PIP3 activates AKT signaling (Homo sapiens)

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1107593, 96, 12425, 56, 10515, 758448, 11664, 113, 13648, 110, 11655, 604963, 9435, 37, 72, 8031, 701109946576721, 1074148, 110, 11612767, 11748, 1168367, 11724, 13717, 27, 28, 51, 54...nucleoplasmcytosolmiR-26A1 PDPK1:p-S473-AKT1E17K mutant:PIP2p-S9/21-GSK3Activator:PI3KPI(3,4,5)P3Intrinsic Pathwayfor ApoptosisPI(4,5)P2 miR-26A2 Signaling by the BCell Receptor (BCR)ADPTHEM4 PI3K Inhibitors:PI3KPTEN:Mg2+TSC2Mg2+ ADPPTEN TNRC6B Active AKTATPAKT inhibitors:AKTAKT1 E17Kmutant:PIP2p-S-AKT:PDPK1:PIP3p-S133-CREB1PTEN mRNA:miR-26ARISCp-S99-BADAKT inhibitorsTORC2 complexp-S196-CASP9(1-416)ADPSignaling by ERBB2TNRC6C p-S351-NR4A1PiSignaling by EGFRNR4A1Forkhead boxtranscriptionfactorMn2+ ATPPI3K inhibitorsPI(3,4,5)P3 ADPATPSignaling by ERBB4EIF2C4 ATPMDM2IKKAp-T-AKTGSK3p-T-CDKN1A/Bp-S473-AKT1 E17Kmutant:PIP2PDPK1:PIP3PI(4,5)P2PI(3,4,5)P3 PI3Kmutants,Activator:PI3KPTEN mRNA PI(4,5)P2 THEM4/TRIB3ADPPI(4,5)P2 AKT:PIP3:THEM4/TRIB3p-T308,S473-AKT1E17KTNRC6A ATPp-S473-AKT1 E17K H2OADPPDPK1 H2OAKT:PIP3PDPK1Pip-S939,T1462-TSC2PHLPP2 ADPPDPK1 Signaling by SCF-KITMLST8 miR-26A RISCADPATPRPS6KB2PHLPP (Mn2+cofactor)p-T23-CHUKTriciribine PHLPP1 AKT1 E17K Costimulation by theCD28 familyATPPDPK1 BADPDPK1 TRIB3 p-S473-AKT1 E17K Signaling by FGFRMAPKAP1 ATPCDKN1A/BMTOR CASP9(1-416)ATPRICTOR Signalling by NGFCREB1PI(4,5)P2 ADPp-S15,S356-RPS6KB2MOV10 Signaling by PDGFEIF2C1 PTEN mRNAATPp-S166,S188-MDM2PI(3,4,5)P3 AKTAKT/AKT1 E17K mutantATPperifosine PDPK1:PIP2EIF2C3 Active AKTPI(3,4,5)P3 AKT1 E17KPI(3,4,5)P3 MK2206 Phospho-Forkhead boxtranscriptionfactorp-S183,T246-AKT1S1Mitotic G1-G1/Sphasesp-S-AKT:PIP3EIF2C2 AKT1S18, 38, 50, 65, 106...22, 52, 1041163751, 54, 66, 71, 72, 78...1, 77, 1233711611, 47, 87, 89, 109...35803, 4, 9, 12, 14...11610, 40, 1142, 5, 42, 596, 7, 13, 18, 23...116116


Description

Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007. Source:Reactome.

