAS:GTP-bound BRAF heterodimerizes with additional RAF monomers, allowing cis-autophosphorylation in the activation loop of the second RAF protein. Once activated by BRAF in this manner, the 'receiver' kinase monomer is competent to dimerize with and transactivate other monomers in turn (Weber et al, 2001; Garnett et al, 2005; Hu et al, 2013; reviewed in Cseh et al, 2014). Intriguingingly, the scaffold protein KSR1 is activated by BRAF in a manner analogous other RAF monomers and can similarly act as a RAF activator once it is itself activated (Brennan et al, 2011; Ory et al, 2003; reviewed in Raabe and Rapp, 2003; Cseh et al, 2014). Although this pathway shows PP2A-mediated dephosphorylation of RAF and transient displacement of 14-3-3 proteins as preceding RAS and plasma membrane binding of RAF proteins, the order and dependency of these events is not clear. Both membrane binding and 14-3-3 displacement also appear to be facilitated by an interaction between RAF and the cell cycle protein Prohibitin (PHB; Rajalingam et al, 2005; reviewed in Rajalingam and Rudel, 2005; Chowdhury et al, 2014).
			R-HSA-5672951 (Reactome)	In quiescent cells, RAF is maintained in a closed state in which the N-terminal regulatory region sterically blocks the catalytic region (Cutler et al, 1998; Tran et al, 2003; Terai et al, 2005; Tran et al, 2005; reviewed in Udell et al, 2011). This closed state is mediated in part by the intramolecular binding of YWHAB/14-3-3 dimers to two phosphorylated serine residues (S259 and S621 in RAF1, S214 and S582 in ARAF and S365 and S729 in BRAF) (Ory et al, 2003; Jaumot et al, 2001; Fischer et al, 2009; reviewed in Udell et al, 2011).
			R-HSA-5672954 (Reactome)	MARK3-mediated phosphorylation of S311 and particularly S406 promotes the binding of 14-3-3 dimers, sequestering KSR1 in the cytosol in quiescent cells (Cacace et al, 1999; Muller et al, 2000; Muller et al, 2001; reviewed in Raabe and Raap, 2003). Mutation of S406 abrogates 14-3-3 binding and results in constitutive plasma membrane localization of KSR1 (Muller et al, 2001).
			R-HSA-5672957 (Reactome)	Upon growth factor stimulation, KSR1 is dephosphorylated at S406 by PP2A, disrupting 14-3-3 binding and promoting membrane translocation of KSR1 (Ory et al, 2003; Muller et al, 2001; reviewed in Raabe and Raap, 2003).
			R-HSA-5672958 (Reactome)	Dephosphorylation of KSR1 S406 by PP2A promotes the dissociation of 14-3-3 from this site, exposing both the CR1 region that is required for membrane localization of KSR1 and the MAPK-binding FxFP motif (Ory et al, 2003; Muller et al, 2001; reviewed in Raabe and Raap, 2003).
			R-HSA-5672960 (Reactome)	Dephosphorylation of S259 (S365/S214) by PP2A promotes the transient dissociation of 14-3-3 dimers from this site (Ory et al, 2003; Jaumot et al, 2001; Rommel et al, 1996; reviewed in Raabe and Raap, 2003; Matallanas et al, 2011). In the case of RAF1, displacement of 14-3-3 has also been shown to be promoted by a direct interaction between RAF1 and the cell cycle protein prohibitin (PHB; Rajalingam et al, 2005; reviewed in Rajalingam and Rudel, 2005; Chowdhury et al, 2014).
			R-HSA-5672961 (Reactome)	Upon growth factor stimulation, RAF1 S259 (or S365 and S214 in BRAF and ARAF respectively) is dephosphorylated by PP2A and/or PP1, abrogating one of the YWHAB/14-3-3 binding sites (Terai et al, 2005; Ory et al, 2003; Kubicek et al, 2002; Jaumot et al, 2001; Rommel et al, 1996; reviewed in Roskoski, 2010; Matallanas et al, 2011). Release of 14-3-3 binding from the N-terminal site promotes a conformational change that exposes the membrane and RAS interacting RBD and CRD and facilitates recruitment of RAF to the plasma membrane where it binds RAS:GTP (Kubicek et al, 2002; Goetz et al, 2003; Ory et al, 2003). Dephosphorylation of S259/S365/S214 may also promote dimerization of RAF monomers by replacing the intramolecular 14-3-3 binding interaction with an intermolecular one (Rushworth et al, 2006; Weber et al, 2001; Ritt et al, 2010; reviewed in Matallanas et al, 2011). Although the PP2A-mediated dephosphorylation is shown as occurring before both YWHAB displacement and recruitment of RAF to the plasma membrane, the order of and relationship between these events is not completely clear. In addition, the displacement of 14-3-3 and recruitment of RAF1 to the membrane is also promoted by a direct interaction with cell cycle protein Prohibitin (PHB; Rajalingam et al, 2005; reviewed in Rajalingam and Rudel, 2005; Chowdhury et al, 2014).
