The functional significance of Shc in insulin signaling as a substrate of the insulin receptor.
Shc is composed of 46-, 52-, 66-kDa isoforms which arise from alternative splicing of the primary Shc transcript. Upon insulin stimulation, the activated insulin receptor interacts with Shc. The NPXY motif around 960-Tyr residue of the insulin receptor binds to the N-terminal PTB domain of Shc. Subsequently, the 52-kDa, and, to a lesser extent, the 46-kDa Shc isoforms are tyrosine phosphorylated. Although Tyr-239/240 and Tyr-317 residues are the possible candidates of Shc phosphorylation sites, insulin predominantly phosphorylates the Shc Tyr-317 residue. Phosphorylated Shc binds to Grb2 which forms a complex with Sos guanine nucleotide exchange factor for p21ras. Both tyrosine-phosphorylated Shc and IRS can bind to Grb2, but Shc . Grb2 . Sos is the predominant coupling pathway from the activated insulin receptor to p21ras. Along this line, microinjection of anti-Shc antibody inhibited insulin-induced mitogenesis, and the guanine nucleotide exchange activity for p21ras is tightly associated with Shc, but not with IRS. On the other hand, insulin only transiently activates p21ras for the strict hormonal regulation. For this regulation, longer time of insulin treatment deactivates p21ras by dissociation of Sos from the Shc . Grb2 . Sos complex while Shc is still complexed with Grb2. Thus, Shc plays a critical role in insulin-induced mitogenesis through regulation of p21ras activity. As regards the impact of Shc on the metabolic aspects, Shc is shown to compete with IRS as the substrate of the insulin receptor. Thus, IRS mediated downstream signaling leading to glycogen synthesis was decreased by overexpression of Shc. Taken together, Shc appears to play an important role in insulin induced mitogenesis, whereas Shc may not be required for regulation of the metabolic aspects of insulin.
Sasaoka
T
T
Department of Clinical Pharmacology, Toyama Medical & Pharmaceutical University, Japan.
Kobayashi
M
M
D000818:Animals; D006801:Humans; D007328:Insulin / Q000502:physiology*; D019751:Intramolecular Transferases / Q000502:physiology*; D011972:Receptor, Insulin / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D007328:Insulin; D011972:Receptor, Insulin; D019751:Intramolecular Transferases; C066630:squalene-hopene cyclase