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).
View original pathway at Reactome.
Amoui M, Craddock BP, Miller WT.; ''Differential phosphorylation of IRS-1 by insulin and insulin-like growth factor I receptors in Chinese hamster ovary cells.''; PubMedEurope PMCScholia
Germain-Lee EL, Janicot M, Lammers R, Ullrich A, Casella SJ.; ''Expression of a type I insulin-like growth factor receptor with low affinity for insulin-like growth factor II.''; PubMedEurope PMCScholia
Steele-Perkins G, Turner J, Edman JC, Hari J, Pierce SB, Stover C, Rutter WJ, Roth RA.; ''Expression and characterization of a functional human insulin-like growth factor I receptor.''; PubMedEurope PMCScholia
LeBon TR, Jacobs S, Cuatrecasas P, Kathuria S, Fujita-Yamaguchi Y.; ''Purification of insulin-like growth factor I receptor from human placental membranes.''; PubMedEurope PMCScholia
Cuevas EP, Escribano O, Chiloeches A, Ramirez Rubio S, Román ID, Fernández-Moreno MD, Guijarro LG.; ''Role of insulin receptor substrate-4 in IGF-I-stimulated HEPG2 proliferation.''; PubMedEurope PMCScholia
Maki RG.; ''Small is beautiful: insulin-like growth factors and their role in growth, development, and cancer.''; PubMedEurope PMCScholia
Keyhanfar M, Booker GW, Whittaker J, Wallace JC, Forbes BE.; ''Precise mapping of an IGF-I-binding site on the IGF-1R.''; PubMedEurope PMCScholia
Alvino CL, McNeil KA, Ong SC, Delaine C, Booker GW, Wallace JC, Whittaker J, Forbes BE.; ''A novel approach to identify two distinct receptor binding surfaces of insulin-like growth factor II.''; PubMedEurope PMCScholia
Maly P, Lüthi C.; ''Characterization of affinity-purified type I insulin-like growth factor receptor from human placenta.''; PubMedEurope PMCScholia
Rakatzi I, Stosik M, Gromke T, Siddle K, Eckel J.; ''Differential phosphorylation of IRS-1 and IRS-2 by insulin and IGF-I receptors.''; PubMedEurope PMCScholia
Karas M, Koval AP, Zick Y, LeRoith D.; ''The insulin-like growth factor I receptor-induced interaction of insulin receptor substrate-4 and Crk-II.''; PubMedEurope PMCScholia
Stenkula KG, Thorn H, Franck N, Hallin E, Sauma L, Nystrom FH, Strålfors P.; ''Human, but not rat, IRS1 targets to the plasma membrane in both human and rat adipocytes.''; PubMedEurope PMCScholia
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA.; ''Mutations of the BRAF gene in human cancer.''; PubMedEurope PMCScholia
Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMedEurope PMCScholia
Fukumoto T, Kubota Y, Kitanaka A, Yamaoka G, Ohara-Waki F, Imataki O, Ohnishi H, Ishida T, Tanaka T.; ''Gab1 transduces PI3K-mediated erythropoietin signals to the Erk pathway and regulates erythropoietin-dependent proliferation and survival of erythroid cells.''; PubMedEurope PMCScholia
Boriack-Sjodin PA, Margarit SM, Bar-Sagi D, Kuriyan J.; ''The structural basis of the activation of Ras by Sos.''; PubMedEurope PMCScholia
Parrella E, Longo VD.; ''Insulin/IGF-I and related signaling pathways regulate aging in nondividing cells: from yeast to the mammalian brain.''; PubMedEurope PMCScholia
Giorgetti S, Pelicci PG, Pelicci G, Van Obberghen E.; ''Involvement of Src-homology/collagen (SHC) proteins in signaling through the insulin receptor and the insulin-like-growth-factor-I-receptor.''; PubMedEurope PMCScholia
Okada S, Pessin JE.; ''Interactions between Src homology (SH) 2/SH3 adapter proteins and the guanylnucleotide exchange factor SOS are differentially regulated by insulin and epidermal growth factor.''; PubMedEurope PMCScholia
Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMedEurope PMCScholia
Casella SJ, Han VK, D'Ercole AJ, Svoboda ME, Van Wyk JJ.; ''Insulin-like growth factor II binding to the type I somatomedin receptor. Evidence for two high affinity binding sites.''; PubMedEurope PMCScholia
Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMedEurope PMCScholia
Xu B, Bird VG, Miller WT.; ''Substrate specificities of the insulin and insulin-like growth factor 1 receptor tyrosine kinase catalytic domains.''; PubMedEurope PMCScholia