			R-HSA-5672965 (Reactome)	The human genome is predicted to encode 27 RAS guanine nucleotide exchange factors (GEFs) that promote the exchange of GDP for GTP on membrane-associated RAS in response to RAS-MAPK pathway activation by growth factors, hormones, cytokines and other stimuli (reviewed in Cherfils and Zeghouf, 2013; Cargnello and Roux, 2011). Nucleotide exchange stimulates a conformational change in RAS to facilitate its interaction with RAF, ultimately promoting the phosphorylation of downstream effectors MAPK3 and MAPK1 (also known as ERK1 and ERK2) (reviewed in Cseh et al, 2014; Vigil et al, 2010).
			R-HSA-5672966 (Reactome)	RAF activation depends on the formation of a side-by-side asymmetric homo- or heterodimer (formed from either 2 RAF monomers or a RAF monomer and KSR1) (Weber et al, 2001; Garnett et al, 2005; Rushworth et al, 2006; Rajakulendran et al, 2009; Hu et al, 2013). Dimerization is mediated by cluster of basic residues in the kinase domain, and mutation of these critical residues abrogates RAF activation (Rajakulendran et al, 2009). Dimerization is required for the 'activator' monomer to induce an allosteric change in the 'receiver' monomer that, in conjunction with activation loop phosphorylation, activates the kinase activity of the receiver (Hu et al, 2013). BRAF, by virtue of its constitutive negative charge in the NtA region, is uniquely able to function as an activator RAF without further modification, while RAF1, ARAF and KSR1 can function as activators after being phosphorylated in the NtA region downstream of RAF pathway activation (Hu et al, 2013; Leicht et al, 2013; reviewed in Cseh et al, 2014). Homo and heterodimerization of RAF monomers may be promoted by association with MAP3K11, which interacts with BRAF and RAF1 in vitro and in vivo and which is required for RAF activation (Chadee et al, 2004a, Chadee et al ,2004b; Chadee et al, 2006).
			R-HSA-5672969 (Reactome)	Downstream of RAF dimerization and allosteric activation, RAF monomers and KSR1 undergo a series of activating phosphorylations in both the activation loop (AL) and, in the case of ARAF, RAF1 and KSR1, in the NtA . Phosphorylation of the activation loop residues (T491, S494 in RAF1, T452, T455 in ARAF and T599, S602 in BRAF) contributes to full kinase activity, although this may be less critical for ARAF, and RAFs in general, than for other kinases due to their regulation by 14-3-3 binding (Zhu et al, 2005; Zhang et al, 2000; Baljuls et al, 2008, reviewed in Matallanas et al, 2011; Udell et al, 2011). AL phosphorylation may occur through cis-autophosphorylation within the RAF dimer, although phosphorylation by other kinases is also possible (Hu et al, 2013; reviewed in Matallanas et al, 2011). Phosphorylation in the RAF NtA region is required for full kinase activity, for interaction with MAP2K substrates and for the ability of activated RAF to act as an allosteric activator of other RAF monomers (Marais et al, 1995; Diaz et al, 1997; Xiang et al, 2002; Edin et al, 2005; Hu et al, 2013; Mason et al, 1999). Phosphorylation of these residues (S338 and Y441 in RAF1, S299 and Y302 in ARAF and Y602 in KSR1) may be mediated by a kinase of the SRC, JAK or PAK family kinases, by MAP2K kinases or through autophosphorylation by RAF itself (Marais et al, 1995; Xia et al, 1996; King et al, 1998; Sun et al, 2000; Tran et al, 2003; Tran et al, 2005; Hu et al, 2013; reviewed in Matallanas et al, 2011). The phosphorylated NtA of RAF1 is also the binding site for the negative regulator PEPB1, also known as RKIP. PEBP1 binding to RAF1 prevents phosphorylation of the MAP2K substrates (Park et al, 2006; Rath et al, 2008; reviewed in Shin et al, 2009).
