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 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.
Boriack-Sjodin PA, Margarit SM, Bar-Sagi D, Kuriyan J.; ''The structural basis of the activation of Ras by Sos.''; PubMedEurope PMCScholia
Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMedEurope PMCScholia
Wick KR, Werner ED, Langlais P, Ramos FJ, Dong LQ, Shoelson SE, Liu F.; ''Grb10 inhibits insulin-stimulated insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase/Akt signaling pathway by disrupting the association of IRS-1/IRS-2 with the insulin receptor.''; PubMedEurope PMCScholia
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Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMedEurope PMCScholia
Tavaré JM, Denton RM.; ''Studies on the autophosphorylation of the insulin receptor from human placenta. Analysis of the sites phosphorylated by two-dimensional peptide mapping.''; PubMedEurope PMCScholia
Cheatham B, Kahn CR.; ''Insulin action and the insulin signaling network.''; 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
Duckworth WC.; ''Insulin degradation: mechanisms, products, and significance.''; PubMedEurope PMCScholia
Drake PG, Posner BI.; ''Insulin receptor-associated protein tyrosine phosphatase(s): role in insulin action.''; PubMedEurope PMCScholia
Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMedEurope PMCScholia
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Waters SB, Yamauchi K, Pessin JE.; ''Insulin-stimulated disassociation of the SOS-Grb2 complex.''; 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
Zoncu R, Efeyan A, Sabatini DM.; ''mTOR: from growth signal integration to cancer, diabetes and ageing.''; PubMedEurope PMCScholia
Di Guglielmo GM, Drake PG, Baass PC, Authier F, Posner BI, Bergeron JJ.; ''Insulin receptor internalization and signalling.''; 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
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
Bevan AP, Drake PG, Bergeron JJ, Posner BI.; ''Intracellular signal transduction: The role of endosomes.''; 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
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
Li N, Batzer A, Daly R, Yajnik V, Skolnik E, Chardin P, Bar-Sagi D, Margolis B, Schlessinger J.; ''Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling.''; PubMedEurope PMCScholia
Duan C, Li M, Rui L.; ''SH2-B promotes insulin receptor substrate 1 (IRS1)- and IRS2-mediated activation of the phosphatidylinositol 3-kinase pathway in response to leptin.''; PubMedEurope PMCScholia
Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMedEurope PMCScholia
Liu YF, Paz K, Herschkovitz A, Alt A, Tennenbaum T, Sampson SR, Ohba M, Kuroki T, LeRoith D, Zick Y.; ''Insulin stimulates PKCzeta -mediated phosphorylation of insulin receptor substrate-1 (IRS-1). A self-attenuated mechanism to negatively regulate the function of IRS proteins.''; PubMedEurope PMCScholia
Qin A, Cheng TS, Lin Z, Pavlos NJ, Jiang Q, Xu J, Dai KR, Zheng MH.; ''Versatile roles of V-ATPases accessory subunit Ac45 in osteoclast formation and function.''; PubMedEurope PMCScholia
Ullrich A, Bell JR, Chen EY, Herrera R, Petruzzelli LM, Dull TJ, Gray A, Coussens L, Liao YC, Tsubokawa M.; ''Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes.''; PubMedEurope PMCScholia
Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMedEurope PMCScholia
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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
Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMedEurope PMCScholia
Van Obberghen E, Baron V, Delahaye L, Emanuelli B, Filippa N, Giorgetti-Peraldi S, Lebrun P, Mothe-Satney I, Peraldi P, Rocchi S, Sawka-Verhelle D, Tartare-Deckert S, Giudicelli J.; ''Surfing the insulin signaling web.''; PubMedEurope PMCScholia
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McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMedEurope PMCScholia
White MF.; ''The IRS-signalling system: a network of docking proteins that mediate insulin action.''; 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
Sasaoka T, Kobayashi M.; ''The functional significance of Shc in insulin signaling as a substrate of the insulin receptor.''; PubMedEurope PMCScholia
Bergeron JJ, Cruz J, Khan MN, Posner BI.; ''Uptake of insulin and other ligands into receptor-rich endocytic components of target cells: the endosomal apparatus.''; PubMedEurope PMCScholia
Langlais P, Dong LQ, Ramos FJ, Hu D, Li Y, Quon MJ, Liu F.; ''Negative regulation of insulin-stimulated mitogen-activated protein kinase signaling by Grb10.''; 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
Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMedEurope PMCScholia
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Xu B, Bird VG, Miller WT.; ''Substrate specificities of the insulin and insulin-like growth factor 1 receptor tyrosine kinase catalytic domains.''; PubMedEurope PMCScholia
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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
Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMedEurope PMCScholia
Sasaoka T, Ishihara H, Sawa T, Ishiki M, Morioka H, Imamura T, Usui I, Takata Y, Kobayashi M.; ''Functional importance of amino-terminal domain of Shc for interaction with insulin and epidermal growth factor receptors in phosphorylation-independent manner.''; PubMedEurope PMCScholia
The proteins mentioned here are examples of IRS family members acting as indicated for IRS. More family members are to be confirmed and added in the future.
