
International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #59: Mechanisms of insulin signal transduction Part 3 of 8
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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #59: Mechanisms of insulin signal transduction Part 3 of 8
Following insulin binding and receptor autophosphorylation, the next committed step in signal transduction is tyrosine phosphorylation of intracellular proteins. To accomplish this, autophosphorylation of the subunit mediates noncovalent but stable interactions between the receptor and intracellular substrate proteins, and this positions these molecules for tyrosine phosphorylation by the activated insulin receptor kinase [26 28]. Several proteins are rapidly phosphorylated on tyrosine residues by ligand-bound insulin receptors, including six insulin receptor substrate proteins (IRS-1, IRS-2, IRS-3, IRS-4, IRS-5, IRS-6) [29 33], Src-homology-collagen proteins (SHC) [34] and, growth factor receptor bound-2 (Grb2) associated binder-1 (Gab-1) [35], signal-regulatory protein (SIRP) family members [36,37], the CAP/c-Cbl complex [38,39], an adapter protein with a PH and SH2 domain (APS) [40], signal transducer and activator of transcription 5B (STAT5B) [41], and proteins referred to as downstream of kinase (DOK 1-6) [33,42].
There is no known enzymatic activity associated with insulin receptor substrate molecules; however, their primary structure is noteworthy for multiple sites capable of interaction with other proteins. The receptor substrates are characterized by a representative architecture, par
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