Opposite regulation of tyrosine-phosphorylation of p130(Cas) by insulin and insulin-like growth factor I.
To investigate the difference in signaling between insulin and insulin-like growth factor I (IGF-I), we studied the effects of these hormones on the phosphorylation state of Crk-associated substrate (Cas) in cells expressing human insulin receptor (HIRc). In the basal state, Cas was heavily tyrosine-phosphorylated, and insulin dephosphorylated Cas in a ... time- and dose-dependent manner. On the other hand, IGF-I phosphorylated rather than dephosphorylated Cas in HIRc cells. In HIRY/F2 cells expressing a mutant insulin receptor lacking a binding site of SHP-2, a protein-tyrosine phosphatase containing src homology 2 (SH2) regions, insulin accelerated phosphorylation of Cas, as did IGF-I. In HIRc cells expressing a mutant SHP-2 lacking a PTPase domain (DeltaPTP), which interfered with SHP-2 function, insulin failed to dephosphorylate Cas. In whole cell lysate obtained in the basal state, Cas bound to a glutathione-S transferase fusion protein containing SH2 domains of SHP-2 and dissociated from this GST protein in response to insulin. These results indicate that the opposite regulation of Cas phosphorylation by insulin and IGF-I may be mediated through different properties of their receptors, and that the interaction of the insulin receptor with SHP-2 may play an important role in determining the tyrosine-phosphorylation state of Cas.
Mesh Terms:
Animals, Binding Sites, Cells, Cultured, Fibroblasts, Glutathione Transferase, Humans, Insulin, Insulin-Like Growth Factor I, Intracellular Signaling Peptides and Proteins, Mutation, Phosphorylation, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Rats, Receptor, Insulin, Recombinant Fusion Proteins, Signal Transduction, Tyrosine, Ubiquitin-Protein Ligases
Animals, Binding Sites, Cells, Cultured, Fibroblasts, Glutathione Transferase, Humans, Insulin, Insulin-Like Growth Factor I, Intracellular Signaling Peptides and Proteins, Mutation, Phosphorylation, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Rats, Receptor, Insulin, Recombinant Fusion Proteins, Signal Transduction, Tyrosine, Ubiquitin-Protein Ligases
J. Biochem.
Date: Dec. 01, 1998
PubMed ID: 9832615
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