The human insulin receptor is expressed as two isoforms that are generated by alternate splicing of its mRNA; the B isoform has 12 additional amino acids (718-729) encoded by exon 11 of the gene.
The MAP kinase cascade describes a sequence of phosphorylation events involving serine/threonine-specific protein kinases. Used by various signal transduction pathways, this cascade constitutes a common 'module' in the transmission of an extracellular signal into the nucleus.
At the beginning of this reaction, 1 molecule of 'activated insulin receptor', and 1 molecule of 'SHC transforming protein' are present. At the end of this reaction, 1 molecule of 'SHC:activated insulin receptor' is present.
This reaction takes place on the 'internal side of plasma membrane'.
The cytosolic AMPK complex is activated by phosphorylation. LKB1 phosphorylates AMPK heterotrimer on Thr174 of the alpha 1 subunit (or Thr172 on alpha 2 subunit) leading to activation of AMPK (if cellular AMP/ATP ratio is high) (Hawley SA et al, 2003; Woods A et al, 2003; Shaw RJ et al, 2004). Signals leading to this phosphorylation event can be mediated by exercise, leptin and adiponectin, the hypothalamic-sympathetic nervous system (SNS), and alpha adrenergic receptors, as demonstrated in studies of rat and human skeletal muscle (Minoksohi et al, 2002, Kahn et al, 2005). The details of AMPK activation in response to these stimuli will be annotated in the future. Nuclear AMPK may well be a substrate for LKB1 but, to date, there is no clear evidence for this.
As the endosomal lumen acidifies the insulin dissociates from the insulin receptor making it available for degradation by the insulin degrading activity (IDA) present in the endosomal membrane.
At the beginning of this reaction, 1 molecule of 'insulin' is present.
This reaction takes place in the 'endosome' and is mediated by the 'insulysin activity of IDA (insulin degrading activity' of 'IDA (insulin degrading activity)'.
At the beginning of this reaction, 1 molecule of 'phospho-SHC' is present. At the end of this reaction, 1 molecule of 'Orthophosphate', and 1 molecule of 'SHC transforming protein' are present.
This reaction takes place in the 'cytosol' and is mediated by the 'protein tyrosine phosphatase activity' of 'protein tyrosine phosphatase'.
At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'GRB2:SOS:SHC-P' are present. At the end of this reaction, 1 molecule of 'GRB2:SHC-P', 1 molecule of 'phospho-SOS', and 1 molecule of 'ADP' are present.
This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'kinase activity' of 'ERK1'.
Under normal physiological conditions blood glucose levels are kept under tight control by a series of regulated steps that ensure glucose homeostasis. Upon feeding glucose levels rise and in response to this the body secretes insulin from pancreatic beta-cells into the blood. At physiological concentrations insulin is present in the blood in its monomeric form. Binding of insulin to its receptor occurs on the receptor alpha-subunits. There are two binding domains involved on the receptor (L1 and L2) and it is thought that the amino-terminus of insulin binds with L1 on one of the alpha-subunits and the carboxyterminus with L2 on the other alpha-subunit.
The binding of insulin to its receptor causes a conformational change in the alpha-subunits. This in turn produces a conformational change in the beta-subunits leading to the activation of the intrinsic insulin receptor tyrosine kinase.
