Signaling by insulin receptor (Homo sapiens)
From WikiPathways
Description
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.Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=74752</div>
Quality Tags
Ontology Terms
Saving...Bibliography
View all... |
- Boriack-Sjodin PA, Margarit SM, Bar-Sagi D, Kuriyan J.; ''The structural basis of the activation of Ras by Sos.''; PubMed Europe PMC Scholia
- Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- Bouzakri K, Zachrisson A, Al-Khalili L, Zhang BB, Koistinen HA, Krook A, Zierath JR.; ''siRNA-based gene silencing reveals specialized roles of IRS-1/Akt2 and IRS-2/Akt1 in glucose and lipid metabolism in human skeletal muscle.''; PubMed Europe PMC Scholia
- Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- Cheatham B, Kahn CR.; ''Insulin action and the insulin signaling network.''; PubMed Europe PMC Scholia
- White MF, Kahn CR.; ''The insulin signaling system.''; PubMed Europe PMC Scholia
- Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMed Europe PMC Scholia
- Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMed Europe PMC Scholia
- Fantin VR, Sparling JD, Slot JW, Keller SR, Lienhard GE, Lavan BE.; ''Characterization of insulin receptor substrate 4 in human embryonic kidney 293 cells.''; PubMed Europe PMC Scholia
- Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMed Europe PMC Scholia
- Kandror KV, Pilch PF.; ''Compartmentalization of protein traffic in insulin-sensitive cells.''; PubMed Europe PMC Scholia
- Duckworth WC, Bennett RG, Hamel FG.; ''Insulin degradation: progress and potential.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- Duckworth WC.; ''Insulin degradation: mechanisms, products, and significance.''; PubMed Europe PMC Scholia
- Drake PG, Posner BI.; ''Insulin receptor-associated protein tyrosine phosphatase(s): role in insulin action.''; PubMed Europe PMC Scholia
- Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMed Europe PMC Scholia
- Kleiman LB, Maiwald T, Conzelmann H, Lauffenburger DA, Sorger PK.; ''Rapid phospho-turnover by receptor tyrosine kinases impacts downstream signaling and drug binding.''; PubMed Europe PMC Scholia
- Waters SB, Yamauchi K, Pessin JE.; ''Insulin-stimulated disassociation of the SOS-Grb2 complex.''; PubMed Europe PMC Scholia
- Kim B, Cheng HL, Margolis B, Feldman EL.; ''Insulin receptor substrate 2 and Shc play different roles in insulin-like growth factor I signaling.''; PubMed Europe PMC Scholia
- Zoncu R, Efeyan A, Sabatini DM.; ''mTOR: from growth signal integration to cancer, diabetes and ageing.''; PubMed Europe PMC Scholia
- Di Guglielmo GM, Drake PG, Baass PC, Authier F, Posner BI, Bergeron JJ.; ''Insulin receptor internalization and signalling.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- Bevan AP, Drake PG, Bergeron JJ, Posner BI.; ''Intracellular signal transduction: The role of endosomes.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- Liang L, Zhou T, Jiang J, Pierce JH, Gustafson TA, Frank SJ.; ''Insulin receptor substrate-1 enhances growth hormone-induced proliferation.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- Roskoski R.; ''ERK1/2 MAP kinases: structure, function, and regulation.''; PubMed Europe PMC Scholia
- Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed Europe PMC Scholia
- Supek F, Supekova L, Mandiyan S, Pan YC, Nelson H, Nelson N.; ''A novel accessory subunit for vacuolar H(+)-ATPase from chromaffin granules.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- Downward J.; ''PI 3-kinase, Akt and cell survival.''; PubMed Europe PMC Scholia
- Authier F, Posner BI, Bergeron JJ.; ''Endosomal proteolysis of internalized proteins.''; PubMed Europe PMC Scholia
- Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- Ebina Y, Ellis L, Jarnagin K, Edery M, Graf L, Clauser E, Ou JH, Masiarz F, Kan YW, Goldfine ID.; ''The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling.''; PubMed Europe PMC Scholia
- McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMed Europe PMC Scholia
- White MF.; ''The IRS-signalling system: a network of docking proteins that mediate insulin action.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- Sasaoka T, Kobayashi M.; ''The functional significance of Shc in insulin signaling as a substrate of the insulin receptor.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMed Europe PMC Scholia
- Corbalan-Garcia S, Yang SS, Degenhardt KR, Bar-Sagi D.; ''Identification of the mitogen-activated protein kinase phosphorylation sites on human Sos1 that regulate interaction with Grb2.''; PubMed Europe PMC Scholia
- Xu B, Bird VG, Miller WT.; ''Substrate specificities of the insulin and insulin-like growth factor 1 receptor tyrosine kinase catalytic domains.''; PubMed Europe PMC Scholia
- Gu J, Tamura M, Pankov R, Danen EH, Takino T, Matsumoto K, Yamada KM.; ''Shc and FAK differentially regulate cell motility and directionality modulated by PTEN.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
- Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMed Europe PMC Scholia
- 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.''; PubMed Europe PMC Scholia
History
View all... |
External references
DataNodes
| View all... |
| Name | Type | Database reference | Comment |
|---|---|---|---|
| 2xHC-INS(25-54)
[extracellular region] | Protein | P01308 (Uniprot-TrEMBL)  | |
| 3',5'-Cyclic AMP | Metabolite | CHEBI:17489 (ChEBI) | |
| 4xHC-INS(90-110)
[extracellular region] | Protein | P01308 (Uniprot-TrEMBL) | |
| ADP | Metabolite | CHEBI:16761 (ChEBI) | |
| AKT2 [cytosol] | Protein | P31751 (Uniprot-TrEMBL) | |
| AMP [cytosol] | Metabolite | CHEBI:16027 (ChEBI) | |
| AMP | Metabolite | CHEBI:16027 (ChEBI) | |
| AMPK heterotrimer | Complex | REACT_18135 (Reactome) | |
| ATP6V0A1 [endosome membrane] | Protein | Q93050 (Uniprot-TrEMBL) | |
| ATP6V0A2 [endosome membrane] | Protein | Q9Y487 (Uniprot-TrEMBL) | |
| ATP6V0A4 [endosome membrane] | Protein | Q9HBG4 (Uniprot-TrEMBL) | |
| ATP6V0B [endosome membrane] | Protein | Q99437 (Uniprot-TrEMBL) | |
| ATP6V0C [endosome membrane] | Protein | P27449 (Uniprot-TrEMBL) | |
| ATP6V0D1 [endosome membrane] | Protein | P61421 (Uniprot-TrEMBL) | |
| ATP6V0D2 [endosome membrane] | Protein | Q8N8Y2 (Uniprot-TrEMBL) | |
| ATP6V0E1 [endosome membrane] | Protein | O15342 (Uniprot-TrEMBL) | |
| ATP6V0E2 [endosome membrane] | Protein | Q8NHE4 (Uniprot-TrEMBL) | |
| ATP6V1A [cytosol] | Protein | P38606 (Uniprot-TrEMBL) | |
| ATP6V1B1 [cytosol] | Protein | P15313 (Uniprot-TrEMBL) | |
| ATP6V1B2 [cytosol] | Protein | P21281 (Uniprot-TrEMBL) | |
| ATP6V1C1 [cytosol] | Protein | P21283 (Uniprot-TrEMBL) | |
| ATP6V1C2 [cytosol] | Protein | Q8NEY4 (Uniprot-TrEMBL) | |
| ATP6V1D [cytosol] | Protein | Q9Y5K8 (Uniprot-TrEMBL) | |
| ATP6V1E1(2-226) [cytosol] | Protein | P36543 (Uniprot-TrEMBL) | |
| ATP6V1E2 [cytosol] | Protein | Q96A05 (Uniprot-TrEMBL) | |
| ATP6V1F [cytosol] | Protein | Q16864 (Uniprot-TrEMBL) | |
| ATP6V1G1 [cytosol] | Protein | O75348 (Uniprot-TrEMBL) | |
| ATP6V1G2 [cytosol] | Protein | O95670 (Uniprot-TrEMBL) | |
| ATP6V1G3 [cytosol] | Protein | Q96LB4 (Uniprot-TrEMBL) | |
| ATP6V1H [cytosol] | Protein | Q9UI12 (Uniprot-TrEMBL) | |
| ATP | Metabolite | CHEBI:15422 (ChEBI) | |
| Activated PI3K | REACT_9165 (Reactome) | ||
| Activated mTORC1 | Complex | REACT_7770 (Reactome) | |
| CAB39 [cytosol] | Protein | Q9Y376 (Uniprot-TrEMBL) | |
| CAB39L [cytosol] | Protein | Q9H9S4 (Uniprot-TrEMBL) | |
| CRK(2-304) [cytosol] | Protein | P46108 (Uniprot-TrEMBL) | |
| Crk:IRS-P | Complex | REACT_4822 (Reactome) | |
| Crk:SOS:IRS-P | Complex | REACT_2957 (Reactome) | |
| DOK1 [cytosol] | Protein | Q99704 (Uniprot-TrEMBL) | |
| EEF2K | Protein | O00418 (Uniprot-TrEMBL) | |