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History

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114764view16:25, 25 January 2021ReactomeTeamReactome version 75
113208view11:27, 2 November 2020ReactomeTeamReactome version 74
112432view15:37, 9 October 2020ReactomeTeamReactome version 73
101336view11:22, 1 November 2018ReactomeTeamreactome version 66
100874view20:56, 31 October 2018ReactomeTeamreactome version 65
100415view19:30, 31 October 2018ReactomeTeamreactome version 64
99964view16:14, 31 October 2018ReactomeTeamreactome version 63
99519view14:47, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99161view12:41, 31 October 2018ReactomeTeamreactome version 62
93830view13:39, 16 August 2017ReactomeTeamreactome version 61
93382view11:22, 9 August 2017ReactomeTeamreactome version 61
88094view09:28, 26 July 2016RyanmillerOntology Term : 'kinase mediated signaling pathway' added !
88093view09:25, 26 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86468view09:18, 11 July 2016ReactomeTeamreactome version 56
83247view10:30, 18 November 2015ReactomeTeamVersion54
81352view12:52, 21 August 2015ReactomeTeamVersion53
76821view08:04, 17 July 2014ReactomeTeamFixed remaining interactions
76525view11:45, 16 July 2014ReactomeTeamFixed remaining interactions
75858view09:50, 11 June 2014ReactomeTeamRe-fixing comment source
75558view10:35, 10 June 2014ReactomeTeamReactome 48 Update
74913view13:44, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74557view08:35, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
AKT inhibitors:AKTComplexR-HSA-2400006 (Reactome)
AKT inhibitorsR-ALL-2399923 (Reactome)
AKT/AKT1 E17K mutantR-HSA-2400013 (Reactome)
AKT1 E17K mutant:PIP2ComplexR-HSA-2219527 (Reactome)
AKT1 E17K ProteinP31749 (Uniprot-TrEMBL)
AKT1 E17KProteinP31749 (Uniprot-TrEMBL)
AKT1S1ProteinQ96B36 (Uniprot-TrEMBL)
AKT:PIP3:THEM4/TRIB3ComplexR-HSA-199453 (Reactome)
AKT:PIP3ComplexR-HSA-2317329 (Reactome)
AKTR-HSA-202088 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
ATPMetaboliteCHEBI:15422 (ChEBI)
Activator:PI3KR-HSA-2316432 (Reactome)
Active AKTR-HSA-202072 (Reactome)
Active AKTR-HSA-202074 (Reactome)
BADProteinQ92934 (Uniprot-TrEMBL)
CASP9(1-416)ProteinP55211 (Uniprot-TrEMBL) any remaining instances associated here should be reassociated with the complex Cleaved Caspase-9
CDKN1A/BR-HSA-198625 (Reactome)
CREB1ProteinP16220 (Uniprot-TrEMBL)
Costimulation by the CD28 familyPathwayR-HSA-388841 (Reactome) Optimal activation of T-lymphocytes requires at least two signals. A primary one is delivered by the T-cell receptor (TCR) complex after antigen recognition and additional costimulatory signals are delivered by the engagement of costimulatory receptors such as CD28. The best-characterized costimulatory pathways are mediated by a set of cosignaling molecules belonging to the CD28 superfamily, including CD28, CTLA4, ICOS, PD1 and BTLA receptors. These proteins deliver both positive and negative second signals to T-cells by interacting with B7 family ligands expressed on antigen presenting cells. Different subsets of T-cells have very different requirements for costimulation. CD28 family mediated costimulation is not required for all T-cell responses in vivo, and alternative costimulatory pathways also exist. Different receptors of the CD28 family and their ligands have different regulation of expression. CD28 is constitutively expressed on naive T cells whereas CTLA4 expression is dependent on CD28/B7 engagement and the other receptor members ICOS, PD1 and BTLA are induced after initial T-cell stimulation.
The positive signals induced by CD28 and ICOS molecules are counterbalanced by other members of the CD28 family, including cytotoxic T-lymphocyte associated antigen (CTLA)4, programmed cell death (PD)1, and B and T lymphocyte attenuator (BTLA), which dampen immune responses. The balance of stimulatory and inhibitory signals is crucial to maximize protective immune responses while maintaining immunological tolerance and preventing autoimmunity.
The costimulatory receptors CD28, CTLA4, ICOS and PD1 are composed of single extracellular IgV-like domains, whereas BTLA has one IgC-like domain. Receptors CTLA4, CD28 and ICOS are covalent homodimers, due to an interchain disulphide linkage. The costimulatory ligands B71, B72, B7H2, B7H1 and B7DC, have a membrane proximal IgC-like domain and a membrane distal IgV-like domain that is responsible for receptor binding and dimerization. CD28 and CTLA4 have no known intrinsic enzymatic activity. Instead, engagement by their physiologic ligands B71 and B72 leads to the physical recruitment and activation of downstream T-cell effector molecules.
EIF2C1 ProteinQ9UL18 (Uniprot-TrEMBL)
EIF2C2 ProteinQ9UKV8 (Uniprot-TrEMBL)
EIF2C3 ProteinQ9H9G7 (Uniprot-TrEMBL)
EIF2C4 ProteinQ9HCK5 (Uniprot-TrEMBL)
Forkhead box

transcription

factor		R-HSA-199272 (Reactome)
GSK3R-HSA-198358 (Reactome)
H2OMetaboliteCHEBI:15377 (ChEBI)
IKKAProteinO15111 (Uniprot-TrEMBL)
Intrinsic Pathway for ApoptosisPathwayR-HSA-109606 (Reactome) The intrinsic (Bcl-2 inhibitable or mitochondrial) pathway of apoptosis functions in response to various types of intracellular stress including growth factor withdrawal, DNA damage, unfolding stresses in the endoplasmic reticulum and death receptor stimulation. Following the reception of stress signals, proapoptotic BCL-2 family proteins are activated and subsequently interact with and inactivate antiapoptotic BCL-2 proteins. This interaction leads to the destabilization of the mitochondrial membrane and release of apoptotic factors. These factors induce the caspase proteolytic cascade, chromatin condensation, and DNA fragmentation, ultimately leading to cell death. The key players in the Intrinsic pathway are the Bcl-2 family of proteins that are critical death regulators residing immediately upstream of mitochondria. The Bcl-2 family consists of both anti- and proapoptotic members that possess conserved alpha-helices with sequence conservation clustered in BCL-2 Homology (BH) domains. Proapoptotic members are organized as follows:

1. "Multidomain" BAX family proteins such as BAX, BAK etc. that display sequence conservation in their BH1-3 regions. These proteins act downstream in mitochondrial disruption.

2. "BH3-only" proteins such as BID,BAD, NOXA, PUMA,BIM, and BMF have only the short BH3 motif. These act upstream in the pathway, detecting developmental death cues or intracellular damage. Anti-apoptotic members like Bcl-2, Bcl-XL and their relatives exhibit homology in all segments BH1-4. One of the critical functions of BCL-2/BCL-XL proteins is to maintain the integrity of the mitochondrial outer membrane.