			R-HSA-5672972 (Reactome)	RAF kinases have restricted substrate specificity and have as their primary substrates the two MAP2K proteins MAP2K1 and MAP2K2 (also known as MEK1 and 2). MAP2K1 knockout is embryonic lethal in mice, while MAP2K2 knockouts have no apparent abnormalities, suggesting that MAP2K1 can compensate for MAP2K2 in vivo (Giroux et al, 1999; Belanger et al, 2003). MAP2K proteins exist as stable homo- and heterodimers independent of growth factor stimulation and are generally recruited to activated RAF proteins in conjunction with a scaffolding protein and the MAP2K substrates, MAPK1 and 3 (also known as ERK1 and 2) (Ohren et al, 2004; Catalanotti et al, 2009; Catling et al, 1995; reviewed in Matallanas et al, 2011; Roskoski et al, 2012a; Roskoski et al, 2012b). Scaffolding proteins promote signaling by providing a docking platform that colocalizes components of the signaling cascade, and provide specificity by controlling the spatial and temporal regulation of the pathway (reviewed in Brown and Sacks, 2009; Matallanas et al, 2011). KSR1 and 2, CNKSR1 and 2, IQGAP1 and the beta arrestins are among the known MAPK scaffold proteins that act at the plasma membrane upon MAPK pathway activation; in addition, paxillin localizes MAPK pathway components to focal adhesion sites in the plasma membrane (Roy et al, 2005; Ren et al, 2007; DeFea et al, 2000; Togho et al, 2003; Ishibe et al, 2003; reviewed in Claperon and Therrien, 2007; Brown and Sacks, 2009; Matallanas et al, 2011). Although this reaction depicts these scaffolding proteins acting equivalently, the details of how they promote pathway activation vary. For instance, KSR1 and 2 are constitutively bound to MAP2K dimers but recruit MAPKs only upon pathway stimulation, while IQGAP1 associates constitutively with both MAP2K and MAPK proteins in unstimulated cells and shows increased interaction with MAP2K1 upon pathway activation by EGF (Stewart et al, 1999; Cacace et al, 2000; Muller et al, 2000; Roy et al, 2004; Roy et al, 2005; reviewed in Brown and Sacks, 2009). Scaffolding complexes may be particularly important for the phosphorylation of cytosolic MAPK targets (reviewed in Casar et al, 2009).
			R-HSA-5672973 (Reactome)	Activated MAP2K phosphorylates MAPK on threonine and tyrosine residues in the activation loop (residues T202 and Y204 in MAPK3, residues T185 and Y187 in MAPK1) (Ray et al, 1988; reviewed in Roskoski, 2012b). MAPK3 and MAPK1 are 84% identical and appear to be stimulated in parallel by all known activators of the MAPK pathway (Lefloch et al, 2009; reviewed in Lloyd, 2006).
			R-HSA-5672978 (Reactome)	Activated RAF phosphorylates the MEK kinases MAP2K1 and MAP2K2 on 2 serine residues in the MAP2K activation loop (S218 and S222 in MAP2K1 and S222 and S226 in MAP2K2 (Zheng and Guan, 1994; Alessi et al, 1994; Catling et al, 1995; Papin et al, 1995; Seger et al, 1994; reviewed in Roskoski, 2012a). Although all three RAF kinases can phosphorylate MAP2K1 and MAP2K2, BRAF appears to be the primary activator in vivo (Marais et al, 1997; Jaiswal et al, 1994; Pritchard et al, 1995; reviewed in Welbrock et al, 2004)
			R-HSA-5672980 (Reactome)	The mechanisms governing the dissociation or trafficking of activated MAPK signaling complexes at the plasma membrane is not fully worked out. Some active complexes may be endocytosed and targeted to other cellular locations, for example the Golgi complex (Lorentzen et al, 2010). Activated RAF monomers may dissociate and homo- or heterodimerize with additional inactive RAF monomers and in this way amplify the signal (reviewed in Matallanas et al, 2011; Cseh et al, 2014). Ultimately, active RAF complexes are subject to PP5- and PP2A-mediated dephosphorylation, which promotes a return to the inactive state. Hydrolysis of RAS-bound GTP by the intrinsic GTPase activity, stimulated by association with RAS GAP proteins, ultimately promotes dissociation of RAS from RAF allowing a return to the quiescent state (reviewed in Wellbrock et al, 2004; Matallanas et al, 2011).