Tartare-Deckert S, Sawka-Verhelle D, Murdaca J, Van Obberghen E.; ''Evidence for a differential interaction of SHC and the insulin receptor substrate-1 (IRS-1) with the insulin-like growth factor-I (IGF-I) receptor in the yeast two-hybrid system.''; PubMedEurope PMCScholia
Kim B, Leventhal PS, White MF, Feldman EL.; ''Differential regulation of insulin receptor substrate-2 and mitogen-activated protein kinase tyrosine phosphorylation by phosphatidylinositol 3-kinase inhibitors in SH-SY5Y human neuroblastoma cells.''; PubMedEurope PMCScholia
Ward CW, Gough KH, Rashke M, Wan SS, Tribbick G, Wang J.; ''Systematic mapping of potential binding sites for Shc and Grb2 SH2 domains on insulin receptor substrate-1 and the receptors for insulin, epidermal growth factor, platelet-derived growth factor, and fibroblast growth factor.''; PubMedEurope PMCScholia
Skolnik EY, Batzer A, Li N, Lee CH, Lowenstein E, Mohammadi M, Margolis B, Schlessinger J.; ''The function of GRB2 in linking the insulin receptor to Ras signaling pathways.''; PubMedEurope PMCScholia
Karlsson M, Thorn H, Danielsson A, Stenkula KG, Ost A, Gustavsson J, Nystrom FH, Strålfors P.; ''Colocalization of insulin receptor and insulin receptor substrate-1 to caveolae in primary human adipocytes. Cholesterol depletion blocks insulin signalling for metabolic and mitogenic control.''; PubMedEurope PMCScholia
Fantin VR, Sparling JD, Slot JW, Keller SR, Lienhard GE, Lavan BE.; ''Characterization of insulin receptor substrate 4 in human embryonic kidney 293 cells.''; PubMedEurope PMCScholia
Zoncu R, Efeyan A, Sabatini DM.; ''mTOR: from growth signal integration to cancer, diabetes and ageing.''; PubMedEurope PMCScholia
Cascieri MA, Chicchi GG, Applebaum J, Hayes NS, Green BG, Bayne ML.; ''Mutants of human insulin-like growth factor I with reduced affinity for the type 1 insulin-like growth factor receptor.''; PubMedEurope PMCScholia
Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMedEurope PMCScholia
McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMedEurope PMCScholia
Craparo A, O'Neill TJ, Gustafson TA.; ''Non-SH2 domains within insulin receptor substrate-1 and SHC mediate their phosphotyrosine-dependent interaction with the NPEY motif of the insulin-like growth factor I receptor.''; PubMedEurope PMCScholia
Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMedEurope PMCScholia
Chardin P, Camonis JH, Gale NW, van Aelst L, Schlessinger J, Wigler MH, Bar-Sagi D.; ''Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2.''; PubMedEurope PMCScholia
Schreyer S, Ledwig D, Rakatzi I, Klöting I, Eckel J.; ''Insulin receptor substrate-4 is expressed in muscle tissue without acting as a substrate for the insulin receptor.''; PubMedEurope PMCScholia
Pavelić J, Matijević T, Knezević J.; ''Biological & physiological aspects of action of insulin-like growth factor peptide family.''; PubMedEurope PMCScholia
Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMedEurope PMCScholia
Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMedEurope PMCScholia
Yu KT, Peters MA, Czech MP.; ''Similar control mechanisms regulate the insulin and type I insulin-like growth factor receptor kinases. Affinity-purified insulin-like growth factor I receptor kinase is activated by tyrosine phosphorylation of its beta subunit.''; PubMedEurope PMCScholia
He W, O'Neill TJ, Gustafson TA.; ''Distinct modes of interaction of SHC and insulin receptor substrate-1 with the insulin receptor NPEY region via non-SH2 domains.''; PubMedEurope PMCScholia
Hernández-Sánchez C, Blakesley V, Kalebic T, Helman L, LeRoith D.; ''The role of the tyrosine kinase domain of the insulin-like growth factor-I receptor in intracellular signaling, cellular proliferation, and tumorigenesis.''; PubMedEurope PMCScholia
Ravichandran LV, Esposito DL, Chen J, Quon MJ.; ''Protein kinase C-zeta phosphorylates insulin receptor substrate-1 and impairs its ability to activate phosphatidylinositol 3-kinase in response to insulin.''; PubMedEurope PMCScholia
Takahashi Y, Tobe K, Kadowaki H, Katsumata D, Fukushima Y, Yazaki Y, Akanuma Y, Kadowaki T.; ''Roles of insulin receptor substrate-1 and Shc on insulin-like growth factor I receptor signaling in early passages of cultured human fibroblasts.''; PubMedEurope PMCScholia