At the beginning of this reaction, 1 molecule of 'PKB:PKB Regulator', and 1 molecule of 'Phosphatidylinositol-3,4,5-trisphosphate' are present. At the end of this reaction, 1 molecule of 'PKB regulator', and 1 molecule of 'PIP3:PKB complex ' are present.
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.
At the beginning of this reaction, 4 molecules of 'ATP', and 1 molecule of 'GRB2:SOS:IRS-P' are present. At the end of this reaction, 1 molecule of 'GRB2:IRS-P', 1 molecule of 'phospho-SOS', and 4 molecules of 'ADP' are present.
This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'kinase activity' of 'ERK1'.
Tyrosine receptor kinase stimulation phosphorylates Shc which recruits the SH2 domain of the adaptor protein GRB2, which is complexed with SOS, an exchange factor for p21ras and RAC, through its SH3 domain. 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.
At the beginning of this reaction, 1 molecule of 'phospho-IRS' is present. At the end of this reaction, 1 molecule of 'Orthophosphate', and 1 molecule of 'IRS' are present.
This reaction takes place in the 'cytosol' and is mediated by the 'protein tyrosine phosphatase activity' of 'protein tyrosine phosphatase'.
At the beginning of this reaction, 2 molecules of 'ATP', and 1 molecule of 'PDE3B' are present. At the end of this reaction, 1 molecule of 'Phosphorylated PDE3B', and 2 molecules of 'ADP' are present.
This reaction is mediated by the 'kinase activity' of 'PIP3:Phosphorylated PKB complex'.
The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome. The net effect of this is to lower the pH of the lumen from pH 7.4 (the pH at the plasma membrane) to pH 6.0 (documented with studies using FITC-labeled insulin - a pH dependent fluorescence marker).
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.
At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'SHC:activated insulin receptor' are present. At the end of this reaction, 1 molecule of 'phospho-SHC: activated insulin receptor', and 1 molecule of 'ADP' are present.
This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'transmembrane receptor protein tyrosine kinase activity' of 'SHC:activated insulin receptor'.
At the beginning of this reaction, 1 molecule of 'activated insulin receptor', and 1 molecule of 'IRS' are present. At the end of this reaction, 1 molecule of 'IRS:activated insulin receptor' is present.
This reaction takes place on the 'internal side of plasma membrane'.
TSC2 (in the TSC complex) functions as a GTPase-activating protein and stimulates the intrinsic GTPase activity of a small G-protein Rheb. This results in the conversion of Rheb-GTP into Rheb-GDP and in the inhibition of the mTOR activation by GTP-bound Rheb (Inoki K et al, 2003; Tee AR et al, 2003).
If AMP:ATP ratio rises, AMP (instead of ATP) is bound by the AMPK-gamma subunit, which inhibits the dephosphorylation of the AMPK-alpha subunit resulting in activation of AMPK. It is not clear, as of yet, whether AMP binds to unphosphorylated AMPK.
Upon complex formation with STRAD and MO25, LKB1 (also known as serine/threonine kinase 11, STK11) is mostly cytosolic. LKB1 attains 20x activity towards the substrates belonging to the subfamily of AMPK-like kinases (5'AMP-activated protein kinases).
Activated AMPK (phosphorylated on the alpha subunit and AMP bound) phosphorylates TSC2 on Ser1387, thereby activating the GAP activity of the TSC complex via an unknown mechanism.
Activated AMPK (phosphorylated on Thr172/Thr174 and AMP bound) phosphorylates Raptor on Ser 722 and Ser 792. These phosphorylations are required for inhibition of mTORC1 activity in response to energy stress (Gwinn DM et al, 2008).
For the receptor to autophosphorylate requires a lysine at position 1030 to stabilize the gamma phosphate of ATP whilst the adenosine of ATP itself interacts with three glycines at residues 1003 - 1008. The first tyrosine residues to be autophosphorylated are 1158, 1162 and 1163 in the tyrosine kinase domain. This is shortly followed by tyrosine 972 in the juxtamembrane domain and tyrosines 1328 and 1330. These tyrosines fall into the three distinct tyrosine phosphorylation domains of the beta-subunit. In total there are 13 potential tyrosines that may be phosphorylated. The receptor phosphorylates itself in a trans rather than cis manner. That is one beta-subunit of the receptor phosphorylates the other rather than itself.