			R-HSA-5674018 (Reactome)	BRAP is a negative regulator of the RAF/MAPK cascade that inhibits the homo- and heterodimerization of KSR1 and RAF and preventing downstream signal propagation (Matheny et al, 2004; Chen et al, 2008; reviewed in Matheny et al, 2009). Upon RAS stimulation, BRAP binds to RAS:GTP. This stimulates BRAP's E3 HECT ubiquitin ligase activity, promoting its autoubiquitination and thereby relieving the inhibition of KSR1 activity (Matheny et al, 2004; reviewed in Matheny et al, 2009). USP15 is a deubiquitinase that stabilizes BRAP protein levels and thus acts to dampen MAPK signaling (Hayes et al, 2013).
			R-HSA-5674019 (Reactome)	BRAP is a negative regulator of MAPK signaling that binds KSR1 as assessed by coimmunoprecipitation. This interaction abrogates KSR1 homodimer and KSR1:RAF heterodimer formation, and disrupts the recruitment of MAP2K kinases to RAF (Methany et al, 2004; Chen et al, 2008; reviewed in Methany et al, 2009). BRAP inhibition of KSR1 is relieved in an unknown manner by autoubiquitination after RAS pathway activation (reviewed in Methany et al, 2009).
			R-HSA-5674022 (Reactome)	Binding to activated RAS stimulates the ubiquitinase activity of BRAP, promoting autoubiquitination and relieving the inhibition of KSR1 (Methany et al, 2004; Chen et al, 2008; Methany et al, 2009).
			R-HSA-5674130 (Reactome)	Interaction of MAPK pathway components with LAMTOR2, 3 and MORG1 facilitates pathway activation in response to varied stimuli, resulting in the phosphorylation of MAP2K and MAPK proteins at conserved sites in their activation loops (Schaeffer et al, 1998; Teis et al, 2002; Teis et al, 2006; Vomastek et al, 2004; Sharma et al, 2005; reviewed in Matallanas et al, 2011).
			R-HSA-5674132 (Reactome)	LAMTOR3 (also known as MEK partner 1, MP1) exists in an obligatory complex with LAMTOR2 (p14) at the endosomal membrane where they act as a scaffold and promote MAPK activation (Schaeffer et al, 1998; Teis et al, 2002; Teis et al, 2006; Sharma et al, 2005). The LAMTOR2/LAMTOR3 complex may also be part of a larger molecular weight complex at the endosome that includes the MAPK organizer protein MORG1 (Vomastek et al, 2004; Sharma et al, 2005; reviewed in Matallanas et al, 2011).
			R-HSA-5674140 (Reactome)	PAQR3, also known as RKTG (Raf kinase trapping to Golgi) is a multi-pass transmembrane protein that binds to RAF1 and BRAF and sequesters them in the Golgi. This inhibits the interaction of RAF with activated RAS and the plasma membrane and inhibits RAF signaling (Feng et al, 2007; Fan et al, 2008; Luo et al, 2008).
			R-HSA-5674366 (Reactome)	IL17RD, also known as SEF (similar expression to FGF), was identified as a negative regulator of nuclear MAPK signaling (Tsang et al, 2002; Furthauer et al, 2002). IL17RD is a spatial regulator of MAPK signaling that binds activated MAP2K dimers at the Golgi membrane and prevents the dissociation and translocation of phosphorylated MAPK into the nucleus. In this way, IL17RD restricts activation of nuclear MAPK targets while not affecting activation of cytosolic ones (Torii et al, 2004; reviewed in Phillips, 2004; Matallanas et al, 2011).
			R-HSA-5674373 (Reactome)	Activated MAP2Ks in complex with IL17RD phosphorylate MAPKs at the Golgi membrane. IL17RD prevents the dissociation of phosphorylated MAPK from the complex at the Golgi as assessed by coimmunoprecipitation, preventing MAPK nuclear translocation and activation of nuclear targets (Torii et al, 2004; reviewed in Philips, 2004; Brown and Sacks, 2009).