MAPKAP1 ProteinQ9BPZ7 (Uniprot-TrEMBL)
MDM2ProteinQ00987 (Uniprot-TrEMBL)
MK2206 MetaboliteCHEBI:716367 (ChEBI)
MLST8 ProteinQ9BVC4 (Uniprot-TrEMBL)
MOV10 ProteinQ9HCE1 (Uniprot-TrEMBL)
MTOR ProteinP42345 (Uniprot-TrEMBL)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
Mitotic G1-G1/S phasesPathwayR-HSA-453279 (Reactome)
Mn2+ MetaboliteCHEBI:29035 (ChEBI)
NR4A1ProteinP22736 (Uniprot-TrEMBL)
PDPK1 ProteinO15530 (Uniprot-TrEMBL)
PDPK1:PIP2ComplexR-HSA-2219520 (Reactome)
PDPK1:PIP3ComplexR-HSA-377179 (Reactome)
PDPK1:p-S473-AKT1 E17K mutant:PIP2ComplexR-HSA-2243941 (Reactome)
PDPK1ProteinO15530 (Uniprot-TrEMBL)
PHLPP (Mn2+ cofactor)ComplexR-HSA-199450 (Reactome)
PHLPP1 ProteinO60346 (Uniprot-TrEMBL)
PHLPP2 ProteinQ6ZVD8 (Uniprot-TrEMBL)
PI(3,4,5)P3 MetaboliteCHEBI:16618 (ChEBI)
PI(3,4,5)P3MetaboliteCHEBI:16618 (ChEBI)
PI(4,5)P2 MetaboliteCHEBI:18348 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PI3K mutants,Activator:PI3KR-HSA-2400011 (Reactome)
PI3K Inhibitors:PI3KComplexR-HSA-2400008 (Reactome)
PI3K inhibitorsR-ALL-2399811 (Reactome) PI3K inhibitors bind the catalytic subunit of PIK3CA, blocking its phosphoinositide kinase activity.
PTEN ProteinP60484 (Uniprot-TrEMBL)
PTEN mRNA ProteinENST00000371953 (ENSEMBL)
PTEN mRNA:miR-26A RISCComplexR-HSA-2318750 (Reactome)
PTEN mRNARnaENST00000371953 (ENSEMBL)
PTEN:Mg2+ComplexR-HSA-199426 (Reactome)
Phospho-Forkhead box

transcription

factor		R-HSA-199269 (Reactome)
PiMetaboliteCHEBI:18367 (ChEBI)
RICTOR ProteinQ6R327 (Uniprot-TrEMBL)
RPS6KB2ProteinQ9UBS0 (Uniprot-TrEMBL)
Signaling by EGFRPathwayR-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 ERBB2PathwayR-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 ERBB4PathwayR-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 FGFRPathwayR-HSA-190236 (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 PDGFPathwayR-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-KITPathwayR-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 the B Cell Receptor (BCR)PathwayR-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).
Signalling by NGFPathwayR-HSA-166520 (Reactome) Neurotrophins (NGF, BDNF, NT-3, NT-4/5) play pivotal roles in survival, differentiation, and plasticity of neurons in the peripheral and central nervous system. They are produced, and secreted in minute amounts, by a variety of tissues. They signal through two types of receptors: TRK tyrosine kinase receptors (TRKA, TRKB, TRKC), which specifically interact with the different neurotrophins, and p75NTR, which interacts with all neurotrophins. TRK receptors are reported in a variety of tissues in addition to neurons. p75NTRs are also widespread.