At the beginning of this reaction, 1 molecule of 'Phosphatidyl-myo-inositol 4,5-bisphosphate', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'Phosphatidylinositol-3,4,5-trisphosphate', and 1 molecule of 'ADP' are present.
This reaction takes place in the 'cell' and is mediated by the 'kinase activity' of 'phospho-IRS:PI3K'.
At the beginning of this reaction, 1 molecule of '3-phosphoinositide dependent protein kinase-1 ', and 1 molecule of 'Phosphatidylinositol-3,4,5-trisphosphate' are present. At the end of this reaction, 1 molecule of 'PIP3:PDK complex [plasma membrane]' is present.
At the beginning of this reaction, 4 molecules of 'ATP', and 1 molecule of 'Crk:SOS:IRS-P' are present. At the end of this reaction, 1 molecule of 'Crk:IRS-P', 1 molecule of 'phospho-SOS', and 4 molecules of 'ADP' are present.
This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'kinase activity' of 'ERK1'.
At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'IRS:activated insulin receptor' are present. At the end of this reaction, 1 molecule of 'phospho-IRS:activated insulin receptor', and 1 molecule of 'ADP' are present.
This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'transmembrane receptor protein tyrosine kinase activity' of 'IRS:activated insulin receptor'.
With insulin dissociated from its receptor the signal to sustain the receptor kinase's activity is also removed. Thus endosomally-associated protein tyrosine phosphatases (PTPs) are able to dephosphorylate the receptor which now can not rephosphorylate themselves since insulin is removed and the receptor is in the inactive protein conformation. (The identity of these PTPs is not clearly established yet. A discussion of candidates will be added in the near future.)
The dephosphorylation of the receptor is also a signal for the receptor to recycle back to the plasma membrane.
The endosome fuses with the plasma membrane allowing the insulin receptor to re-integrate there. Any degraded insulin remnants which remained in the endosome are also expelled (The majority having been excreted into the cytoplasm and secreted out of the cell via other mechanisms).
The cycle is complete with the dephosphorylated receptor now back in the plasma membrane available to bind the next insulin molecule presented to it. There is some insulin receptor degradation over time when damaged insulin receptors are not recycled but fuse instead with the lysosomes where they are degraded. However the majority of insulin receptors are recycled back to the plasma membrane with greater than 95% efficiency.
At the beginning of this reaction, 1 molecule of 'activated insulin receptor', and 1 molecule of 'GRB10' are present. At the end of this reaction, 1 molecule of 'GRB10:INSR' is present.
This reaction takes place on the 'internal side of plasma membrane'.
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.
At the beginning of this reaction, 1 molecule of 'phospho-IRS:activated insulin receptor' is present. At the end of this reaction, 1 molecule of 'activated insulin receptor', and 1 molecule of 'phospho-IRS' are present.
This reaction takes place on the 'internal side of plasma membrane'.
At the beginning of this reaction, 1 molecule of 'phospho-SHC: activated insulin receptor' is present. At the end of this reaction, 1 molecule of 'phospho-SHC', and 1 molecule of 'activated insulin receptor' are present.
This reaction takes place on the 'internal side of plasma membrane'.
Almost concomitantly a second effect resulting from the tyrosine phosphorylation of the insulin receptor begins to occur. The phosphorylation of the tyrosine in the NPEY sequence found in the juxtamembrane is also a signal for endocytosis to occur. Whilst invagination of the plasma membrane commences the receptor tyrosine kinase activity continues unabated as does substrate phosphorylation.
As the invagination continues certain proteins are concentrated in the area of invagination. In addition to the insulin receptor itself there is a recruitment of insulin-specific protein tyrosine phosphatases (PTPs). This process takes less than one minute. (The identity of these PTPs is not clearly established yet. A discussion of candidates will be added in the near future.)
The formation of the endosome containing the activated ligand-receptor complex is completed within two minutes following ligand presentation at the plasma membrane and is maximal by five minutes. Endocytosis of activated receptors has the dual effect of concentrating receptors within endosomes and allowing the insulin receptor tyrosine kinase to phosphorylate substrates that are spatially distinct from those accessible at the plasma membrane. The endosome also contains other proteins crucial to the signal transduction process. These include a proton pump and the insulin degrading activity. It is not certain how these proteins arrive in the endosome since it could be via the endosome maturation or fusion pathways.