| EIF4B(2-118) | Protein | P23588 (Uniprot-TrEMBL) | |
| EIF4E [cytosol] | Protein | P06730 (Uniprot-TrEMBL) | |
| EIF4EBP1 [cytosol] | Protein | Q13541 (Uniprot-TrEMBL) | |
| EIF4E | Protein | P06730 (Uniprot-TrEMBL) | |
| EIF4G1 | Protein | Q04637 (Uniprot-TrEMBL) | |
| GDP [cytosol] | Metabolite | CHEBI:17552 (ChEBI) | |
| GDP | Metabolite | CHEBI:17552 (ChEBI) | |
| GRB10 [cytosol] | Protein | Q13322 (Uniprot-TrEMBL) | |
| GRB10:INSR | Complex | REACT_5054 (Reactome) | |
| GRB10 | Protein | Q13322 (Uniprot-TrEMBL) | |
| GRB2-1 [cytosol] | Protein | P62993-1 (Uniprot-TrEMBL) | |
| GRB2:IRS-P | Complex | REACT_5160 (Reactome) | |
| GRB2:SOS1 | Complex | REACT_4435 (Reactome) | |
| GRB2:SOS:IRS-P | Complex | REACT_3414 (Reactome) | |
| GRB2:SOS:Phospho-SHC | Complex | REACT_2380 (Reactome) | |
| GRB2:phospho-SHC | Complex | REACT_2584 (Reactome) | |
| GTP [cytosol] | Metabolite | CHEBI:15996 (ChEBI) | |
| GTP | Metabolite | CHEBI:15996 (ChEBI) | |
| H+ | Metabolite | CHEBI:15378 (ChEBI) | |
| H2O | Metabolite | CHEBI:15377 (ChEBI) | |
| HRAS(1-186) [plasma membrane] | Protein | P01112 (Uniprot-TrEMBL) | |
| IDA | REACT_2385 (Reactome) | ||
| INS(25-54) [endosome lumen] | Protein | P01308 (Uniprot-TrEMBL) | |
| INS(90-110) [endosome lumen] | Protein | P01308 (Uniprot-TrEMBL) | |
| INSR(28-758) [endosome membrane] | Protein | P06213 (Uniprot-TrEMBL) | |
| INSR(28-758) [plasma membrane] | Protein | P06213 (Uniprot-TrEMBL) | |
| INSR(763-1382) [endosome membrane] | Protein | P06213 (Uniprot-TrEMBL) | |
| INSR(763-1382) [plasma membrane] | Protein | P06213 (Uniprot-TrEMBL) | |
| IRS1 [cytosol] | Protein | P35568 (Uniprot-TrEMBL) | |
| IRS2 [cytosol] | Protein | Q9Y4H2 (Uniprot-TrEMBL) | |
| IRS:activated insulin receptor | Complex | REACT_3393 (Reactome) | |
| IRS | Protein | REACT_2507 (Reactome) | 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. |
| Insulin receptor | Complex | REACT_5691 (Reactome) | 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. |
| KRAS(1-186) [plasma membrane] | Protein | P01116 (Uniprot-TrEMBL) | |
| LKB1:STRAD:MO25 | Complex | REACT_17994 (Reactome) | |
| MAPK3 | Protein | P27361 (Uniprot-TrEMBL) | |
| MLST8 [cytosol] | Protein | Q9BVC4 (Uniprot-TrEMBL) | |
| MLST8 | Protein | Q9BVC4 (Uniprot-TrEMBL) | |
| MO25 | Protein | REACT_17734 (Reactome) | |
| MTOR [cytosol] | Protein | P42345 (Uniprot-TrEMBL) | |
| MTOR | Protein | P42345 (Uniprot-TrEMBL) | |
| NRAS [plasma membrane] | Protein | P01111 (Uniprot-TrEMBL) | |
| PDE3B | Protein | Q13370 (Uniprot-TrEMBL) | Can hydrolyze both cAMP and cGMP |
| PDPK1 [plasma membrane] | Protein | O15530 (Uniprot-TrEMBL) | |
| PDPK1 | Protein | O15530 (Uniprot-TrEMBL) | |
| PI(4,5)P2 | Metabolite | CHEBI:18348 (ChEBI) | |
| PI3K | Complex | REACT_4240 (Reactome) | |
| PIK3CA [cytosol] | Protein | P42336 (Uniprot-TrEMBL) | |
| PIK3CB [cytosol] | Protein | P42338 (Uniprot-TrEMBL) | |
| PIK3R1 [cytosol] | Protein | P27986 (Uniprot-TrEMBL) | |
| PIK3R2 [cytosol] | Protein | O00459 (Uniprot-TrEMBL) | |
| PIP3 [plasma membrane] | Metabolite | CHEBI:16618 (ChEBI) | |
| PIP3:AKT2 complex | Complex | REACT_4871 (Reactome) | |
| PIP3:PDK1 complex | Complex | REACT_5409 (Reactome) | |
| PIP3:Phosphorylated PKB complex | Complex | REACT_3373 (Reactome) | |
| PIP3 | CHEBI:16618 (ChEBI) | ||
| PKB regulator | Protein | REACT_5778 (Reactome) | |
| PKB:PKB Regulator | Complex | REACT_4747 (Reactome) | |
| PPM1A(2-382) | Protein | P35813 (Uniprot-TrEMBL) | |
| PRKAA1 [cytosol] | Protein | Q13131 (Uniprot-TrEMBL) | |
| PRKAA2 [cytosol] | Protein | P54646 (Uniprot-TrEMBL) | |
| PRKAB1(2-270) [cytosol] | Protein | Q9Y478 (Uniprot-TrEMBL) | |
| PRKAB2 [cytosol] | Protein | O43741 (Uniprot-TrEMBL) | |
| PRKAG1 [cytosol] | Protein | P54619 (Uniprot-TrEMBL) | |
| PRKAG2 [cytosol] | Protein | Q9UGJ0 (Uniprot-TrEMBL) | |
| PRKAG3 [cytosol] | Protein | Q9UGI9 (Uniprot-TrEMBL) | |