Neurotrophins and their receptors are synthesized as several different splice variants, which differ in terms of their biological activities. The nerve growth factor (NGF) was the first growth factor to be identified and has served as a model for studying the mechanisms of action of neurotrophins and growth factors. The mechanisms by which NGF generates diverse cellular responses have been studied extensively in the rat pheochromocytoma cell line PC12. When exposed to NGF, PC12 cells exit the cell cycle and differentiate into sympathetic neuron-like cells. Current data show that signalling by the other neurotrophins is similar to NGF signalling.
THEM4 ProteinQ5T1C6 (Uniprot-TrEMBL)
THEM4/TRIB3R-HSA-2400007 (Reactome)
TNRC6A ProteinQ8NDV7 (Uniprot-TrEMBL)
TNRC6B ProteinQ9UPQ9 (Uniprot-TrEMBL)
TNRC6C ProteinQ9HCJ0 (Uniprot-TrEMBL)
TORC2 complexComplexR-HSA-198626 (Reactome)
TRIB3 ProteinQ96RU7 (Uniprot-TrEMBL)
TSC2ProteinP49815 (Uniprot-TrEMBL)
Triciribine MetaboliteCHEBI:65310 (ChEBI)
miR-26A RISCR-HSA-2318737 (Reactome)
miR-26A1 ProteinMI0000083 (miRBase)
miR-26A2 ProteinMI0000750 (miRBase)
p-S-AKT:PDPK1:PIP3ComplexR-HSA-2317313 (Reactome)
p-S-AKT:PIP3ComplexR-HSA-2317310 (Reactome)
p-S133-CREB1ProteinP16220 (Uniprot-TrEMBL)
p-S15,S356-RPS6KB2ProteinQ9UBS0 (Uniprot-TrEMBL)
p-S166,S188-MDM2ProteinQ00987 (Uniprot-TrEMBL)
p-S183,T246-AKT1S1ProteinQ96B36 (Uniprot-TrEMBL)
p-S196-CASP9(1-416)ProteinP55211 (Uniprot-TrEMBL) any remaining instances associated here should be reassociated with the complex Cleaved Caspase-9
p-S351-NR4A1ProteinP22736 (Uniprot-TrEMBL)
p-S473-AKT1 E17K mutant:PIP2ComplexR-HSA-2243943 (Reactome)
p-S473-AKT1 E17K ProteinP31749 (Uniprot-TrEMBL)
p-S9/21-GSK3R-HSA-198373 (Reactome)
p-S939,T1462-TSC2ProteinP49815 (Uniprot-TrEMBL)
p-S99-BADProteinQ92934 (Uniprot-TrEMBL)
p-T-AKTR-HSA-202084 (Reactome)
p-T-CDKN1A/BR-HSA-198605 (Reactome)
p-T23-CHUKProteinO15111 (Uniprot-TrEMBL)
p-T308,S473-AKT1 E17KProteinP31749 (Uniprot-TrEMBL)
perifosine MetaboliteCHEBI:428891 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-198270 (Reactome)
ADPArrowR-HSA-198347 (Reactome)
ADPArrowR-HSA-198371 (Reactome)
ADPArrowR-HSA-198599 (Reactome)
ADPArrowR-HSA-198609 (Reactome)
ADPArrowR-HSA-198611 (Reactome)
ADPArrowR-HSA-198613 (Reactome)
ADPArrowR-HSA-198621 (Reactome)
ADPArrowR-HSA-198640 (Reactome)
ADPArrowR-HSA-199298 (Reactome)
ADPArrowR-HSA-199299 (Reactome)
ADPArrowR-HSA-199839 (Reactome)
ADPArrowR-HSA-199863 (Reactome)
ADPArrowR-HSA-200143 (Reactome)
ADPArrowR-HSA-2243938 (Reactome)
ADPArrowR-HSA-2243942 (Reactome)
ADPArrowR-HSA-2316434 (Reactome)
AKT inhibitors:AKTArrowR-HSA-2400010 (Reactome)
AKT inhibitorsR-HSA-2400010 (Reactome)
AKT/AKT1 E17K mutantR-HSA-2400010 (Reactome)
AKT1 E17K mutant:PIP2ArrowR-HSA-2219536 (Reactome)
AKT1 E17K mutant:PIP2R-HSA-2243938 (Reactome)
AKT1 E17KR-HSA-2219536 (Reactome)
AKT1S1R-HSA-200143 (Reactome)
AKT:PIP3:THEM4/TRIB3ArrowR-HSA-199443 (Reactome)
AKT:PIP3:THEM4/TRIB3TBarR-HSA-198640 (Reactome)
AKT:PIP3ArrowR-HSA-2317332 (Reactome)
AKT:PIP3R-HSA-198640 (Reactome)
AKT:PIP3R-HSA-199443 (Reactome)
AKTR-HSA-2317332 (Reactome)
ATPR-HSA-198270 (Reactome)
ATPR-HSA-198347 (Reactome)
ATPR-HSA-198371 (Reactome)
ATPR-HSA-198599 (Reactome)
ATPR-HSA-198609 (Reactome)
ATPR-HSA-198611 (Reactome)
ATPR-HSA-198613 (Reactome)
ATPR-HSA-198621 (Reactome)
ATPR-HSA-198640 (Reactome)
ATPR-HSA-199298 (Reactome)
ATPR-HSA-199299 (Reactome)
ATPR-HSA-199839 (Reactome)
ATPR-HSA-199863 (Reactome)
ATPR-HSA-200143 (Reactome)
ATPR-HSA-2243938 (Reactome)
ATPR-HSA-2243942 (Reactome)
ATPR-HSA-2316434 (Reactome)
Activator:PI3Kmim-catalysisR-HSA-2316434 (Reactome)
Active AKTArrowR-HSA-198270 (Reactome)
Active AKTArrowR-HSA-198298 (Reactome)
Active AKTR-HSA-198298 (Reactome)
Active AKTR-HSA-199425 (Reactome)
Active AKTmim-catalysisR-HSA-198347 (Reactome)
Active AKTmim-catalysisR-HSA-198371 (Reactome)
Active AKTmim-catalysisR-HSA-198599 (Reactome)
Active AKTmim-catalysisR-HSA-198609 (Reactome)
Active AKTmim-catalysisR-HSA-198611 (Reactome)
Active AKTmim-catalysisR-HSA-198613 (Reactome)
Active AKTmim-catalysisR-HSA-198621 (Reactome)
Active AKTmim-catalysisR-HSA-199298 (Reactome)
Active AKTmim-catalysisR-HSA-199299 (Reactome)
Active AKTmim-catalysisR-HSA-199839 (Reactome)
Active AKTmim-catalysisR-HSA-199863 (Reactome)
Active AKTmim-catalysisR-HSA-200143 (Reactome)
BADR-HSA-198347 (Reactome)
CASP9(1-416)R-HSA-198621 (Reactome)
CDKN1A/BR-HSA-198613 (Reactome)
CREB1R-HSA-199298 (Reactome)
Forkhead box