Inactive p21ras-GDP is found anchored to the plasma membrane by a farnesyl residue. Insulin stimulation results in phosphorylation of IRS1/2 on tyrosine residues (Y). GRB2 binds the phosphotyrosine residues of IRS via its SH2 domain. As IRS is phosphorylated by the insulin receptor near to the plasma membrane, the SOS-GRB2:IRS interaction brings the SOS enzyme into close proximity to p21ras.
At the beginning of this reaction, 3 molecules of 'ATP', and 1 molecule of 'TSC2-1' are present. At the end of this reaction, 3 molecules of 'ADP', and 1 molecule of 'Inhibited TSC2-1-P at Ser 939, 1130 and Thr 1462' are present.
This reaction is mediated by the 'kinase activity' of 'PIP3:Phosphorylated PKB complex'.
At the beginning of this reaction, 1 molecule of 'eIF4E:4E-BP1-P' is present. At the end of this reaction, 1 molecule of '4E-BP1-P', and 1 molecule of 'eIF4E' are present.
eIF4B is a physiologically relevant target of S6K1. Once phosphorylated and activated by S6K1, eIF4B specifically stimulates the ATPase and RNA helicase activities of eIF4A.
mTOR forms a functional protein complex with at least two proteins: Raptor (Regulated Associated Protein of mTOR) and mLst8. This complex is called mammalian TOR complex 1 (mTORC1). Raptor serves as a scaffolding protein to bridge the interaction between mTOR and its substrates. mLst8 enhances the association of mTOR with Raptor. [Rheb:GTP] binds and activates mTORC1. Besides binding directly to mTOR, Rheb can also bind to Raptor and mLst8 (PMIDs 15854902, 15755954 and 12150926).
At the beginning of this reaction, 3 molecules of 'ATP', and 1 molecule of 'eIF4G' are present. At the end of this reaction, 3 molecules of 'ADP', and 1 molecule of 'eIF4G-P' are present.
This reaction takes place in the 'cytosol' and is mediated by the 'kinase activity' of 'S6K1-P'.
At the beginning of this reaction, 2 molecules of 'ATP', and 1 molecule of 'eIF4E:4E-BP' are present. At the end of this reaction, 1 molecule of 'eIF4E:4E-BP1-P', and 2 molecules of 'ADP' are present.
This reaction is mediated by the 'kinase activity' of 'Activated mTORC1'.
Phosphorylation of eEF2 kinase by S6K1-P results in decreased activity of this kinase. eEF2 kinase normally phosphorylates and deactivates eEF2, preventing its binding to the ribosome.
Rheb is a GTP binding protein that exhibits GTPase activity. GDP is exchanged for GTP in the [Rheb:GDP] complex to form [Rheb:GTP], which binds and activates the mTORC1 complex. This exchange is catalysed by an as yet unidentified guanine exchange factor (GEF) (PMIDs 15951850 and 15755954).
Once phosphorylated, S6K1-P phosphorylates and activates ribosomal protein S6 (rpS6), which in turn selectively increases the translation of 5’TOP mRNAs. These mRNAs encode exclusively for components of the translation machinery (PMID 15809305).
At the beginning of this reaction, 3 molecules of 'ATP', and 1 molecule of 'TSC1:TSC2' are present. At the end of this reaction, 3 molecules of 'ADP', and 1 molecule of 'TSC1:Inhibited TSC2-1-P' are present.
This reaction is mediated by the 'kinase activity' of 'PIP3:Phosphorylated PKB complex'.
At the beginning of this reaction, 2 molecules of 'ATP', and 1 molecule of 'PIP3:PKB complex ' are present. At the end of this reaction, 1 molecule of 'PIP3:Phosphorylated PKB complex', and 2 molecules of 'ADP' are present.
This reaction takes place on the 'plasma membrane' and is mediated by the 'kinase activity' of 'PIP3:PDK complex [plasma membrane]'.
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.
