Structural and functional characterization of insulin receptor substrate proteins and the molecular mechanisms of their interaction with insulin superfamily tyrosine kinase receptors and effector proteins.
The literature data on the role of IRS1/IRS2 proteins, endogenous substrates for insulin receptor tyrosine kinase, in transduction of signals generated by insulin superfamily peptides (insulin, insulin-like growth factor) were analyzed. The molecular mechanisms of the functional coupling of IRS proteins with peptide receptors possessing a tyrosine kinase activity and SH2 domain-containing proteins (phosphatidylinositol 3-kinase, Grb2 adaptor protein, protein phosphotyrosine phosphatase) were discussed. The structural and functional properties of IRS proteins (distribution of functional domains and sites for tyrosine phosphorylation; conservatism of amino acid sequences) were characterized. The data on the alternative pathways of transduction of signals which are generated by insulin and related peptides and do not involve IRS proteins were analyzed. These pathways are realized through Shc proteins or via direct interaction between receptors and SH2 proteins. Amino acid sequences of IRS proteins and insulin superfamily tyrosine kinase receptors were compared. The homologous regions in IRS proteins and receptors, which can be responsible for their coupling with phosphatidylinositol 3-kinase and protein phosphotyrosine phosphatases, were identified.
Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg. shpakov@ief.spb.su
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D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D018909:src Homology Domains / Q000502:physiology
C526292:IRS1 protein, human; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D007334:Insulin-Like Growth Factor I; D011972:Receptor, Insulin