Inhibition of insulin-induced glucose uptake by atypical protein kinase C isotype-specific interacting protein in 3T3-L1 adipocytes

Atypical protein kinase C (PKC) isotype-specific interacting protein (ASIP) specifically interacts with the atypical protein kinase C isozymes PKC lam bda and PKC zeta. ASIP and atypical PKC, as well as their Caenorhabditis el egans counterparts (PAR-3 and PKC-3, respectively), are thought to coordina tely participate in intracellular signaling that contributes to the mainten ance of cellular polarity and to the formation of junctional complexes. The potential role of ASIP in other cellular functions of atypical PKC was inv estigated by examining the effect of overexpression of ASIP on insulin-indu ced glucose uptake, previously shown to be mediated through PKC lambda, in 3T3-L1 adipocytes. When overexpressed in these cells, which contain PKC lam bda but not PKC zeta, ASIP was co-immunoprecipitated with endogenous PKC la mbda but not with PKC epsilon or with Akt, The subcellular localization of PKC lambda was also altered in cells overexpressing ASIP. Overexpression of ASIP inhibited insulin stimulation of both glucose uptake and translocatio n of the glucose transporter GLUT4 to the plasma membrane, but it did not i nhibit glucose uptake induced by either growth hormone or hyperosmolarity b oth of which promote glucose uptake in a PKC lambda-independent manner. Mor eover, glucose uptake stimulated by a constitutively active mutant of PKC l ambda, but not that induced by an active form of Akt, was inhibited by ASIP . Insulin-induced activation of PKC lambda, but not that of phosphoinositid e 3-kinase or Akt, was also inhibited by overexpression of ASIP. These data suggest that overexpression of ASIP inhibits insulin-induced glucose uptak e by specifically interfering with signals transmitted through PKC lambda.