			R-HSA-5674385 (Reactome)	Phosphorylated MAPK monomers can dimerize - generally into MAPK1 and MAPK3 homodimers, as the heterodimer is unstable- but the physiological significance of dimerization is unclear (Khokhlatchev et al, 1998; reviewed Rosokoski, 2012b). MAPKs have both cytosolic and nuclear targets and dimerization may be particularly important for MAPK-dependent phosphorylation of cytosolic targets. Phosphorylation of cytosolic MAPK targets appears to happen predominantly in the context of larger scaffolding complexes, and since the scaffolds and cytosolic MAPK substrates contact the same hydrophobic surface of MAPK, dimerization is necessary to allow assembly of a functional complex (Casar et al, 2008; Lidke et al, 2010; reviewed in Casar et al, 2009). Consistent with this, disrupting either MAPK dimerization or the MAPK interaction with the scaffolding protein abrogated proliferation and transformation (Casar et al, 2008). Note that, for simplicity in this diagram, dimerization is shown as happening between free cytosolic monomers of activated MAPK rather than in the context of the scaffolding complex. Although predominantly cytoplasmic in resting cells, a proportion of activated MAPK translocates to the nucleus upon stimulation where it activates nuclear targets. Despite early studies to the suggesting that dimerization was required for nuclear translocation, a few recent papers have challenged this notion (Lenormand et al, 1993; Chen et al, 1992; Khokhlatchev et al, 1998; Casar et al, 2008; Lidke et al, 2010; Burack and Shaw, 2005; reviewed in Roskoski, 2012b).
			R-HSA-5674387 (Reactome)	After phosphorylation by MAP2Ks, a proportion of activated MAPK translocates into the nucleus where it activates nuclear targets (reviewed in Roskoski, 2012b). MAPKs, which lack a nuclear localization signal (NLS), may 'piggyback' into the nucleus in complex with other nuclear-targeted proteins or may translocate by virtue of interaction with components of the nuclear pore complex (Brunet et al, 1999; Adachi et al, 1999; Matsubayashi et al, 2001; Whitehurst et al, 2002; Khokhlatchev et al, 1998; reviewed in Roskoski, 2012b). Although dimerization of MAPKs was thought to be critical for nuclear translocation, a number of studies have now challenged the physiological relevance of MAPK dimerization and this remains an area of uncertainty (Lenormand et al, 1993; Chen et al, 1992; Casar et al, 2008; Lidke et al, 2010; Burack and Shaw, 2005; reviewed in Casar et al, 2009; Roskoski, 2012b)
			R-HSA-5674496 (Reactome)	Activated MAPK proteins negatively regulate MAP2K1:MAP2K2 heterodimers by phosphorylating MAP2K1 at T292, a residue that is not present in MAP2K2. Phosphorylation of this site in MAP2K1 promotes the dephosphorylation of the MAP2K phosphorylated activation loop (AL) by an unknown mechanism, establishing a negative feedback loop that limits MAPK signaling (Catalanotti et al, 2009; Brunet et al, 1994; Xu et al, 1999). Deletion of MAP2K1 or mutation of this site prolongs MAP2K2 AL phosphorylation and MAPK activation (Catalanotti et al, 2009).
			R-HSA-5675194 (Reactome)	RAF1 is phosphorylated by activated MAPK at 6 serine residues (S29, S43, S289, S296, S301 and S642). MAPK-dependent hyperphosphorylation of RAF1 abrogates the ability of activated RAF1 to interact with RAS and is coincident with inactivation of RAF1. RAF1 proteins containing mutation of these phosphorylation sites persist at the plasma membrane, show sustained S338 phosphorylation and persistent activation relative to WT RAF1 protein. In wild type cells, PP2A and the prolyl-isomerase PIN1 contribute to the dephosphorylation of hyperphosphorylated RAF1, allowing subsequent cycles of activation to occur (Dougherty et al, 2005; reviewed in Roskoski, 2010)
			R-HSA-5675198 (Reactome)	BRAF is subject to MAPK-dependent phosphorylation that limits its activity. Phosphorylation of S151 inhibits binding of BRAF to activated RAS, while phosphorylation of T401, S750 and S753 abrogates heterodimerization with RAF1 (Ritt et al, 2010; Rushworth et al, 2006; Brummer et al, 2003).