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=74752
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DataNodes
SOS
IRS-PSOS
IRS-PSOS
Phospho-SHCSTRAD
MO25Annotated Interactions
SOS
IRS-PSOS
IRS-PSOS
IRS-PSOS
Phospho-SHCSOS
Phospho-SHCSTRAD
MO25This reaction takes place on the 'internal side of plasma membrane'.
This reaction takes place in the 'endosome' and is mediated by the 'insulysin activity of IDA (insulin degrading activity' of 'IDA (insulin degrading activity)'.
This reaction takes place in the 'cytosol' and is mediated by the 'protein tyrosine phosphatase activity' of 'protein tyrosine phosphatase'.
This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'kinase activity' of 'ERK1'.
The binding of insulin to its receptor causes a conformational change in the alpha-subunits. This in turn produces a conformational change in the beta-subunits leading to the activation of the intrinsic insulin receptor tyrosine kinase.
This reaction takes place in the 'cell'.
This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'kinase activity' of 'ERK1'.
This reaction takes place in the 'cytosol' and is mediated by the 'protein tyrosine phosphatase activity' of 'protein tyrosine phosphatase'.
This reaction is mediated by the 'kinase activity' of 'PIP3:Phosphorylated PKB complex'.
This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'transmembrane receptor protein tyrosine kinase activity' of 'SHC:activated insulin receptor'.
This reaction takes place on the 'internal side of plasma membrane'.
This reaction takes place in the 'cell' and is mediated by the 'kinase activity' of 'phospho-IRS:PI3K'.
This reaction takes place in the 'cell'.
This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'kinase activity' of 'ERK1'.
This reaction is mediated by the 'hydrolase activity' of 'Phosphorylated PDE3B'.
This reaction takes place on the 'internal side of plasma membrane' and is mediated by the 'transmembrane receptor protein tyrosine kinase activity' of 'IRS:activated insulin receptor'.
The dephosphorylation of the receptor is also a signal for the receptor to recycle back to the plasma membrane.
The cycle is complete with the dephosphorylated receptor now back in the plasma membrane available to bind the next insulin molecule presented to it. There is some insulin receptor degradation over time when damaged insulin receptors are not recycled but fuse instead with the lysosomes where they are degraded. However the majority of insulin receptors are recycled back to the plasma membrane with greater than 95% efficiency.
This reaction takes place on the 'internal side of plasma membrane'.
This reaction takes place on the 'internal side of plasma membrane'.
This reaction takes place on the 'internal side of plasma membrane'.
As the invagination continues certain proteins are concentrated in the area of invagination. In addition to the insulin receptor itself there is a recruitment of insulin-specific protein tyrosine phosphatases (PTPs). This process takes less than one minute. (The identity of these PTPs is not clearly established yet. A discussion of candidates will be added in the near future.)
The formation of the endosome containing the activated ligand-receptor complex is completed within two minutes following ligand presentation at the plasma membrane and is maximal by five minutes. Endocytosis of activated receptors has the dual effect of concentrating receptors within endosomes and allowing the insulin receptor tyrosine kinase to phosphorylate substrates that are spatially distinct from those accessible at the plasma membrane. The endosome also contains other proteins crucial to the signal transduction process. These include a proton pump and the insulin degrading activity. It is not certain how these proteins arrive in the endosome since it could be via the endosome maturation or fusion pathways.
Insulin stimulation results in phosphorylation of IRS1/2 on tyrosine residues (Y). GRB2 binds the phosphotyrosine residues of IRS via its SH2 domain. As IRS is phosphorylated by the insulin receptor near to the plasma membrane, the SOS-GRB2:IRS interaction brings the SOS enzyme into close proximity to p21ras.
This reaction is mediated by the 'kinase activity' of 'PIP3:Phosphorylated PKB complex'.
This reaction takes place in the 'cytosol'.
This reaction takes place in the 'cytosol' and is mediated by the 'kinase activity' of 'S6K1-P'.
This reaction is mediated by the 'kinase activity' of 'Activated mTORC1'.
This reaction is mediated by the 'kinase activity' of 'PIP3:Phosphorylated PKB complex'.
This reaction takes place on the 'plasma membrane' and is mediated by the 'kinase activity' of 'PIP3:PDK complex [plasma membrane]'.