J. Cell Biol., Volume 144, Number 3, February 8, 1999 413-425

Evidence That Atypical Protein Kinase C- and Atypical Protein Kinase C- Participate in Ras-mediated Reorganization of the F-actin Cytoskeleton

Florian Überall,^* Karina Hellbert,^* Sonja Kampfer,^* Karl Maly,^* Andreas Villunger,^* Martin Spitaler,^* James Mwanjewe,^* Gabriele Baier-Bitterlich,^* Gottfried Baier, and Hans H. Grunicke^*

^* Institute of Medical Chemistry and Biochemistry and  Institute of Medical Biology and Human Genetics, University of Innsbruck, A-6020 Innsbruck, Austria

Expression of transforming Ha-Ras L61 in NIH3T3 cells causes profound morphological alterations which include a disassembly of actin stress fibers. The Ras-induced dissolution of actin stress fibers is blocked by the specific PKC inhibitor GF109203X at concentrations which inhibit the activity of the atypical aPKC isotypes  and , whereas lower concentrations of the inhibitor which block conventional and novel PKC isotypes are ineffective. Coexpression of transforming Ha-Ras L61 with kinase-defective, dominant-negative (DN) mutants of aPKC- and aPKC-, as well as antisense constructs encoding RNA-directed against isotype-specific 5' sequences of the corresponding mRNA, abrogates the Ha-Ras-induced reorganization of the actin cytoskeleton. Expression of a kinase-defective, DN mutant of cPKC- was unable to counteract Ras with regard to the dissolution of actin stress fibers. Transfection of cells with constructs encoding constitutively active (CA) mutants of atypical aPKC- and aPKC- lead to a disassembly of stress fibers independent of oncogenic Ha-Ras. Coexpression of (DN) Rac-1 N17 and addition of the phosphatidylinositol 3'-kinase (PI3K) inhibitors wortmannin and LY294002 are in agreement with a tentative model suggesting that, in the signaling pathway from Ha-Ras to the cytoskeleton aPKC- acts upstream of PI3K and Rac-1, whereas aPKC- functions downstream of PI3K and Rac-1.

This model is supported by studies demonstrating that cotransfection with plasmids encoding L61Ras and either aPKC- or aPKC- results in a stimulation of the kinase activity of both enzymes. Furthermore, the Ras-mediated activation of PKC- was abrogated by coexpression of DN Rac-1 N17.

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