			R-HSA-5675206 (Reactome)	PEA15 is a cytoplasmic anchor that binds directly to activated MAPKs prevents their translocation into the nucleus (Formstecher et al, 2001; Whitehurst et al, 2004; Hill et al, 2002; Chou et al, 2003). PEA15 also protects phosphorylated MAPKs in the cytoplasm from inactivating dephosphorylation (Mace et al, 2013). In this way, binding of PEA15 promotes phosphorylation of cytoplasmic MAPK targets at the expense of nuclear ones.
			R-HSA-5675373 (Reactome)	MAPKs are inactivated by dephosphorylation of the activation loop T and Y residues by dual-specificity MAPK phosphatases (DUSPs) (reviewed in Roskoski, 2012b). Class 1 DUSPs, including DUSP 1, 2, 4 and 5 are nuclear and are generally activated by the same extracellular stimuli that promote MAPK signaling, establishing a negative feedback loop. DUSP5 is specific for MAPK3 and 1, while the other class 1 enzymes have broad specificity. Nuclear MAPKs may also be inactivated by nuclear forms of class III DUSPs, including DUSP8, 10 and 16, although the preferred substrate of these enzymes are the p38 and JNK MAP kinases (reviewed in Bermudez et al, 2010; Kondoh and Nishida, 2007).
			R-HSA-5675376 (Reactome)	MAPKs are inactivated by dephosphorylation of the activation loop T and Y residues by dual-specificity MAPK phosphatases (DUSPs) (reviewed in Roskoski, 2012b). Cytosolic MAPKs are dephosphorylated by the MAPK-specific class II DUSPs 6,7 and 9, but may also be dephosphorylated by cytosolic forms of class III DUSPs 8, 10 and 16, which preferentially dephosphorylate p38 and JNK MAP kinases (reviewed in Bermudez et al, 2010; Kandoh and Nishida, 2007).
			R-HSA-5675417 (Reactome)	PEBP1, also known as RKIP (Raf kinase inhibitor protein), is a negative regulator of RAF1 that binds to the phosphorylated NtA region and prevents activation of MAP2K substrates (Yeung et al, 1999; Yeung et al, 2000; Rath et al, 2008; Park et al, 2006; reviewed in Lorenz et al, 2014). Relief of this PEBP1 repression of RAF1 activity is stimulated by phosphorylation of PEBP1, which promotes it dissociation from RAF1. Candidate kinases for phosphorylation of PEBP1 include PKC and the MAPKs themselves, which would establish a positive feedback loop stimulating MAPK pathway activity (Corbit et al, 2003; Cho et al, 2003; Shin et al, 2009).
			R-HSA-5675431 (Reactome)	Along with PPP5C-mediated dephophosphorylation of the NtA region, PP2A contributes to the inactivation of RAF1 by mediating the dephosphorylation of AL loop residues. PP2A-mediated dephosphorylation of RAF1 may be stimulated by the prior hyperphosphorylation of RAF1 by MAPKs (Dougherty et al, 2005; reviewed in Matallanas et al, 2011).
			R-HSA-5675433 (Reactome)	PPP5C dephosphorylates S338 in the NtA region of RAF1, which reduces the catalytic activity of RAF1 towards MAP2K proteins (von Kriegsheim et al, 2006; reviewed in Matallanas et al, 2011).