| Pi | Metabolite | CHEBI:18367 (ChEBI) | |
| RAF/MAP kinase cascade | Pathway | WP2735 (WikiPathways) | 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. |
| RHEB [cytosol] | Protein | Q15382 (Uniprot-TrEMBL) | |
| RPS6KB1 | Protein | P23443 (Uniprot-TrEMBL) | |
| RPS6 | Protein | P62753 (Uniprot-TrEMBL) | |
| RPTOR [cytosol] | Protein | Q8N122 (Uniprot-TrEMBL) | |
| RPTOR | Protein | Q8N122 (Uniprot-TrEMBL) | |
| Rheb:GDP | Complex | REACT_7464 (Reactome) | |
| Rheb:GTP | Complex | REACT_7765 (Reactome) | |
| SHC1 [cytosol] | Protein | P29353 (Uniprot-TrEMBL) | |
| SHC1 | Protein | P29353 (Uniprot-TrEMBL) | |
| SHC:activated insulin receptor | Complex | REACT_3791 (Reactome) | |
| SOS1 [cytosol] | Protein | Q07889 (Uniprot-TrEMBL) | |
| STK11(1-433) [cytosol] | Protein | Q15831 (Uniprot-TrEMBL) | |
| STK11(1-433) | Protein | Q15831 (Uniprot-TrEMBL) | |
| STRADA [cytosol] | Protein | Q7RTN6 (Uniprot-TrEMBL) | |
| STRADB [cytosol] | Protein | Q9C0K7 (Uniprot-TrEMBL) | |
| STRAD | Protein | REACT_17339 (Reactome) | |
| TCIRG1 [endosome membrane] | Protein | Q13488 (Uniprot-TrEMBL) | |
| THEM4 [cytosol] | Protein | Q5T1C6 (Uniprot-TrEMBL) | |
| TRIB3 [cytosol] | Protein | Q96RU7 (Uniprot-TrEMBL) | |
| TSC1 [cytosol] | Protein | Q92574 (Uniprot-TrEMBL) | |
| TSC1:Inhibited TSC2-1-P | Complex | REACT_7650 (Reactome) | |
| TSC1:TSC2 | Complex | REACT_7850 (Reactome) | |
| TSC1:p-S1387-TSC2 | Complex | REACT_21675 (Reactome) | |
| TSC2 [cytosol] | Protein | P49815 (Uniprot-TrEMBL) | |
| TSC2 | Protein | P49815 (Uniprot-TrEMBL) | |
| V-ATPase | Complex | REACT_24332 (Reactome) | |
| activated insulin receptor | Complex | REACT_3057 (Reactome) | |
| activated insulin receptor | Complex | REACT_4836 (Reactome) | |
| eIF4E:4E-BP1-P | Complex | REACT_7838 (Reactome) | |
| eIF4E:4E-BP | Complex | REACT_3978 (Reactome) | |
| insulin receptor | Complex | REACT_3854 (Reactome) | |
| insulin:insulin receptor | Complex | REACT_3518 (Reactome) | |
| insulin | Complex | REACT_3655 (Reactome) | |
| insulin | Complex | REACT_5828 (Reactome) | |
| p-4S-SOS1 | Protein | Q07889 (Uniprot-TrEMBL) | |
| p-5S-RPS6 | Protein | P62753 (Uniprot-TrEMBL) | |
| p-6Y-INSR(763-1382) [endosome membrane] | Protein | P06213 (Uniprot-TrEMBL) | |
| p-6Y-INSR(763-1382) [plasma membrane] | Protein | P06213 (Uniprot-TrEMBL) | |
| p-AMPK heterotrimer:AMP | Complex | REACT_21851 (Reactome) | |
| p-AMPK heterotrimer | Complex | REACT_17720 (Reactome) | |
| p-IRS1,2 | Protein | REACT_4523 (Reactome) | |
| p-S1108,S1148,S1192-EIF4G1 | Protein | Q04637 (Uniprot-TrEMBL) | |
| p-S1387-TSC2 [cytosol] | Protein | P49815 (Uniprot-TrEMBL) | |
| p-S318-PDE3B | Protein | Q13370 (Uniprot-TrEMBL) | |
| p-S366-EEF2K | Protein | O00418 (Uniprot-TrEMBL) | |
| p-S371,T389-RPS6KB1 | Protein | P23443 (Uniprot-TrEMBL) | |
| p-S422-EIF4B | Protein | P23588 (Uniprot-TrEMBL) | |
| p-S722,S792-RPTOR-1 | Protein | Q8N122-1 (Uniprot-TrEMBL) | |
| p-S939,S1130,T1462-TSC2 [cytosol] | Protein | P49815 (Uniprot-TrEMBL) | |
| p-S939,S1130,T1462-TSC2 | Protein | P49815 (Uniprot-TrEMBL) | |
| p-SHC | Protein | REACT_12146 (Reactome) | |
| p-T172-PRKAA2 [cytosol] | Protein | P54646 (Uniprot-TrEMBL) | |
| p-T174-PRKAA1(1-550) [cytosol] | Protein | Q13131 (Uniprot-TrEMBL) | |
| p-T37,T46-EIF4EBP1 [cytosol] | Protein | Q13541 (Uniprot-TrEMBL) | |
| p-T37,T46-EIF4EBP1 | Protein | Q13541 (Uniprot-TrEMBL) | |
| p-Y-DOK1 [cytosol] | Protein | Q99704 (Uniprot-TrEMBL) | |
| p-Y-IRS1 [cytosol] | Protein | P35568 (Uniprot-TrEMBL) | |
| p-Y-IRS2 [cytosol] | Protein | Q9Y4H2 (Uniprot-TrEMBL) | |
| p-Y-SHC1 [cytosol] | Protein | P29353 (Uniprot-TrEMBL) | |
| p-Y-SHC2 [cytosol] | Protein | P98077 (Uniprot-TrEMBL) | |
| p-Y-SHC3 [cytosol] | Protein | Q92529 (Uniprot-TrEMBL) | |
| p-Y317-SHC1 [cytosol] | Protein | P29353 (Uniprot-TrEMBL) | |
| p-Y317-SHC1 | Protein | P29353 (Uniprot-TrEMBL) | |