transcription

factor		R-HSA-199299 (Reactome)
GSK3R-HSA-198371 (Reactome)
H2OR-HSA-199425 (Reactome)
H2OR-HSA-199456 (Reactome)
IKKAR-HSA-198611 (Reactome)
MDM2R-HSA-198599 (Reactome)
NR4A1R-HSA-199863 (Reactome)
PDPK1:PIP2ArrowR-HSA-2219524 (Reactome)
PDPK1:PIP2ArrowR-HSA-2243942 (Reactome)
PDPK1:PIP2R-HSA-2243937 (Reactome)
PDPK1:PIP3ArrowR-HSA-198270 (Reactome)
PDPK1:PIP3ArrowR-HSA-2316429 (Reactome)
PDPK1:PIP3R-HSA-2317314 (Reactome)
PDPK1:p-S473-AKT1 E17K mutant:PIP2ArrowR-HSA-2243937 (Reactome)
PDPK1:p-S473-AKT1 E17K mutant:PIP2R-HSA-2243942 (Reactome)
PDPK1:p-S473-AKT1 E17K mutant:PIP2mim-catalysisR-HSA-2243942 (Reactome)
PDPK1R-HSA-2219524 (Reactome)
PDPK1R-HSA-2316429 (Reactome)
PHLPP (Mn2+ cofactor)mim-catalysisR-HSA-199425 (Reactome)
PI(3,4,5)P3ArrowR-HSA-2316434 (Reactome)
PI(3,4,5)P3R-HSA-199456 (Reactome)
PI(3,4,5)P3R-HSA-2316429 (Reactome)
PI(3,4,5)P3R-HSA-2317332 (Reactome)
PI(4,5)P2ArrowR-HSA-199456 (Reactome)
PI(4,5)P2R-HSA-2219524 (Reactome)
PI(4,5)P2R-HSA-2219536 (Reactome)
PI(4,5)P2R-HSA-2316434 (Reactome)
PI3K mutants,Activator:PI3KR-HSA-2400009 (Reactome)
PI3K Inhibitors:PI3KArrowR-HSA-2400009 (Reactome)
PI3K inhibitorsR-HSA-2400009 (Reactome)
PTEN mRNA:miR-26A RISCArrowR-HSA-2318752 (Reactome)
PTEN mRNA:miR-26A RISCTBarR-HSA-2321904 (Reactome)
PTEN mRNAR-HSA-2318752 (Reactome)
PTEN mRNAR-HSA-2321904 (Reactome)
PTEN:Mg2+ArrowR-HSA-2321904 (Reactome)
PTEN:Mg2+mim-catalysisR-HSA-199456 (Reactome)
Phospho-Forkhead box

