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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,,{dagger} 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; {lambda} and/or {zeta}) 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{lambda} 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{zeta} 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.

* Corresponding author. Mailing address: Department of Molecular, Cellular and Developmental Biology, 347 UCB, University of Colorado, Boulder, CO 80309. Phone: (303) 492-6816. Fax: (303) 492-1587. E-mail: Bradley.Olwin{at}colorado.edu.

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

Molecular and Cellular Biology, February 2002, p. 1140-1149, Vol. 22, No. 4
0022-538X/01/$04.00+0     DOI: 10.1128/MCB.22.4.1140-1149.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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