| p21 RAS:GDP | Complex | REACT_2657 (Reactome) | |
| p21 RAS:GTP | Complex | REACT_4782 (Reactome) | |
| phospho-IRS:PI3K | Complex | REACT_3175 (Reactome) | |
| phospho-IRS:activated insulin receptor | Complex | REACT_4013 (Reactome) | |
| phospho-IRS | Protein | REACT_4422 (Reactome) | |
| phospho-SHC:
activated insulin receptor | Complex | REACT_4738 (Reactome) | |
| phospho-insulin receptor | Complex | REACT_3809 (Reactome) | |
| protein tyrosine phosphatase | REACT_3980 (Reactome) |
Annotated Interactions
| View all... |
| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| 3',5'-Cyclic AMP | REACT_325 (Reactome) | |||
| ADP | Arrow | REACT_11183 (Reactome) | ||
| ADP | Arrow | REACT_1420 (Reactome) | ||
| ADP | Arrow | REACT_169 (Reactome) | ||
| ADP | Arrow | REACT_1878 (Reactome) | ||
| ADP | Arrow | REACT_2015 (Reactome) | ||
| ADP | Arrow | REACT_21348 (Reactome) | ||
| ADP | Arrow | REACT_21413 (Reactome) | ||
| ADP | Arrow | REACT_2211 (Reactome) | ||
| ADP | Arrow | REACT_244 (Reactome) | ||
| ADP | Arrow | REACT_26 (Reactome) | ||
| ADP | Arrow | REACT_342 (Reactome) | ||
| ADP | Arrow | REACT_6725 (Reactome) | ||
| ADP | Arrow | REACT_6778 (Reactome) | ||
| ADP | Arrow | REACT_6870 (Reactome) | ||
| ADP | Arrow | REACT_6873 (Reactome) | ||
| ADP | Arrow | REACT_6883 (Reactome) | ||
| ADP | Arrow | REACT_6912 (Reactome) | ||
| ADP | Arrow | REACT_6948 (Reactome) | ||
| ADP | Arrow | REACT_6952 (Reactome) | ||
| ADP | Arrow | REACT_908 (Reactome) | ||
| AMP | Arrow | REACT_11183 (Reactome) | ||
| AMP | Arrow | REACT_325 (Reactome) | ||
| AMPK heterotrimer | Arrow | REACT_21418 (Reactome) | ||
| AMPK heterotrimer | REACT_11183 (Reactome) | |||
| AMP | REACT_21293 (Reactome) | |||
| ATP | REACT_11183 (Reactome) | |||
| ATP | REACT_1420 (Reactome) | |||
| ATP | REACT_169 (Reactome) | |||
| ATP | REACT_1878 (Reactome) | |||
| ATP | REACT_2015 (Reactome) | |||
| ATP | REACT_21348 (Reactome) | |||
| ATP | REACT_21413 (Reactome) | |||
| ATP | REACT_2211 (Reactome) | |||
| ATP | REACT_244 (Reactome) | |||
| ATP | REACT_26 (Reactome) | |||
| ATP | REACT_342 (Reactome) | |||
| ATP | REACT_6725 (Reactome) | |||
| ATP | REACT_6778 (Reactome) | |||
| ATP | REACT_6870 (Reactome) | |||
| ATP | REACT_6873 (Reactome) | |||
| ATP | REACT_6883 (Reactome) | |||
| ATP | REACT_6912 (Reactome) | |||
| ATP | REACT_6948 (Reactome) | |||
| ATP | REACT_6952 (Reactome) | |||
| ATP | REACT_908 (Reactome) | |||
| ATP | TBar | REACT_11183 (Reactome) | ||
| Activated PI3K | mim-catalysis | REACT_244 (Reactome) | ||
| Activated mTORC1 | Arrow | REACT_6851 (Reactome) | ||
| Activated mTORC1 | mim-catalysis | REACT_6873 (Reactome) | ||
| Activated mTORC1 | mim-catalysis | REACT_6948 (Reactome) | ||
| Crk:IRS-P | Arrow | REACT_26 (Reactome) | ||
| Crk:SOS:IRS-P | REACT_26 (Reactome) | |||
| EEF2K | REACT_6883 (Reactome) | |||
| EIF4B(2-118) | REACT_6778 (Reactome) | |||
| EIF4E | Arrow | REACT_6742 (Reactome) | ||
| EIF4G1 | REACT_6870 (Reactome) | |||
| GDP | Arrow | REACT_1672 (Reactome) | ||
| GDP | Arrow | REACT_2010 (Reactome) | ||
| GDP | Arrow | REACT_6895 (Reactome) | ||
| GRB10:INSR | Arrow | REACT_509 (Reactome) | ||
| GRB10 | REACT_509 (Reactome) | |||
| GRB2:IRS-P | Arrow | REACT_169 (Reactome) | ||
| GRB2:SOS1 | REACT_176 (Reactome) | |||
| GRB2:SOS1 | REACT_646 (Reactome) | |||
| GRB2:SOS:IRS-P | Arrow | REACT_646 (Reactome) | ||
| GRB2:SOS:IRS-P | REACT_169 (Reactome) | |||
| GRB2:SOS:IRS-P | mim-catalysis | REACT_1672 (Reactome) | ||
| GRB2:SOS:Phospho-SHC | Arrow | REACT_176 (Reactome) | ||
| GRB2:SOS:Phospho-SHC | REACT_1420 (Reactome) | |||
| GRB2:SOS:Phospho-SHC | mim-catalysis | REACT_2010 (Reactome) | ||
| GRB2:phospho-SHC | Arrow | REACT_1420 (Reactome) | ||
| GTP | REACT_1672 (Reactome) | |||
| GTP | REACT_2010 (Reactome) | |||
| GTP | REACT_6895 (Reactome) | |||
| H+ | Arrow | REACT_2002 (Reactome) | ||