transcription

factor		ArrowR-HSA-199299 (Reactome)
PiArrowR-HSA-199425 (Reactome)
PiArrowR-HSA-199456 (Reactome)
R-HSA-198270 (Reactome) Once AKT is localized at the plasma membrane, it is phosphorylated at two critical residues for its full activation. These residues are a threonine (T308 in AKT1) in the activation loop within the catalytic domain, and a serine (S473 in AKT1), in a hydrophobic motif (HM) within the carboxy terminal, non-catalytic region. PDPK1 (PDK1) is the activation loop kinase; this kinase can also directly phosphorylate p70S6K. The HM kinase, previously termed PDK2, has been identified as the mammalian TOR (Target Of Rapamycin; Sarbassov et al., 2005) but several other kinases are also able to phosphorylate AKT at S473. Phosphorylation of AKT at S473 by TORC2 complex is a prerequisite for PDPK1-mediated phosphorylation of AKT threonine T308 (Scheid et al. 2002, Sarabassov et al. 2005).
R-HSA-198298 (Reactome) AKT, phosphorylated at threonine (AKT1 308; AKT2 309; AKT3 305) and serine (AKT1 473; AKT2 474; AKT3 472) translocates to the nucleus, reaching a maximum after 15 min and returning to a basal level after 45 min of NGF stimulation. Control of the amount of nuclear AKT is achieved through the action of the phosphatase PP2A.
R-HSA-198347 (Reactome) Activated AKT phosphorylates the BCL-2 family member BAD at serine 99 (corresponds to serine residue S136 of mouse Bad), blocking the BAD-induced cell death (Datta et al. 1997, del Peso et al. 1997, Khor et al. 2004).
R-HSA-198371 (Reactome) GSK3 (glycogen synthase kinase-3) participates in the Wnt signaling pathway. It is implicated in the hormonal control of several regulatory proteins including glycogen synthase, and the transcription factors MYB and JUN. GSK3 phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. GSK3 is inhibited when phosphorylated by AKT1.
R-HSA-198599 (Reactome) AKT phosphorylates MDM2 on two serine residues, at positions 166 and 188 (Feng et al. 2004, Milne et al. 2004). AKT-mediated phosphorylation of ubiquitin-protein ligase E3 MDM2 promotes nuclear localization and inhibits interaction between MDM2 and p19ARF, thereby decreasing p53 stability. This leads to a decreased expression of p53 target genes, such as BAX, that promote apoptosis (Zhou et al. 2001).
R-HSA-198609 (Reactome) AKT phosphorylates and inhibits TSC2 (tuberin), a suppressor of the TOR kinase pathway, which senses nutrient levels in the environment. TSC2 forms a TSC1:TSC2 protein complex that is a GAP (GTPase activating protein) for the RHEB G-protein. RHEB, in turn, activates the TOR kinase. Thus, an active AKT1 activates the TOR kinase, both of which are positive signals for cell growth (an increase in cell mass) and division.
The TOR kinase regulates two major processes: translation of selected mRNAs in the cell and autophagy. In the presence of high nutrient levels TOR is active and phosphorylates the 4EBP protein releasing the eukaryotic initiation factor 4E (eIF4E), which is essential for cap-dependent initiation of translation and promoting growth of the cell (PMID: 15314020). TOR also phosphorylates the S6 kinase, which is implicated in ribosome biogenesis as well as in the modification of the S6 ribosomal protein. AKT can also activate mTOR by another mechanism, involving phosphorylation of PRAS40, an inhibitor of mTOR activity.
R-HSA-198611 (Reactome) AKT mediates IKKalpha (Inhibitor of nuclear factor kappa B kinase subunit alpha) phosphorylation at threonine 23, which is required for NF-kB activation. NF-kB promoted gene transcription enhances neuronal survival.
R-HSA-198613 (Reactome) Phosphorylation of p27Kip1 at T157 and of p21Cip1 at T145 by AKT leads to their retention in the cytoplasm, segregating these cyclin-dependent kinase (CDK) inhibitors from cyclin-CDK complexes.
R-HSA-198621 (Reactome) AKT can phosphorylate the apoptotic protease caspase-9, inhibiting it.
R-HSA-198640 (Reactome) Under conditions of growth and mitogen stimulation S473 phosphorylation of AKT is carried out by mTOR (mammalian Target of Rapamycin). This kinase is found in two structurally and functionally distinct protein complexes, named TOR complex 1 (TORC1) and TOR complex 2 (TORC2). It is TORC2 complex, which is composed of mTOR, RICTOR, SIN1 (also named MAPKAP1) and LST8, that phosphorylates AKT at S473 (Sarbassov et al., 2005). This complex also regulates actin cytoskeletal reorganization (Jacinto et al., 2004; Sarbassov et al., 2004). TORC1, on the other hand, is a major regulator of ribosomal biogenesis and protein synthesis (Hay and Sonenberg, 2004). TORC1 regulates these processes largely by the phosphorylation/inactivation of the repressors of mRNA translation 4E binding proteins (4E BPs) and by the phosphorylation/activation of ribosomal S6 kinase (S6K1). TORC1 is also the principal regulator of autophagy. In other physiological conditions, other kinases may be responsible for AKT S473 phosphorylation.
Phosphorylation of AKT on S473 by TORC2 complex is a prerequisite for AKT phosphorylation on T308 by PDPK1 (Scheid et al. 2002, Sarabassov et al. 2005).
R-HSA-199298 (Reactome) AKT phosphorylates CREB (cAMP response element-binding protein) at serine 133 and activates gene expression via a CREB-dependent mechanism, thus promoting cell survival.
R-HSA-199299 (Reactome) Cell survival and growth are also promoted by AKT phosphorylation of Forkhead box (FOX) transcription factors, most notably FoxO1, FoxO3a and FoxO4. Once phosphorylated by AKT, these factors are removed from the nucleus, associate with 14-3-3 proteins, and are retained in the cytoplasm, thus producing a change in their transcriptional activity. For instance, unphosphorylated FoxO3a in the nucleus triggers apoptosis, most likely by inducing the expression of critical genes, such as the Fas ligand gene. In another example, AKT phosphorylation of FOXO4 prevents FOXO4-mediated upregulation of p27Kip1.
R-HSA-199425 (Reactome) The PH domain leucine-rich repeat-containing protein phosphatases, PHLPP1 (Gao et al. 2005) and PHLPP2 (Brognard et al. 2007) can specifically dephosphorylate the serine residue and inactivate AKT.
R-HSA-199443 (Reactome) The phosphorylation of membrane-recruited AKT at threonine and serine can be inhibited by direct binding of two different proteins, C-terminal modulator protein (THEM4 i.e. CTMP), which binds to the carboxy-terminal tail of AKT (Maira et al. 2001), or Tribbles homolog 3 (TRIB3), which binds to the catalytic domain of AKT (Du et al. 2003).
R-HSA-199456 (Reactome) The PI3K network is negatively regulated by phospholipid phosphatases that dephosphorylate PIP3, thus hampering AKT activation (Maehema et al. 1998). The tumour suppressor PTEN is the primary phospholipid phosphatase. The role of other phosphoinositide phosphatases (INPP5D, INPPL1, INPP5K, PTPRQ, INPP4B) in the negative regulation of PI3K/AKT signaling will be described in future editions of Reactome.
R-HSA-199839 (Reactome) Ribosomal protein S6 kinase beta-2 (RSK) activation is a highly conserved mitogenic response, and the activities of RSK are stimulated by multiple serine/threonine phosphorylations by different upstream kinases, one of which is AKT.
R-HSA-199863 (Reactome) AKT inhibits DNA binding of NUR77 and inhibits its pro-apoptotic function (PMID 11438550). However, the relevance of AKT for NUR77 phosphorylation has recently been questioned: according to recent work, NUR77 is phosphorylated by RSK (and MSK) rather than by AKT (PMID 16223362).
R-HSA-200143 (Reactome) PRAS40 (proline-rich Akt/PKB substrate 40 kDa) is a substrate of AKT, the phosphorylation of which leads to the binding of this protein to 14-3-3. PRAS40 binds to mTOR complexes, mediating AKT signals to mTOR. Interaction of PRAS40 with the mTOR kinase domain is induced under conditions that inhibit mTOR signalling, such as growth factor deprivation. Binding of PRAS40 inhibits mTOR. PRAS40 phosphorylation by AKT and association with the cytosolic anchor protein 14-3-3, lead to mTOR stimulation (Vander Haar E, et al, 2007). Although it was originally identified in the context of insulin signalling, it was later shown that PRAS40 may also play a role in nerve growth factor-mediated neuroprotection (Saito A, et al, 2004).
R-HSA-2219524 (Reactome) PDPK1 (PDK1) possesses low affinity for PIP2, so small amounts of PDPK1 are always present at the membrane, in the absence of PI3K activity (Currie et al. 1999).
R-HSA-2219536 (Reactome) Substitution of glutamic acid with lysine at position 17 of AKT1 results in constitutive plasma membrane localization of AKT1, independent of PI3K activity and PIP3 generation (Carpten et al. 2007). This constitutive plasma membrane targeting of AKT1 E17K mutant is due to an increased affinity for PIP2 (Landgraf et al. 2008).
R-HSA-2243937 (Reactome) A portion of PDPK1 (PDK1) is anchored to the plasma membrane in the absence of PI3K activity through PIP2 binding (Currie et al. 1999). This PIP2-bound PDPK1 is able to bind and phosphorylate PIP2-bound AKT E17K mutants (Carpten et al. 2007, Landgraf et al. 2008) phosphorylated on serine residue S473.
R-HSA-2243938 (Reactome) PIP2-binding AKT1 E17K mutants are anchored to the plasma membrane in the absence of PI3K activity and are constitutively phosphorylated on serine S473, presumably by the TORC2 complex (Carpten et al. 2007, Landgraf et al. 2008).
R-HSA-2243942 (Reactome) PIP2-bound AKT1 E17K mutant is constitutively phosphorylated on threonine residue T308 (Carpten et al. 2007, Landgraf et al. 2008), presumably by PIP2-bound PDPK1 (Currie et al. 1999).
R-HSA-2316429 (Reactome) PIP3 generated by PI3K recruits phosphatidylinositide-dependent protein kinase 1 (PDPK1 i.e. PDK1) to the membrane, through its PH (pleckstrin-homology) domain. PDPK1 binds PIP3 with high affinity, and also shows low affinity for PIP2 (Currie et al. 1999).
R-HSA-2316434 (Reactome) A number of different extracellular signals converge on PI3K activation. PI3K can be activated downstream of receptor tyrosine kinases (RTKs) such as FGFR (Ong et al. 2001, Eswarakumar et al. 2005), KIT (Chian et al. 2001, Ronnstrand 2004, Reber et al. 2006), PDGF (Coughlin et al. 1989, Fantl et al. 1992, Heldin et al. 1998), insulin receptor IGF1R (Hadari et al. 1992, Kooijman et al. 1995), and EGFR and its family members (Rodrigues et al. 2000, Jackson et al. 2004, Kainulainen et al. 2000, Junttila et al. 2009). Other proteins, such as CD28 (Pages et al. 1996, Koyasu 2003, Kane and Weiss, 2003) and TRAT1 (Bruyns et al. 1998, Koyasu 2003, Kolsch et al. 2006), can also trigger PI3K activity.

