Atypical protein kinase C (PKCζ/λ) is a convergent downstream target of the insulin-stimulated phosphatidylinositol 3-kinase and TC10 signaling pathways

Abstract

Insulin stimulation of adipocytes resulted in the recruitment of atypical PKC (PKCζ/λ) to plasma membrane lipid raft microdomains. This redistribution of PKCζ/λ 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 PKCζ/λ 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 PKCζ. Although PI 3-kinase activation also resulted in PKCζ/λ phosphorylation, it was not recruited to the plasma membrane. Furthermore, insulin-induced GSK-3β phosphorylation was mediated by both PI 3-kinase–PKB and the TC10–Par6–atypical PKC signaling pathways. Together, these data demonstrate that PKCζ/λ 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.

Regulation of glioblastoma cell invasion by PKCι and RhoB

“…The effects of pharmacological inhibition of PKCi on RhoB expression were assessed using a myristoylated atypical PKC pseudosubstrate peptide (Kanzaki et al, 2004). For these experiments, PKCi activity was monitored with an antibody that recognizes Thr555-phosphorylated PKCi.…”

“…The PI3K pathway activates multiple downstream kinases including protein kinase C type i (PKCi), a member of the atypical protein kinase C family (Akimoto et al, 1996). PKCi activation involves phosphorylation by PDK1 and binding to a Cdc42 family protein (Kanzaki et al, 2004). The potential importance of PKCi as a downstream mediator in the PI3K pathway has been emphasized by the recent finding that it can itself function as an oncogene in both lung and ovarian cancers (Eder et al, 2005;Regala et al, 2005b).…”

Specific protein kinase C isoforms as transducers and modulators of insulin signaling

“…Tyrosine phosphorylation of PKC isoforms has the ability to utilize the enzyme as a docking protein, like IRS, for various other proteins. This could be especially important in the alternative signaling pathway involving c-cbl and TC10 [154] where the caveolae contain multiple PKC binding proteins that have not been characterized [155]. These proteins could play some role in endocytosis/exocytosis or fatty acid transport.…”

Repression of cancer cell senescence by PKCι

“…Both of the atypical PKCs are distinguished from the other members of the PKC family by their lack of dependence on diacylglycerol for activation. PKCi is activated by PDK1 phosphorylation either on its own or in association with a complex of an activated member of the Cdc42 family of GTPases and Par6 (Kanzaki et al, 2004). Of the two enzymes, PKCi is the most ubiquitously expressed and there is now considerable evidence linking PKCi to the transformed phenotype (Fields and Regala, 2007).…”