| H+ | REACT_2002 (Reactome) | |||
| H2O | REACT_21418 (Reactome) | |||
| H2O | REACT_325 (Reactome) | |||
| IDA | mim-catalysis | REACT_1355 (Reactome) | ||
| IRS:activated insulin receptor | Arrow | REACT_2120 (Reactome) | ||
| IRS:activated insulin receptor | REACT_342 (Reactome) | |||
| IRS:activated insulin receptor | mim-catalysis | REACT_342 (Reactome) | ||
| IRS | Arrow | REACT_1810 (Reactome) | ||
| IRS | REACT_2120 (Reactome) | |||
| Insulin receptor | Arrow | REACT_490 (Reactome) | ||
| Insulin receptor | REACT_1459 (Reactome) | |||
| LKB1:STRAD:MO25 | Arrow | REACT_21345 (Reactome) | ||
| LKB1:STRAD:MO25 | mim-catalysis | REACT_11183 (Reactome) | ||
| MAPK3 | mim-catalysis | REACT_1420 (Reactome) | ||
| MAPK3 | mim-catalysis | REACT_169 (Reactome) | ||
| MAPK3 | mim-catalysis | REACT_26 (Reactome) | ||
| MLST8 | REACT_6851 (Reactome) | |||
| MO25 | REACT_21345 (Reactome) | |||
| MTOR | REACT_6851 (Reactome) | |||
| PDE3B | REACT_1878 (Reactome) | |||
| PDPK1 | REACT_260 (Reactome) | |||
| PI(4,5)P2 | REACT_244 (Reactome) | |||
| PI3K | REACT_537 (Reactome) | |||
| PIP3:AKT2 complex | Arrow | REACT_1622 (Reactome) | ||
| PIP3:AKT2 complex | REACT_908 (Reactome) | |||
| PIP3:PDK1 complex | Arrow | REACT_260 (Reactome) | ||
| PIP3:PDK1 complex | mim-catalysis | REACT_908 (Reactome) | ||
| PIP3:Phosphorylated PKB complex | Arrow | REACT_908 (Reactome) | ||
| PIP3:Phosphorylated PKB complex | mim-catalysis | REACT_1878 (Reactome) | ||
| PIP3:Phosphorylated PKB complex | mim-catalysis | REACT_6725 (Reactome) | ||
| PIP3:Phosphorylated PKB complex | mim-catalysis | REACT_6952 (Reactome) | ||
| PIP3 | Arrow | REACT_244 (Reactome) | ||
| PIP3 | REACT_1622 (Reactome) | |||
| PIP3 | REACT_260 (Reactome) | |||
| PKB regulator | Arrow | REACT_1622 (Reactome) | ||
| PKB:PKB Regulator | REACT_1622 (Reactome) | |||
| PPM1A(2-382) | mim-catalysis | REACT_21418 (Reactome) | ||
| Pi | Arrow | REACT_1411 (Reactome) | ||
| Pi | Arrow | REACT_1810 (Reactome) | ||
| Pi | Arrow | REACT_21261 (Reactome) | ||
| Pi | Arrow | REACT_21418 (Reactome) | ||
| Pi | Arrow | REACT_453 (Reactome) | ||
| REACT_106 (Reactome) | 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'. | |||
| REACT_11183 (Reactome) | 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. | |||
| REACT_134 (Reactome) | 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. | |||
| REACT_1355 (Reactome) | 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)'. | |||
| REACT_1411 (Reactome) | 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'. | |||
| REACT_1420 (Reactome) | 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'. | |||
| REACT_1459 (Reactome) | 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. | |||
| REACT_1622 (Reactome) | 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. This reaction takes place in the 'cell'. | |||
| REACT_1672 (Reactome) | 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. | |||
| REACT_169 (Reactome) | 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'. | |||
| REACT_176 (Reactome) | 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. | |||
| REACT_1810 (Reactome) | 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'. | |||
| REACT_1878 (Reactome) | 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'. | |||
| REACT_2002 (Reactome) | 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). | |||
| REACT_2010 (Reactome) | 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. | |||
| REACT_2015 (Reactome) | 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'. | |||
| REACT_2120 (Reactome) | 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'. | |||
| REACT_21261 (Reactome) | 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). | |||
| REACT_21293 (Reactome) | 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. | |||
| REACT_21345 (Reactome) | 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). | |||