In unstimulated cells, PI3K class IA exists as an inactive heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). Binding of the iSH2 domain of the p85 regulatory subunit to the ABD and C2 domains of the p110 catalytic subunit both stabilizes p110 and inhibits its catalytic activity. This inhibition is relieved when the SH2 domains of p85 bind phosphorylated tyrosines on activated RTKs or their adaptor proteins. Binding to membrane-associated receptors brings activated PI3K in proximity to its membrane-localized substrate, PIP2 (Mandelker et al. 2009, Burke et al. 2011).
R-HSA-2317314 (Reactome) Once phosphorylated on serine residue S473, AKT bound to PIP3 forms a complex with PIP3-bound PDPK1 i.e. PDK1 (Scheid et al. 2002, Sarabassov et al. 2005)
R-HSA-2317332 (Reactome) PIP3 generated by PI3K recruits AKT (also known as protein kinase B) to the membrane, through its PH (pleckstrin-homology) domains. The binding of PIP3 to the PH domain of AKT is the rate-limiting step in AKT activation (Scheid et al. 2002). In mammals there are three AKT isoforms (AKT1-3) encoded by three separate genes. The three isoforms share a high degree of amino acid identity and have indistinguishable substrate specificity in vitro. However, isoform-preferred substrates in vivo cannot be ruled out. The relative expression of the three isoforms differs in different mammalian tissues: AKT1 is the predominant isoform in the majority of tissues, AKT2 is the predominant isoform in insulin-responsive tissues, and AKT3 is the predominant isoform in brain and testes. All 3 isoforms are expressed in human and mouse platelets (Yin et al. 2008; O'Brien et al. 2008). Note: all data in the pathway refer to AKT1, which is the most studied.
R-HSA-2318752 (Reactome) MIR26A microRNAs, miR-26A1 and miR-26A2, transcribed from genes on chromosome 3 and 12, respectively, bind PTEN mRNA (Huse et al. 2009).

