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Molecular and Cellular Biology, February 2002, p. 1140-1149, Vol. 22, No. 4
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.4.1140-1149.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Atypical Protein Kinase Cs Are the Ras Effectors That Mediate Repression of Myogenic Satellite Cell Differentiation

Yuri V. Fedorov, Nathan C. Jones,^, and Bradley B. Olwin^*

Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80309

Received 29 May 2001/ Returned for modification 2 July 2001/ Accepted 5 November 2001

Oncogenic Ha-Ras is a potent inhibitor of skeletal muscle cell differentiation, yet the Ras effector mediating this process remains unidentified. Here we demonstrate that the atypical protein kinases (aPKCs; and/or ) are downstream Ras effectors responsible for Ras-dependent inhibition of myogenic differentiation in a satellite cell line. First, ectopic expression of Ha-RasG12V induces translocation of PKC from the cytosol to the nucleus, suggesting that aPKCs are activated by Ras in myoblasts. The aPKCs function as downstream Ras effectors since inhibition of aPKCs by expression of a dominant negative PKC mutant or by treatment of cells with an inhibitor, GO6983, promotes myogenesis in skeletal muscle satellite cells expressing oncogenic Ha-Ras. Arresting cell proliferation synergistically enhances myogenic differentiation only when aPKCs are also inhibited. Thus, the repression of myogenic differentiation in a satellite cell line appears to be directly mediated by aPKCs acting as Ras effectors and indirectly mediated via stimulation of cell proliferation.

Present address: Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Denver, CO 80262.

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