Siddle K.; ''Molecular basis of signaling specificity of insulin and IGF receptors: neglected corners and recent advances.''; PubMedEurope PMCScholia
Alvino CL, Ong SC, McNeil KA, Delaine C, Booker GW, Wallace JC, Forbes BE.; ''Understanding the mechanism of insulin and insulin-like growth factor (IGF) receptor activation by IGF-II.''; PubMedEurope PMCScholia
Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMedEurope PMCScholia
Bürgisser DM, Roth BV, Giger R, Lüthi C, Weigl S, Zarn J, Humbel RE.; ''Mutants of human insulin-like growth factor II with altered affinities for the type 1 and type 2 insulin-like growth factor receptor.''; PubMedEurope PMCScholia
He W, Craparo A, Zhu Y, O'Neill TJ, Wang LM, Pierce JH, Gustafson TA.; ''Interaction of insulin receptor substrate-2 (IRS-2) with the insulin and insulin-like growth factor I receptors. Evidence for two distinct phosphotyrosine-dependent interaction domains within IRS-2.''; PubMedEurope PMCScholia
Huang M, Lai WP, Wong MS, Yang M.; ''Effect of receptor phosphorylation on the binding between IRS-1 and IGF-1R as revealed by surface plasmon resonance biosensor.''; PubMedEurope PMCScholia
Kim B, van Golen CM, Feldman EL.; ''Insulin-like growth factor-I signaling in human neuroblastoma cells.''; PubMedEurope PMCScholia
Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMedEurope PMCScholia
Chitnis MM, Yuen JS, Protheroe AS, Pollak M, Macaulay VM.; ''The type 1 insulin-like growth factor receptor pathway.''; PubMedEurope PMCScholia
Duronio V.; ''Insulin receptor is phosphorylated in response to treatment of HepG2 cells with insulin-like growth factor I.''; PubMedEurope PMCScholia
Kim B, Cheng HL, Margolis B, Feldman EL.; ''Insulin receptor substrate 2 and Shc play different roles in insulin-like growth factor I signaling.''; PubMedEurope PMCScholia
Qu BH, Karas M, Koval A, LeRoith D.; ''Insulin receptor substrate-4 enhances insulin-like growth factor-I-induced cell proliferation.''; PubMedEurope PMCScholia
Siemeister G, al-Hasani H, Klein HW, Kellner S, Streicher R, Krone W, Müller-Wieland D.; ''Recombinant human insulin receptor substrate-1 protein. Tyrosine phosphorylation and in vitro binding of insulin receptor kinase.''; PubMedEurope PMCScholia
Target of rapamycin (mTOR) is a highly-conserved serine/threonine kinase that regulates cell growth and division in response to energy levels, growth signals, and nutrients (Zoncu et al. 2011). Control of mTOR activity is critical for the cell since its dysregulation leads to cancer, metabolic disease, and diabetes (Laplante & Sabatini 2012). In cells, mTOR exists as two structurally distinct complexes termed mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), each one with specificity for different sets of effectors. mTORC1 couples energy and nutrient abundance to cell growth and proliferation by balancing anabolic (protein synthesis and nutrient storage) and catabolic (autophagy and utilization of energy stores) processes.
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).
SOS promotes the formation of GTP-bound RAS, thus activating this protein. RAS activation results in activation of the protein kinases RAF1, B-Raf, and MAP-ERK kinase kinase (MEKK), and the catalytic subunit of PI3K, as well as of a series of RALGEFs. The activation cycle of RAS GTPases is regulated by their interaction with specific guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). GEFs promote activation by inducing the release of GDP, whereas GAPs inactivate RAS-like proteins by stimulating their intrinsic GTPase activity. NGF-induced RAS activation via SHC-GRB2-SOS is maximal at 2 min but it is no longer detected after 5 min. Therefore, the transient activation of RAS obtained through SHC-GRB2-SOS is insufficient for the prolonged activation of ERKs found in NGF-treated cells.
The phosphorylated IGF1R phosphorylates SHC1 (Giorgetti et al. 1994, Hernandez-Sanchez et al. 1995, Kim et al. 1998). Phosphorylation of SHC1 is sustained whereas phosphorylation of IRS2 by IGF1R is transient (Kim et al. 1998).
