|
|
|
|
|
|
|
|
|||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | |||||
CELL SCIENCE AT A GLANCE |
The Sanger Centre, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK
(e-mail: ab6{at}sanger.ac.uk)
Insulin binding to its receptor results in receptor autophosphorylation on tyrosine residues and the tyrosine phosphorylation of insulin receptor substrates (IRS-1, IRS-2 and IRS-3) by the insulin receptor tyrosine kinase. This allows association of IRSs with the regulatory subunit of phosphoinositide 3-kinase (PI3K) through its SRC homology 2 (SH2) domains. Once activated, the catalytic subunit phosphorylates phosphoinositides at the 3' position of the inositol ring or proteins at serine residues. PI3K activates PtdIns(3,4)P2 / PtdIns(3,4,5)P3-dependent kinase 1 (PDK1), which activates PKB/Akt, a serine kinase. PKB in turn deactivates glycogen synthase kinase 3 (GSK-3), leading to activation of glycogen synthase and thus glycogen synthesis. Activation of PKB also results in the translocation of GLUT-4 vesicles from their intracellular pool to the plasma membrane, where they allow uptake of glucose into the cell. PKB also leads to mTOR-mediated activation of protein synthesis by PHAS/elf4 and p70s6k.
Other signal transduction proteins interact with IRS molecules, including GRB2 and SHP2, a protein-tyrosine phosphatase (PTP) containing SH2 domains. GRB2, an adaptor protein, contains an SH3 domain, which allows constitutive association with the guanine nucleotide exchange factor mSOS and is part of the cascade including RAS, RAF and MEK that leads to activation of mitogen-activated protein kinase (MAPK) and mitogenic responses in the form of gene transcription stimulated by FOS and ELK1. SHC is another substrate of the insulin receptor; it exists in three isoforms, of 46 kDa, 52 kDa and 66 kDa and contains SH2 and phosphotyrosine binding (PTB) domains. When tyrosine phosphorylated, SHC associates with GRB2 and can thus activate the RAS/MAPK pathway independently of IRS-1.
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, 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 endosomal acidic insulinase (EAI).) 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 PTPs.
The lifetime of a ligand-receptor complex within the endosomal compartment may be an important factor influencing the types of response produced by a particular receptor. Insulin, which has a relatively short endosomal residence, elicits primarily acute metabolic effects, whereas EGF and IGF-I, which have longer endosomal residences, elicit mitogenic responses. These differences in biological responses could reflect differences in activation of intracellular signalling molecules at specific cellular locations. Thus differences in ligand residency, along with differences in the intrinsic activity of receptors, could contribute to different downstream responses.
|
This article has been cited by other articles:
|
|
 |
|
  P. Bansal and Q. Wang Insulin as a physiological modulator of glucagon secretion Am J Physiol Endocrinol Metab, October 1, 2008; 295(4): E751 - E761. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Xi, X. Shen, and D. R. Clemmons p66shc Negatively Regulates Insulin-Like Growth Factor I Signal Transduction via Inhibition of p52shc Binding to Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Substrate-1 Leading to Impaired Growth Factor Receptor-Bound Protein-2 Membrane Recruitment Mol. Endocrinol., September 1, 2008; 22(9): 2162 - 2175. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. A. Davis, A. Suryawan, R. A. Orellana, H. V. Nguyen, and M. L. Fiorotto Postnatal ontogeny of skeletal muscle protein synthesis in pigs J Anim Sci, April 1, 2008; 86(14_suppl): E13 - E18. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Suryawan, R. A. Orellana, H. V. Nguyen, A. S. Jeyapalan, J. R. Fleming, and T. A. Davis Activation by insulin and amino acids of signaling components leading to translation initiation in skeletal muscle of neonatal pigs is developmentally regulated Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1597 - E1605. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Yuan, J. Deng, T. Wang, C. Zhao, X. Xu, P. Wang, J. W. Voltz, M. L. Edin, X. Xiao, L. Chao, et al. Tissue Kallikrein Reverses Insulin Resistance and Attenuates Nephropathy in Diabetic Rats by Activation of Phosphatidylinositol 3-Kinase/Protein Kinase B and Adenosine 5'-Monophosphate-Activated Protein Kinase Signaling Pathways Endocrinology, May 1, 2007; 148(5): 2016 - 2026. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Suryawan, J. Escobar, J. W. Frank, H. V. Nguyen, and T. A. Davis Developmental regulation of the activation of signaling components leading to translation initiation in skeletal muscle of neonatal pigs Am J Physiol Endocrinol Metab, October 1, 2006; 291(4): E849 - E859. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Su, I. J. Lodhi, A. R. Saltiel, and P. D. Stahl Insulin-stimulated Interaction between Insulin Receptor Substrate 1 and p85{alpha} and Activation of Protein Kinase B/Akt Require Rab5 J. Biol. Chem., September 22, 2006; 281(38): 27982 - 27990. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Galic, C. Hauser, B. B. Kahn, F. G. Haj, B. G. Neel, N. K. Tonks, and T. Tiganis Coordinated Regulation of Insulin Signaling by the Protein Tyrosine Phosphatases PTP1B and TCPTP Mol. Cell. Biol., January 15, 2005; 25(2): 819 - 829. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. C. King and A. C. Newton The Adaptor Protein Grb14 Regulates the Localization of 3-Phosphoinositide-dependent Kinase-1 J. Biol. Chem., September 3, 2004; 279(36): 37518 - 37527. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Schiffer, P. Mundel, A. S. Shaw, and E. P. Bottinger A Novel Role for the Adaptor Molecule CD2-associated Protein in Transforming Growth Factor-{beta}-induced Apoptosis J. Biol. Chem., August 27, 2004; 279(35): 37004 - 37012. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ibarrola, H. Molina, A. Iwahori, and A. Pandey A Novel Proteomic Approach for Specific Identification of Tyrosine Kinase Substrates Using [13C]Tyrosine J. Biol. Chem., April 16, 2004; 279(16): 15805 - 15813. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. H. Mahabeleshwar, R. Das, and G. C. Kundu Tyrosine Kinase, p56lck-induced Cell Motility, and Urokinase-type Plasminogen Activator Secretion Involve Activation of Epidermal Growth Factor Receptor/Extracellular Signal Regulated Kinase Pathways J. Biol. Chem., March 12, 2004; 279(11): 9733 - 9742. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. R. Salas, S. A. Reddy, J. L. Clifford, R. J. Davis, A. Kikuchi, S. M. Lippman, and D. G. Menter Alleviating the Suppression of Glycogen Synthase Kinase-3{beta} by Akt Leads to the Phosphorylation of cAMP-response Element-binding Protein and Its Transactivation in Intact Cell Nuclei J. Biol. Chem., October 17, 2003; 278(42): 41338 - 41346. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Esposito, G. Chirico, N. M. Gesualdi, I. Posadas, R. Ammendola, T. Russo, G. Cirino, and F. Cimino Protein Kinase B Activation by Reactive Oxygen Species Is Independent of Tyrosine Kinase Receptor Phosphorylation and Requires Src Activity J. Biol. Chem., May 30, 2003; 278(23): 20828 - 20834. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rome, K. Clement, R. Rabasa-Lhoret, E. Loizon, C. Poitou, G. S. Barsh, J.-P. Riou, M. Laville, and H. Vidal Microarray Profiling of Human Skeletal Muscle Reveals That Insulin Regulates ~800 Genes during a Hyperinsulinemic Clamp J. Biol. Chem., May 9, 2003; 278(20): 18063 - 18068. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Kilkenny, J. V. Rocheleau, J. Price, M. B. Reich, and G. G. Miller c-Src Regulation of Fibroblast Growth Factor-induced Proliferation in Murine Embryonic Fibroblasts J. Biol. Chem., May 2, 2003; 278(19): 17448 - 17454. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Sanoudou, J. N. Haslett, A. T. Kho, S. Guo, H. T. Gazda, S. A. Greenberg, H. G. W. Lidov, I. S. Kohane, L. M. Kunkel, and A. H. Beggs Expression profiling reveals altered satellite cell numbers and glycolytic enzyme transcription in nemaline myopathy muscle PNAS, April 15, 2003; 100(8): 4666 - 4671. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Galic, M. Klingler-Hoffmann, M. T. Fodero-Tavoletti, M. A. Puryer, T.-C. Meng, N. K. Tonks, and T. Tiganis Regulation of Insulin Receptor Signaling by the Protein Tyrosine Phosphatase TCPTP Mol. Cell. Biol., March 15, 2003; 23(6): 2096 - 2108. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Krebs and D. J. Hilton A New Role for SOCS in Insulin Action Sci. Signal., February 11, 2003; 2003(169): pe6 - pe6. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. P. J. van den Heuvel, A. M. M. de Vries-Smits, P. C. van Weeren, P. F. Dijkers, K. M. T. de Bruyn, J. A. Riedl, and B. M. T. Burgering Binding of protein kinase B to the plakin family member periplakin J. Cell Sci., October 15, 2002; 115(20): 3957 - 3966. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Lawlor and D. R. Alessi PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J. Cell Sci., March 10, 2002; 114(16): 2903 - 2910. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Akeno, J. Robins, M. Zhang, M. F. Czyzyk-Krzeska, and T. L. Clemens Induction of Vascular Endothelial Growth Factor by IGF-I in Osteoblast-Like Cells Is Mediated by the PI3K Signaling Pathway through the Hypoxia-Inducible Factor-2{alpha} Endocrinology, February 1, 2002; 143(2): 420 - 425. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Shao, H. Yamashita, L. Qiao, B. Draznin, and J. E. Friedman Phosphatidylinositol 3-Kinase Redistribution Is Associated With Skeletal Muscle Insulin Resistance in Gestational Diabetes Mellitus Diabetes, January 1, 2002; 51(1): 19 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Park, M. M. Hill, D. Hess, D. P. Brazil, J. Hofsteenge, and B. A. Hemmings Identification of Tyrosine Phosphorylation Sites on 3-Phosphoinositide-dependent Protein Kinase-1 and Their Role in Regulating Kinase Activity J. Biol. Chem., September 28, 2001; 276(40): 37459 - 37471. [Abstract] [Full Text] [PDF]
|
|
