Activation of glycogen synthase by insulin in 3T3-L1 adipocytes involves c-Cbl-associating protein (CAP)-dependent and CAP-independent signaling pathways

In adipose and muscle, insulin stimulates glucose uptake and glycogen synth ase activity. Phosphatidylinositol 3-kinase (PI3K) activation is necessary but not sufficient for these metabolic actions of insulin. The insulin stim ulated translocation of phospho c-Cbl to lipid rafts, via its association w ith CAP, comprises a second pathway regulating GLUT4 translocation. In 3T3- L1 adipocytes, overexpression of a dominant negative CAP mutant (CAP Delta SH3) completely blocked the insulin-stimulated glucose transport and glycog en synthesis but only partially inhibited glycogen synthase activation. In contrast, CAP Delta SH3 expression did not affect glycogen synthase activat ion by insulin in the absence of extracellular glucose. Moreover, CAP Delta SH3 has no effect on the PI3K dependent activation of protein phosphatase- l or phosphorylation of glycogen synthase kinase-3. These results indicate blockade of the c-Cbl/CAP pathway directly inhibits insulin-stimulated gluc ose uptake, which results in secondary inhibition of glycogen synthase acti vation and glycogen synthesis.