RAF activating kinases		mim-catalysis	R-HSA-5672969 (Reactome)
	RAF/MAPK scaffolds	Arrow	R-HSA-5672980 (Reactome)
RAF/MAPK scaffolds			R-HSA-5672972 (Reactome)
	RAS GAPs	Arrow	R-HSA-5658231 (Reactome)
RAS GAPs			R-HSA-5658435 (Reactome)
RAS GEFs		mim-catalysis	R-HSA-5672965 (Reactome)
SPRED dimer:NF1		Arrow	R-HSA-5658231 (Reactome)
	SPRED dimer:NF1	Arrow	R-HSA-5658438 (Reactome)
SPRED dimer:NF1			R-HSA-5658424 (Reactome)
	SPRED dimer:ub-NF1	Arrow	R-HSA-5658424 (Reactome)
SPRED dimer:ub-NF1			R-HSA-5658430 (Reactome)
	SPRED dimer	Arrow	R-HSA-5658430 (Reactome)
SPRED dimer			R-HSA-5658438 (Reactome)
Ub			R-HSA-5658424 (Reactome)
Ub			R-HSA-5674022 (Reactome)
	WDR83:LAMTOR2:LAMTOR3:activated RAF:MAP2K:MAPK complex	Arrow	R-HSA-5674132 (Reactome)
WDR83:LAMTOR2:LAMTOR3:activated RAF:MAP2K:MAPK complex			R-HSA-5674130 (Reactome)
	WDR83:LAMTOR2:LAMTOR3:activated RAF:p-2S MAP2K:p-T,Y MAPK complex	Arrow	R-HSA-5674130 (Reactome)
WDR83:LAMTOR2:LAMTOR3			R-HSA-5674132 (Reactome)
	YWHAB dimer	Arrow	R-HSA-5672958 (Reactome)
	YWHAB dimer	Arrow	R-HSA-5672960 (Reactome)
YWHAB dimer			R-HSA-5672951 (Reactome)
YWHAB dimer			R-HSA-5672954 (Reactome)
	activated RAF:scaffold:MAP2K:MAPK complex	Arrow	R-HSA-5672972 (Reactome)
activated RAF:scaffold:MAP2K:MAPK complex			R-HSA-5672978 (Reactome)
activated RAF:scaffold:MAP2K:MAPK complex		mim-catalysis	R-HSA-5672978 (Reactome)
	activated RAF:scaffold:p-2S MAP2K:MAPK complex	Arrow	R-HSA-5672978 (Reactome)
activated RAF:scaffold:p-2S MAP2K:MAPK complex			R-HSA-5672973 (Reactome)
activated RAF:scaffold:p-2S MAP2K:MAPK complex		mim-catalysis	R-HSA-5672973 (Reactome)
	activated RAF:scaffold:p-2S MAP2K:p-2T MAPK complex	Arrow	R-HSA-5672973 (Reactome)
activated RAF:scaffold:p-2S MAP2K:p-2T MAPK complex			R-HSA-5672980 (Reactome)
activated RAF homo/heterodimer			R-HSA-5674132 (Reactome)
cytosolic MAPK DUSPs		mim-catalysis	R-HSA-5675376 (Reactome)
dephosphorylated "receiver" RAF/KSR1			R-HSA-5672966 (Reactome)
	dephosphorylated inactive RAFS:YWHAB dimer	Arrow	R-HSA-5672961 (Reactome)
dephosphorylated inactive RAFS:YWHAB dimer			R-HSA-5672960 (Reactome)
	dephosphorylated inactive RAFs	Arrow	R-HSA-5672960 (Reactome)
	hyperphosphorylated BRAF	Arrow	R-HSA-5675198 (Reactome)
	hyperphosphorylated RAF1	Arrow	R-HSA-5675194 (Reactome)
hyperphosphorylated RAF1		Arrow	R-HSA-5675431 (Reactome)
	inactive RAFs:YWHAB dimer	Arrow	R-HSA-5672951 (Reactome)
inactive RAFs:YWHAB dimer			R-HSA-5672961 (Reactome)
inactive RAFs			R-HSA-5672951 (Reactome)
inactive RAFs			R-HSA-5674140 (Reactome)
nuclear MAPK DUSPs		mim-catalysis	R-HSA-5675373 (Reactome)
	p-2S MAP2K homo/heterodimers	Arrow	R-HSA-5672980 (Reactome)
p-2S MAP2K homo/heterodimers			R-HSA-5674366 (Reactome)
p-2S MAP2K1:p-2S MAPK2K2 heterodimer			R-HSA-5674496 (Reactome)
	p-2S,T MAP2K1:p-2S MAPK2K2 heterodimer	Arrow	R-HSA-5674496 (Reactome)
	p-S311 KSR1:MARK3:YWHAB dimer	Arrow	R-HSA-5672957 (Reactome)
p-S311 KSR1:MARK3:YWHAB dimer			R-HSA-5672958 (Reactome)