The MIR26A2 locus is frequently amplified in glioma tumors that retained one wild-type PTEN allele. The resulting miR-26A2 overexpression leads to downregulation of PTEN protein level. Overexpression of miR-26A2 was shown to enhance tumorigenesis and prevent loss of heterozigosity at the PTEN locus in a mouse PTEN +/- glioma model, based on a monoallelic PTEN loss (Huse et al. 2009, Kim et al. 2010).
R-HSA-2321904 (Reactome) PTEN protein synthesis is negatively regulated by microRNAs miR-26A1 and miR-26A2, which recruit the RISC complex to PTEN mRNA. Overexpression of miR-26A2, caused by genomic amplification of MIR26A2 locus on chromosome 12, is frequently observed in human brain glioma tumors possessing one wild-type PTEN allele, and is thought to contribute to tumor progression by repressing the remaining PTEN protein expression (Huse et al. 2009).
R-HSA-2400009 (Reactome) A variety of inhibitors capable of blocking the phosphoinositide kinase activity of PI3K have been developed. These inhibitors display differential selectivity and inhibit kinase activity of their substrates by distinct mechanisms. For example, the first-generation PI3K inhibitor wortmannin (Wymann et al. 1996) covalently and irreversibly binds all classes of PI3K enzymes, as well as other kinases including mTOR, at a residue critical for catalytic activity. Although wortmannin is precluded from in vivo and clinical use due to its toxicity, it has proven to be a useful tool for in vitro laboratory studies. Newer inhibitors, such as BEZ235, are currently being investigated in Phase I clinical trials. BEZ235 is a dual pan-class I PI3K/mTOR inhibitor that blocks kinase activity by binding competitively to the ATP-binding pocket of these enzymes (Serra et al. 2008, Maira et al. 2008). BGT226 (Chang et al. 2011) and XL765 (Prasad et al. 2011) also inhibits both PI3K class I enzymes and mTOR. Other inhibitors in clinical trials, such as BKM120 (Maira et al. 2012), GDC0941 (Folkes et al. 2008, Junttila et al. 2009) and XL147 (Chakrabarty et al. 2012), are specific for class I PI3Ks and exhibit no activity against mTOR. Current research aims to identify isoform-specific PI3K inhibitors. Small molecule inhibitors that selectively inhibit PIK3CA (p110alpha), e.g. PIK-75 and A66, were used to study the role of p110alpha in signaling and growth of tumor cells (Knight et al. 2006, Sun et al. 2010, Jamieson et al. 2011, Utermark et al. 2012). The PIK3CB (p110beta) specific inhibitor TGX221 has been used in in vitro models of vascular injury (Jackson et al. 2005), and the TGX221 derivative KIN-193 has been shown to block AKT activity and tumor growth in mice with p110beta activation or PTEN loss (Ni et al. 2012). CAL-101 is a PIK3CD (p110delta) specific inhibitor that is being clinically investigated as a therapeutic for lymphoid malignancies (Herman et al. 2010). It is hoped that, in the future, more specific inhibitors, such as those targeting selective PI3K isoforms, will provide optimum treatment while minimizing unwanted side effects. For a recent review, please refer to Liu et al. 2009.
R-HSA-2400010 (Reactome) AKT inhibitors bind AKT and prevent its association with the membrane, thereby blocking AKT activation (Kondapaka et al. 2003, Yap et al. 2011, Berndt et al. 2010). AKT inhibitors annotated here target all AKT isoforms (AKT1, AKT2 and AKT3). None of the annotated inhibitors are AKT E17K mutant specific and none of them have been approved for clinical use. For a recent review, please refer to Liu et al. 2009.
RPS6KB2R-HSA-199839 (Reactome)
THEM4/TRIB3R-HSA-199443 (Reactome)
TORC2 complexmim-catalysisR-HSA-198640 (Reactome)
TORC2 complexmim-catalysisR-HSA-2243938 (Reactome)
TSC2R-HSA-198609 (Reactome)
miR-26A RISCR-HSA-2318752 (Reactome)
p-S-AKT:PDPK1:PIP3ArrowR-HSA-2317314 (Reactome)
p-S-AKT:PDPK1:PIP3R-HSA-198270 (Reactome)
p-S-AKT:PDPK1:PIP3mim-catalysisR-HSA-198270 (Reactome)
p-S-AKT:PIP3ArrowR-HSA-198640 (Reactome)
p-S-AKT:PIP3R-HSA-2317314 (Reactome)
p-S133-CREB1ArrowR-HSA-199298 (Reactome)
p-S15,S356-RPS6KB2ArrowR-HSA-199839 (Reactome)
p-S166,S188-MDM2ArrowR-HSA-198599 (Reactome)
p-S183,T246-AKT1S1ArrowR-HSA-200143 (Reactome)
p-S196-CASP9(1-416)ArrowR-HSA-198621 (Reactome)
p-S351-NR4A1ArrowR-HSA-199863 (Reactome)
p-S473-AKT1 E17K mutant:PIP2ArrowR-HSA-2243938 (Reactome)
p-S473-AKT1 E17K mutant:PIP2R-HSA-2243937 (Reactome)
p-S9/21-GSK3ArrowR-HSA-198371 (Reactome)
p-S939,T1462-TSC2ArrowR-HSA-198609 (Reactome)
p-S99-BADArrowR-HSA-198347 (Reactome)
p-T-AKTArrowR-HSA-199425 (Reactome)
p-T-CDKN1A/BArrowR-HSA-198613 (Reactome)
p-T23-CHUKArrowR-HSA-198611 (Reactome)
p-T308,S473-AKT1 E17KArrowR-HSA-2243942 (Reactome)
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