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Atypical protein kinase Cs are the Ras effectors that mediate repression of myogenic satellite cell differentiation

Yuri V Fedorov1, Nathan C Jones, Bradley B Olwin

  • 1Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80309, USA.

Molecular and Cellular Biology
|January 26, 2002
PubMed

Insights

Oncogenic Ha-Ras inhibits muscle cell differentiation by activating atypical protein kinases (aPKCs). Inhibiting aPKCs promotes myogenesis, revealing a key pathway in skeletal muscle development.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Oncogenic Ha-Ras is known to inhibit skeletal muscle cell differentiation.
  • The specific Ras effector responsible for this inhibition has not been identified.

Purpose of the Study:

  • To identify the downstream Ras effector mediating the inhibition of myogenic differentiation.
  • To elucidate the role of atypical protein kinases (aPKCs) in Ras-dependent muscle cell differentiation.

Main Methods:

  • Ectopic expression of oncogenic Ha-Ras (Ha-RasG12V) in a satellite cell line.
  • Assessing the translocation of protein kinase C lambda (PKClambda) in response to Ha-Ras.
  • Inhibiting aPKCs using a dominant-negative PKCzeta mutant and the chemical inhibitor GO6983.
  • Evaluating the effects of Ha-Ras and aPKC inhibition on myogenic differentiation and cell proliferation.

Main Results:

  • Oncogenic Ha-Ras expression induced PKClambda translocation to the nucleus, indicating aPKC activation.
  • Inhibition of aPKCs promoted myogenesis in Ha-Ras-expressing skeletal muscle satellite cells.
  • Simultaneous inhibition of aPKCs and cell proliferation synergistically enhanced myogenic differentiation.

Conclusions:

  • Atypical protein kinases (aPKCs) are identified as downstream Ras effectors that directly inhibit myogenic differentiation.
  • Ras-mediated repression of skeletal muscle differentiation occurs both directly via aPKCs and indirectly through the stimulation of cell proliferation.

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