	p-S311 KSR1:MARK3	Arrow	R-HSA-5672958 (Reactome)
	p-S311,S406 KSR1:MARK3:YWHAB dimer	Arrow	R-HSA-5672954 (Reactome)
p-S311,S406 KSR1:MARK3:YWHAB dimer			R-HSA-5672957 (Reactome)
	p-S311,S406 KSR1:MARK3	Arrow	R-HSA-5672948 (Reactome)
p-S311,S406 KSR1:MARK3			R-HSA-5672954 (Reactome)
p-S338,Y341,T491,S494,S621 RAF1			R-HSA-5675194 (Reactome)
p-S445,T599,S602,S729 BRAF			R-HSA-5675198 (Reactome)
	p-T,Y MAPK dimers	Arrow	R-HSA-5674385 (Reactome)
	p-T,Y MAPK monomers and dimers:PEA15	Arrow	R-HSA-5675206 (Reactome)
p-T,Y MAPK monomers and dimers:PEA15		TBar	R-HSA-5674387 (Reactome)
	p-T,Y MAPK monomers and dimers	Arrow	R-HSA-5674387 (Reactome)
p-T,Y MAPK monomers and dimers			R-HSA-5674387 (Reactome)
p-T,Y MAPK monomers and dimers			R-HSA-5675206 (Reactome)
p-T,Y MAPK monomers and dimers			R-HSA-5675373 (Reactome)
p-T,Y MAPK monomers and dimers			R-HSA-5675376 (Reactome)
p-T,Y MAPK monomers and dimers		mim-catalysis	R-HSA-5674496 (Reactome)
p-T,Y MAPK monomers and dimers		mim-catalysis	R-HSA-5675194 (Reactome)
p-T,Y MAPK monomers and dimers		mim-catalysis	R-HSA-5675198 (Reactome)
	p-T,Y MAPKs	Arrow	R-HSA-5672980 (Reactome)
p-T,Y MAPKs			R-HSA-5674385 (Reactome)
	p21 RAS:GTP:'activator' RAF:YWHAB dimer	Arrow	R-HSA-5672950 (Reactome)
p21 RAS:GTP:'activator' RAF:YWHAB dimer			R-HSA-5672966 (Reactome)
	p21 RAS:GTP:activated RAF homo/heterodimer complexes	Arrow	R-HSA-5672969 (Reactome)
p21 RAS:GTP:activated RAF homo/heterodimer complexes			R-HSA-5672972 (Reactome)
	p21 RAS:GTP:activated RAF1 homo/heterodimer:PEBP1	Arrow	R-HSA-5675417 (Reactome)
p21 RAS:GTP:activated RAF1 homo/heterodimer:PEBP1		TBar	R-HSA-5672972 (Reactome)
	p21 RAS:GTP:homo/heterodimerized RAF complex	Arrow	R-HSA-5672966 (Reactome)
p21 RAS:GTP:homo/heterodimerized RAF complex			R-HSA-5672969 (Reactome)
	p21 RAS:GDP	Arrow	R-HSA-5658231 (Reactome)
p21 RAS:GDP			R-HSA-5672965 (Reactome)
	p21 RAS:GTP:BRAP	Arrow	R-HSA-5674018 (Reactome)
p21 RAS:GTP:BRAP			R-HSA-5674022 (Reactome)
p21 RAS:GTP:BRAP		mim-catalysis	R-HSA-5674022 (Reactome)
	p21 RAS:GTP:RAS GAPs	Arrow	R-HSA-5658435 (Reactome)
p21 RAS:GTP:RAS GAPs			R-HSA-5658231 (Reactome)
p21 RAS:GTP:RAS GAPs		mim-catalysis	R-HSA-5658231 (Reactome)
	p21 RAS:GTP:ub-BRAP	Arrow	R-HSA-5674022 (Reactome)
	p21 RAS:GTP	Arrow	R-HSA-5672965 (Reactome)
p21 RAS:GTP			R-HSA-5658435 (Reactome)
p21 RAS:GTP			R-HSA-5672950 (Reactome)
p21 RAS:GTP			R-HSA-5674018 (Reactome)
	p21RAS:GTP:activated RAF homo/heterodimers	Arrow	R-HSA-5672980 (Reactome)
p21RAS:GTP:activated RAF1 homo/heterodimer			R-HSA-5675417 (Reactome)
p21RAS:GTP:activated RAF1 homo/heterodimer			R-HSA-5675433 (Reactome)
	p21RAS:GTP:dephosphorylated RAF1 homo/heterodimer	Arrow	R-HSA-5675433 (Reactome)
p21RAS:GTP:dephosphorylated RAF1 homo/heterodimer			R-HSA-5675431 (Reactome)
	p21RAS:GTP:p-S621 RAF1 homo/heterodimer	Arrow	R-HSA-5675431 (Reactome)

RAF/MAP kinase cascade (Homo sapiens)

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