| REACT_21348 (Reactome) | 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. | |||
| REACT_21413 (Reactome) | 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). | |||
| REACT_21418 (Reactome) | Normally under low AMP:ATP conditions, the active AMPK is dephosphorylated (possibly by PP2C), and thus inactivated. | |||
| REACT_2211 (Reactome) | 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. | |||
| REACT_244 (Reactome) | 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'. | |||
| REACT_260 (Reactome) | 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. This reaction takes place in the 'cell'. | |||
| REACT_26 (Reactome) | 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'. | |||
| REACT_325 (Reactome) | At the beginning of this reaction, 1 molecule of '3',5'-Cyclic AMP' is present. At the end of this reaction, 1 molecule of 'AMP' is present. This reaction is mediated by the 'hydrolase activity' of 'Phosphorylated PDE3B'. | |||
| REACT_342 (Reactome) | 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'. | |||
| REACT_453 (Reactome) | 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. | |||
| REACT_490 (Reactome) | 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. | |||
| REACT_509 (Reactome) | 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'. | |||
| REACT_537 (Reactome) | 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. | |||
| REACT_562 (Reactome) | 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'. | |||
| REACT_596 (Reactome) | 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'. | |||
| REACT_599 (Reactome) | 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. | |||
| REACT_646 (Reactome) | 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. | |||
| REACT_6725 (Reactome) | 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'. | |||
| REACT_6742 (Reactome) | 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. This reaction takes place in the 'cytosol'. | |||
| REACT_6778 (Reactome) | 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. | |||
| REACT_6851 (Reactome) | 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). | |||
| REACT_6870 (Reactome) | 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'. | |||
| REACT_6873 (Reactome) | 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'. | |||
| REACT_6883 (Reactome) | 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. | |||
| REACT_6895 (Reactome) | 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). | |||
| REACT_6912 (Reactome) | 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). | |||
| REACT_6948 (Reactome) | S6K1 contains a TOS motif. mTORC1 requires an intact TOS motif to bind and phosphorylate S6K1 (PMID 15809305). | |||
| REACT_6952 (Reactome) | 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'. | |||
| REACT_908 (Reactome) | 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]'. | |||
| RPS6KB1 | REACT_6948 (Reactome) | |||
| RPS6 | REACT_6912 (Reactome) | |||
| RPTOR | REACT_21413 (Reactome) | |||
| RPTOR | REACT_6851 (Reactome) | |||
| Rheb:GDP | Arrow | REACT_21261 (Reactome) | ||
| Rheb:GDP | REACT_6895 (Reactome) | |||
| Rheb:GTP | Arrow | REACT_6895 (Reactome) | ||
| Rheb:GTP | REACT_21261 (Reactome) | |||
| Rheb:GTP | REACT_6851 (Reactome) | |||
| SHC1 | Arrow | REACT_1411 (Reactome) | ||
| SHC1 | REACT_106 (Reactome) | |||
| SHC:activated insulin receptor | Arrow | REACT_106 (Reactome) | ||
| SHC:activated insulin receptor | REACT_2015 (Reactome) | |||
| SHC:activated insulin receptor | mim-catalysis | REACT_2015 (Reactome) | ||
| STK11(1-433) | REACT_21345 (Reactome) | |||
| STRAD | REACT_21345 (Reactome) | |||
| TSC1:Inhibited TSC2-1-P | Arrow | REACT_6952 (Reactome) | ||
| TSC1:TSC2 | REACT_21348 (Reactome) | |||
| TSC1:TSC2 | REACT_6952 (Reactome) | |||
| TSC1:p-S1387-TSC2 | Arrow | REACT_21348 (Reactome) | ||
