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PLC-1 Enzyme Activity Is Required for Insulin-Induced DNA Synthesis

Medical Research Service (J.E., A.G.K., L.R., D.A.A., N.J.G.W.), San Diego Veterans Affairs Healthcare System, San Diego, California 92161; and University of California San Diego/Whittier Diabetes Program (J.E., A.G.K., D.W.R., N.J.G.W.), Department of Medicine (J.E., A.G.K., D.W.R., N.J.G.W.), and University of California San Diego Cancer Center (N.J.G.W.), University of California, San Diego, California 92093

Address all correspondence and requests for reprints to: Nicholas J. G. Webster, Department of Medicine (0673), University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0673. E-mail: nwebster{at}ucsd.edu

Previously, we had shown that inhibition of PLC activity impaired the ability of insulin to activate ERK in 3T3-L1 adipocytes. In this study, we confirmed that the insulin receptor and PLC-1 are physically associated in hIRcB fibroblasts, insulin stimulates PLC-1 enzyme activity, and inhibition of PLC activity impairs activation of ERK. We subsequently investigated whether PLC-1 is required for insulin-stimulated mitogenesis. First, inhibition of PLC activity using U73122 impairs the ability of insulin to stimulate DNA synthesis. Second, disruption of the interaction of the insulin receptor with PLC-1 by microinjection of SH2 domains derived from PLC-1 or Grb2 but not Shc similarly blocks insulin-induced DNA synthesis. Third, microinjection of neutralizing antibodies to PLC-1 blocks DNA synthesis, but nonneutralizing antibodies do not. The blockade in all three cases is rescued by synthetic diacylglycerols but not by inositol-1,4,5-trisphosphate, indicating a requirement for PLC enzyme activity. These experimental data point to a requirement for PLC-1 in insulin-stimulated mitogenesis in hIRcB cells.

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