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L6 myoblast differentiation is modulated by Cdk5 via the PI3K-AKT-p70S6K signaling pathway

Krishna P Sarker1, Ki-Young Lee

  • 1Department of Cell Biology and Anatomy, Cancer Biology and Neuroscience Research Groups, The University of Calgary, Calgary, Alberta, Canada T2N 4N1.

Oncogene
|June 23, 2004
PubMed

Insights

This study identifies a PI3K-Akt-p70S6K-Egr-1 signaling cascade as a key upstream regulator of Cdk5 activity during L6 myoblast differentiation, uncovering a novel pathway for myogenesis control.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Cyclin-dependent kinase 5 (Cdk5) plays a crucial role in myogenesis, the process of muscle cell differentiation.
  • The precise signaling pathways through which Cdk5 regulates myogenesis are not fully understood.
  • Identifying upstream regulators of Cdk5 is essential for elucidating its role in muscle development.

Purpose of the Study:

  • To investigate the involvement of phosphatidylinositol 3-kinase (PI3K), Akt, p70S6K, p38 mitogen-activated protein kinase (MAPK), p44/42 MAPK, and early growth response protein 1 (Egr-1) as upstream regulators of Cdk5 during L6 myoblast differentiation.
  • To elucidate the signaling cascade connecting these molecules to Cdk5 activation and subsequent myogenesis.

Main Methods:

  • L6 myoblast differentiation was induced by serum reduction.
  • Activities of various signaling molecules including Cdk5, Akt, p70S6K, and MAPKs were assessed.
  • Specific inhibitors (LY294002 for PI3K, Rapamycin for mTOR, SB2023580 for p38 MAPK) and dominant-negative Akt were used to dissect signaling pathways.
  • Expression levels of key proteins like Egr-1 and myogenin were measured.

Main Results:

  • Serum reduction upregulated Cdk5/p35 activity, Egr-1, Akt, p70S6K, and p38 MAPK, while downregulating p44/42 MAPK.
  • PI3K inhibition (LY294002) blocked Akt and p70S6K activation, and subsequently Egr-1, Cdk5 activity, and myogenin expression.
  • mTOR inhibition (Rapamycin) also blocked p70S6K activation, Egr-1, Cdk5 activity, and myogenin expression.
  • p38 MAPK activation was independent of PI3K and did not affect the PI3K-Akt-p70S6K-Egr-1 pathway.

Conclusions:

  • A novel signaling cascade involving PI3K-Akt-p70S6K-Egr-1 acts as an upstream modulator of Cdk5 activity during L6 myoblast differentiation.
  • This pathway is crucial for regulating myogenin expression and facilitating myogenesis.
  • p38 MAPK activation occurs independently and does not directly influence this Cdk5-regulating pathway.

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