SHC binds the NPEY-juxtamembrane motif of the phosphorylated insulin-like growth factor receptor (IGF1R) (Giorgetti et al. 1994, Tartare-Deckert et al. 1995).
The beta peptide of the type 1 insulin-like growth factor (IGF1R) spans the plasma membrane and trans-autophosphorylates tyrosine residues in response to binding of either IGF1 or IGF2 by the extracellular alpha peptide (LeBon et al. 1986, Yu et al. 1986, Doronio et al. 1990, Hernandez-Sanchez et al. 1995, Alvino et al. 2001).
Either IGF1 (IGF-I) or IGF2 (IGF-II) can bind the type 1 insulin-like growth factor receptor (IGF1R) (Casella et al. 1986, LeBon et al. 1986, Maly and Luthi 1986, Cacieri et al. 1988, Steele-Perkins et al. 1988, Burgisser et al. 1991, Germain-Lee et al. 1992, Keyhanfar et al. 2007, Alvino et al. 2009, Alvino et al. 2011). IGF1R has similar affinities for IGF1 and IGF2 (Casella et al. 1986, Steele-Perkins et al. 1988). The binding sites for IGF1 and IGF2 are in a similar location on the alpha peptide of IGF1R but there are some differences in which residues of IGF1R interact with IGF1 vs. IGF2 (Keyhanfar et al. 2007, Alvino et al. 2009, Alvino et al. 2011).
IRS2 binds the NPEY-juxtamembrane motif of phosphorylated IGF1R (He et al. 1996, Kim et al. 1998). IRS2 is cytosolic while IRS1 and IRS4 are located in the plasma membrane.
Phosphorylated IGF1R phosphorylates IRS1 (Siemeister et al. 1995, Xu et al. 1995, Takahashi et al. 1997, Rakatzi et al. 2006), IRS2 (Kim et al. 1998, Kim et al. 2004), and IRS4 (Fantin et al.1998, Karas et al. 2001, Cuevas et al. 2007) on numerous tyrosine residues. IRS4 is phosphorylated by IGF1R in HEK cells but not in primary muscle cells (Fantin et al. 1998, Schreyer et al. 2003). The phosphotyrosine resideus create binding sites for downstream effectors such as GRB2:SOS and PI3K.
IRS1 binds the NPEY-juxtamembrane motif of phosphorylated IGF1R (Craparo et al. 1995, He et al. 1995, Huang et al. 2001). IRS4 is also involved in signaling by IGF1R and is presumed to bind phosphorylated IGF1R in the same way as IRS1 (Qu et al. 1999, Cuevas et al. 2007). IRS1 and IRS4 are located at the plasma membrane (Karlsson et al. 2004, Fantin et al. 1998).
Phosphorylated SHC1 recruits the SH2 domain of the adaptor protein GRB2, which is in a complex with SOS, an exchange factor for p21ras and RAC. Besides SOS, the GRB2 SH3 domain can associate with other intracellular targets, including GAB1. Erk and Rsk mediated phosphorylation results in dissociation of the SOS-GRB2 complex. This may explain why Erk activation through Shc and SOS-GRB2 is transient. Inactive p21ras-GDP is found anchored to the plasma membrane by a farnesyl residue. As Shc is phosphorylated by the the stimulated receptor near to the plasma membrane, the SOS-GRB2:Shc interaction brings the SOS enzyme into close proximity to p21ras.
SOS promotes the formation of GTP-bound RAS, thus activating this protein. RAS activation results in activation of the protein kinases RAF1, B-Raf, and MAP-ERK kinase kinase (MEKK), and the catalytic subunit of PI3K, as well as of a series of RALGEFs. The activation cycle of RAS GTPases is regulated by their interaction with specific guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). GEFs promote activation by inducing the release of GDP, whereas GAPs inactivate RAS-like proteins by stimulating their intrinsic GTPase activity.
Inactive p21ras:GDP is anchored to the plasma membrane by a farnesyl residue. Insulin stimulation results in phosphorylation of IRS1/2 on tyrosine residues. GRB2 binds the phosphotyrosines via its SH2 domain. As IRS is phosphorylated by the insulin receptor near to the plasma membrane, the GRB2:SOS1:IRS interaction brings SOS1 and p21 Ras into close proximity.
IRS1, IRS2 and IRS3 are all known to bind the regulatory subunit of PI3K via its SH2 domain, an interaction that itself activates the kinase activity of the PI3K catalytic subunit (Rivachandran et al. 2001).
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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).
Annotated Interactions