| TSC1:p-S1387-TSC2 | mim-catalysis | REACT_21261 (Reactome) | ||
| TSC2 | REACT_6725 (Reactome) | |||
| V-ATPase | mim-catalysis | REACT_2002 (Reactome) | ||
| activated insulin receptor | Arrow | REACT_2211 (Reactome) | ||
| activated insulin receptor | Arrow | REACT_562 (Reactome) | ||
| activated insulin receptor | Arrow | REACT_596 (Reactome) | ||
| activated insulin receptor | Arrow | REACT_599 (Reactome) | ||
| activated insulin receptor | REACT_106 (Reactome) | |||
| activated insulin receptor | REACT_134 (Reactome) | |||
| activated insulin receptor | REACT_2120 (Reactome) | |||
| activated insulin receptor | REACT_509 (Reactome) | |||
| activated insulin receptor | REACT_599 (Reactome) | |||
| eIF4E:4E-BP1-P | Arrow | REACT_6873 (Reactome) | ||
| eIF4E:4E-BP1-P | REACT_6742 (Reactome) | |||
| eIF4E:4E-BP | REACT_6873 (Reactome) | |||
| insulin receptor | Arrow | REACT_453 (Reactome) | ||
| insulin receptor | REACT_490 (Reactome) | |||
| insulin:insulin receptor | Arrow | REACT_1459 (Reactome) | ||
| insulin:insulin receptor | REACT_2211 (Reactome) | |||
| insulin:insulin receptor | mim-catalysis | REACT_2211 (Reactome) | ||
| insulin | Arrow | REACT_134 (Reactome) | ||
| insulin | REACT_1355 (Reactome) | |||
| insulin | REACT_1459 (Reactome) | |||
| p-4S-SOS1 | Arrow | REACT_1420 (Reactome) | ||
| p-4S-SOS1 | Arrow | REACT_169 (Reactome) | ||
| p-4S-SOS1 | Arrow | REACT_26 (Reactome) | ||
| p-5S-RPS6 | Arrow | REACT_6912 (Reactome) | ||
| p-AMPK heterotrimer:AMP | Arrow | REACT_21293 (Reactome) | ||
| p-AMPK heterotrimer:AMP | mim-catalysis | REACT_21348 (Reactome) | ||
| p-AMPK heterotrimer:AMP | mim-catalysis | REACT_21413 (Reactome) | ||
| p-AMPK heterotrimer | Arrow | REACT_11183 (Reactome) | ||
| p-AMPK heterotrimer | REACT_21293 (Reactome) | |||
| p-AMPK heterotrimer | REACT_21418 (Reactome) | |||
| p-IRS1,2 | REACT_646 (Reactome) | |||
| p-S1108,S1148,S1192-EIF4G1 | Arrow | REACT_6870 (Reactome) | ||
| p-S318-PDE3B | Arrow | REACT_1878 (Reactome) | ||
| p-S318-PDE3B | mim-catalysis | REACT_325 (Reactome) | ||
| p-S366-EEF2K | Arrow | REACT_6883 (Reactome) | ||
| p-S371,T389-RPS6KB1 | Arrow | REACT_6948 (Reactome) | ||
| p-S371,T389-RPS6KB1 | mim-catalysis | REACT_6778 (Reactome) | ||
| p-S371,T389-RPS6KB1 | mim-catalysis | REACT_6870 (Reactome) | ||
| p-S371,T389-RPS6KB1 | mim-catalysis | REACT_6883 (Reactome) | ||
| p-S371,T389-RPS6KB1 | mim-catalysis | REACT_6912 (Reactome) | ||
| p-S422-EIF4B | Arrow | REACT_6778 (Reactome) | ||
| p-S722,S792-RPTOR-1 | Arrow | REACT_21413 (Reactome) | ||
| p-S722,S792-RPTOR-1 | TBar | REACT_6948 (Reactome) | ||
| p-S939,S1130,T1462-TSC2 | Arrow | REACT_6725 (Reactome) | ||
| p-SHC | REACT_176 (Reactome) | |||
| p-T37,T46-EIF4EBP1 | Arrow | REACT_6742 (Reactome) | ||
| p-Y317-SHC1 | Arrow | REACT_596 (Reactome) | ||
| p-Y317-SHC1 | REACT_1411 (Reactome) | |||
| p21 RAS:GDP | REACT_1672 (Reactome) | |||
| p21 RAS:GDP | REACT_2010 (Reactome) | |||
| p21 RAS:GTP | Arrow | REACT_1672 (Reactome) | ||
| p21 RAS:GTP | Arrow | REACT_2010 (Reactome) | ||
| phospho-IRS:PI3K | Arrow | REACT_537 (Reactome) | ||
| phospho-IRS:activated insulin receptor | Arrow | REACT_342 (Reactome) | ||
| phospho-IRS:activated insulin receptor | REACT_562 (Reactome) | |||
| phospho-IRS | Arrow | REACT_562 (Reactome) | ||
| phospho-IRS | REACT_1810 (Reactome) | |||
| phospho-IRS | REACT_537 (Reactome) | |||
| phospho-SHC:
activated insulin receptor | Arrow | REACT_2015 (Reactome) | ||
| phospho-SHC:
activated insulin receptor | REACT_596 (Reactome) | |||
| phospho-insulin receptor | Arrow | REACT_134 (Reactome) | ||
| phospho-insulin receptor | REACT_453 (Reactome) | |||
| protein tyrosine phosphatase | mim-catalysis | REACT_1411 (Reactome) | ||
| protein tyrosine phosphatase | mim-catalysis | REACT_1810 (Reactome) | ||
| protein tyrosine phosphatase | mim-catalysis | REACT_453 (Reactome) |
