Pathway Central: Insulin Receptor Pathway. Insulin is the major hormone controlling critical energy functions such as glucose and lipid metabolism. Insulin elicits a diverse array of biological responses by binding to its specific receptor (Ref. The insulin receptor belongs to a subfamily of receptor tyrosine kinases that includes the IGF (Insulin- like Growth Factor) receptor and the IRR (Insulin Receptor- Related Receptor). These receptors are tetrameric proteins consisting of two alpha and two beta subunits that function as allosteric enzymes in which the alpha subunit inhibits the tyrosine kinase activity of the beta subunit. Insulin has diverse effects on cells including stimulation of glucose transport, gene expression and alterations of cell morphology. The hormone mediates these effects by activation of signaling pathways which utilize, i) adaptor molecules such the IRS (Insulin Receptor Substrates), the SHC (Src and Collagen Homologues) and the GRB2 (Growth Factor Receptor Binding protein- 2), ii) lipid kinases such as PI3. K (Phosphatidylinositol 3- Kinase), iii) small G- proteins like Rac, and iv) serine, threonine and tyrosine kinases (Ref. Tyrosine- phosphorylated IRS then displays binding sites for numerous signaling partners. PI3. K has a major role in insulin functions. It regulates three main classes of signaling molecules: the AGC family of serine/threonine protein kinases, guanine nucleotide- exchange proteins of the Rho family of GTPases, and the Tec family of tyrosine kinases. The best characterized of the AGC kinases is PDK- 1 (Phosphoinositide- Dependent Kinase- 1), one of the serine kinases that phosphorylates and activates the serine/threonine kinase Akt/PKB (Protein Kinase- B). Download PDF Pathway Description: Insulin is the major hormone controlling critical energy functions such as glucose and lipid metabolism. Insulin activates the insulin receptor tyrosine kinase (IR), which phosphorylates and recruits different substrate adaptors. 318-322, February 1972 Isolation ofthe Insulin Receptor ofLiver andFat-Cell Membranes (detergent-solubilized/ Identifiers, CD220, HHF5, insulin receptor External IDs Genetically Related Diseases Disease Name References polycystic ovary syndrome. The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large. The new engl and journal of medicine 1518 n engl j med 356;15 www.nejm.org april 12, 2007 T ype 2 diabetes mellitus occurs when beta-cell function fails to compensate for insulin resistance.1,2 Beta-cell function pro-gressively deteriorates with an increasing dura. Akt possesses a PH domain that also interacts directly with PIP3 (Phosphatidylinositol - 3, 4, 5- Triphosphate), promoting membrane targeting of the protein and catalytic activation. Akt has been suggested to be important in transmission of the insulin signal, by phosphorylation of the enzyme GSK3 (Glycogen Synthase Kinase- 3), the FKHRL1 (Forkhead- Related Family of Mammalian Transcription Factor) and c. AMP (Cyclic Adenosine Monophosphate) response element- binding protein. Akt inhibits apoptosis by phosphorylating the BAD (BCL2 Antagonist of Cell Death) component of the BAD/BCLXL complex. Phosphorylated BAD binds to 1. BAD/BCLXL complex and allowing cell survival, and Akt activates IKK, which ultimately leads to NF- Kappa. B (Nuclear Factor- Kappa. B) activation and cell survival. Akt also activates the m. TOR (Mammalian Target of Rapamycin)/FRAP pathway. Activation of m. TOR results in the phosphorylation of ribosomal protein S6 kinase, p. S6. K, which is also regulated by phosphorylation by PDK- 1. Rapamycin (FRAP) interactions with m. TOR also regulate the activity of p. S6. K, the kinase that phosphorylates the 4. S ribosomal protein S6. S6 is thought to be the only p. S6. K substrate, and by controlling S6 phosphorylation, p. S6. K regulates the translation of an essential family of m. RNAs that contain an oligopyrimidine tract at their transcriptional start site. Activation of m. TOR also results in phosphorylation and inactivation of e. 2000 Nov;49(11):1880-9. Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia. Kubota N(1), Tobe K, Terauchi Y, Eto K, Yamauchi T, Suzuki R, Tsubamoto Y. Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival. Insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus and the onset of Alzheimer/'s disease. IF4. EBP (Eukaryotic Initiation Factor 4. EBinding Protein), also known as PHAS, an inhibitor of the translation initiation factor e. IF4. E (Eukaryotic Initiation Factor- 4. E). Insulin induces dephosphorylation of e. EF2 (Eukaryotic Elongation Factor- 2) and inactivation of e. EF2. K (Eukaryotic Elongation Factor- 2 Kinase), and these effects are blocked by rapamycin, which inhibits the mammalian target of rapamycin, m. TOR. Akt and/or the atypical PKCs (Protein Kinase- C) seem to be required for insulin- stimulated glucose transport. Pdf Insulin Receptor SignalingOfficial Full-Text Publication: Insulin receptor and ageing on ResearchGate, the professional network for scientists. The number of elderly people is increasing worldwide as well as the age-associated diseases, such as the type 2 diabetes. The consequences are. The ability of insulin to stimulate glucose uptake relies on a complex signaling cascade that leads to the translocation of GLUT4 (Glucose Transporter Protein- 4) from an intracellular compartment to the plasma membrane, which results in increased glucose uptake. While the PI3. K/Akt cascade participates in this process, another major pathway leading to GLUT4 translocation involves the insulin receptor- mediated phosphorylation of CAP (c- Cbl Associated Protein) and formation of the CAP: Cbl: Crk. II complex. This complex, through its interaction with flotillin, localizes to lipid rafts facilitating GLUT4 translocation, using in the final step a Synip- containing specialized Snare complex (Ref. The signaling contributions of other proteins bound by phosphorylated IRSs, including the phosphotyrosine phosphatase SHP2, Fyn, and the SH3- containing adaptor Nck, are yet to be clearly defined. Another important protein involved in insulin signaling is GRB1. Growth Factor Receptor- Bound Protein 1. GRB1. 0 interacts directly with IR (Insulin Receptor). IR does not phosphorylate GRB1. Tyrosine Kinases of the Src family negatively regulates binding to IR. GRB1. 0 is believed to interact with MEK and play a role in signaling. As is the case for other growth factors, insulin stimulates the MAPK (Mitogen- Activated Protein) ERK (Extracellular Signal Regulated Kinase). This pathway involves the tyrosine phosphorylation of IRS proteins and/or SHC, which in turn interact with the adapter protein GRB2, recruiting the SOS (Son of Sevenless) exchange protein to the plasma membrane for activation of Ras. The activation of Ras also requires stimulation of the tyrosine phosphatase SHP2, through its interaction with receptor substrates such as GAB1 (GRB2 Associated Binding Protein- 1) or IRS1/2. Once activated, Ras operates as a molecular switch, stimulating a serine kinase cascade through the stepwise activation of Raf, MEK and ERK. Activated ERK can translocate into the nucleus, where it catalyses the phosphorylation of transcription factors such as p. TCF, initiating a transcriptional programme that leads to cellular proliferation or differentiation (Ref. 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 internalized into endosomes, and this process is dependent on tyrosine autophosphorylation. 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. 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 by the EAI (Endosomal Acidic Insulinase). Pdf Insulin Receptor DiagramThis loss of the ligand- receptor complex attenuates any further insulin- driven receptor rephosphorylation events and leads to receptor dephosphorylation by extra lumenal endosomally associated PTPs. PTPase (Protein Tyrosine Phosphatases) catalyze the dephosphorylation of insulin receptor and its substrates, leading to attenuation of insulin action. A number of PTPases have been implicated as the negative regulator of insulin signaling. Among them, the intracellular PTPase, PTP1. B, has been shown to function as the insulin receptor phosphatase. PTEN (Phosphatase and Tensin Homolog Deleted On Chromosome- 1. SHIP2 (SH2- containing Inositol Phosphatase- 2) is another negative regulator of insulin signaling and such negative regulation depends on its 5'- phopshatase activity. Overexpression of SHIP2 protein decreases Insulin- dependent PIP3 production as well as insulin- stimulated Akt activation, GSK3 inactivation, and glycogen synthetase activation. Insulin increases glucose uptake in muscle and fat, and inhibits hepatic glucose production, thus serving as the primary regulator of blood glucose concentration. Insulin also stimulates cell growth and differentiation, and promotes the storage of substrates in fat, liver and muscle by stimulating lipogenesis, glycogen and protein synthesis, and inhibiting lipolysis, glycogenolysis and protein breakdown. Insulin resistance or deficiency results in profound dysregulation of these processes, and produces elevations in fasting and postprandial glucose and lipid levels.
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