Insulin Like Growth Factor 1 Receptor Signal Transduction to the Nucleus
The IGF-1 receptor (IGF-1R) is a member of the tyrosine kinase class of cell surface receptors which become autophosphorylated on tyrosyl residues upon ligand binding (Czech, 1989). It has striking homology to the insulin receptor; however, each receptor maintains a unique specificity for its own ligand (Schumacher et al., 1991). The mechanism by which the binding of IGF-1 to its receptor elicits a cellular effect has been the subject of considerable research with a singular cohesive model having yet to be defined. The autophosphorylation of the IGF-1R via subunit transphosphorylation is clearly a necessary requisite for transmission of an intracellular signal, as found for the insulin receptor (Sweet et al., 1987; Ullrich and Schlessinger, 1990). In the case of other growth factor receptors with tyrosine kinase domains such as the EGF and PDGF receptors, receptor activation results in phospholipase C activation leading to 1,2-diacylglycerol and inositol 1,4,5-trisphosphate production and a corresponding increase in protein kinase C (pkC) and calcium mobilization, respectively (Berridge, 1993). Recently, evidence for a direct association between the EGF and PDGF receptors and a number of key substrates such as phospholipase C-γ, PI-3 kinase and GAP (p21ras GTPase activating protein, Cantley et al., 1991) has been demonstrated. This direct link has also been established for the IGF-1R and PI-3 kinase interactions (Cantley et al., 1991; Yamamoto et al., 1992; Lavan et al., 1992). It was recently reported that in cells stimulated with insulin in the presence of the protein tyrosine phosphatase inhibitor, phenylarsine oxide, 5–10% of the cellular GAP associates with the insulin receptor (Pronk et al., 1992).
KeywordsInsulin Receptor Nuclear Extract PDGF Receptor CaSki Cell Tyrosyl Residue
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