Atypical protein kinase C (PKCzeta/lambda) is a convergent downstream target of the insulin-stimulated phosphatidylinositol 3-kinase and TC10 signaling pathways.
Insulin stimulation of adipocytes resulted in the recruitment of atypical PKC (PKCzeta/lambda) to plasma membrane lipid raft microdomains. This redistribution of PKCzeta/lambda was prevented by Clostridium difficile toxin B and by cholesterol depletion, but was unaffected by inhibition of phosphatidylinositol (PI) 3-kinase activity. Expression of the constitutively active GTP-bound form of TC10 (TC10Q/75L), but not the inactive GDP-bound mutant (TC10/T31N), targeted PKCzeta/lambda to the plasma membrane through an indirect association with the Par6-Par3 protein complex. In parallel, insulin stimulation as well as TC10/Q75L resulted in the activation loop phosphorylation of PKCzeta. Although PI 3-kinase activation also resulted in PKCzeta/lambda phosphorylation, it was not recruited to the plasma membrane. Furthermore, insulin-induced GSK-3beta phosphorylation was mediated by both PI 3-kinase-PKB and the TC10-Par6-atypical PKC signaling pathways. Together, these data demonstrate that PKCzeta/lambda can serve as a convergent downstream target for both the PI 3-kinase and TC10 signaling pathways, but only the TC10 pathway induces a spatially restricted targeting to the plasma membrane.
Kanzaki
Makoto
M
Dept. of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794-8651, USA.
Mora
Silvia
S
Hwang
Joseph B
JB
Saltiel
Alan R
AR
Pessin
Jeffrey E
JE
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000502:physiology*; D000818:Animals; D002458:Cell Fractionation; D002462:Cell Membrane / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D007527:Isoenzymes; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D021381:Protein Transport; D013379:Substrate Specificity; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta
D007328:Insulin; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D020741:rho GTP-Binding Proteins; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta; C503260:Rhoq protein, mouse