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Volume 271, Number 26, Issue of June 28, 1996 pp. 15311-15314
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Interactions of Protein Kinase C with Insulin Signaling
INFLUENCE ON GAP AND SOS ACTIVITIES

(Received for publication, December 20, 1995, and in revised form, March 28, 1996)

From the Medical Research Service and the Department of Medicine, Veterans Affairs Medical Center and the University of Colorado Health Sciences Center, Denver, Colorado 80220

In this study, we investigated the influence of the protein kinase C (PKC)-dependent system upon the ability of insulin to stimulate p21^ras·GTP loading in 3T3-L1 adipocytes. Activation of PKC by 12-0-tetradecanoylphorbol-13-acetate (TPA) did not affect the basal amount of p21^ras·GTP but significantly reduced insulin-induced increases in p21^ras·GTP. This reduction was due to inhibition of the insulin's ability to stimulate guanine nucleotide exchange activity of Sos in cells incubated with 100 nM TPA for either 30 min or 3 h. TPA had no effect on basal activity of Sos.

Depletion of PKC by an 18-h incubation with TPA or inhibition by bisindolylmaleimide resulted in profound inhibition of the insulin-induced p21^ras·GTP loading. In contrast to PKC activation, removal of PKC did not influence Sos activity but resulted in a 2-fold stimulation of GTPase activating protein (GAP). This effect of PKC depletion is unique to 3T3-L1 adipocytes and was not observed in either 3T3-L1 fibroblasts or Rat-1 fibroblasts. Thus, it appears that in 3T3-L1 adipocytes, PKC has a constitutive inhibitory effect on GAP that permits insulin to activate Sos and p21^ras. Removal of this inhibitory influence activates GAP and reduces insulin-stimulated p21^ras·GTP loading.

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