Mek1 alters epidermal growth and differentiation

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12:37

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Published on: September 7, 2013

Florence A Scholl1, Phillip A Dumesic, Paul A Khavari

  • 1VA Palo Alto Healthcare System, Palo Alto, California 94305, USA.

Cancer Research
|September 3, 2004
PubMed

Insights

Mek1 and Mek2 kinases activate ERK. Mek1, but not Mek2, drives epidermal hyperplasia and suppresses differentiation, mimicking neoplasia, even without kinase activity.

Area of Science:

  • Molecular biology
  • Cell signaling
  • Dermatology

Background:

  • Mek1 and Mek2 are homologous kinases downstream of Ras/Raf, activating ERK.
  • Ras/Raf signaling in epidermis promotes hyperplasia via multiple effectors.
  • The specific roles of Mek1 and Mek2 in mediating Ras/Raf effects are not fully understood.

Purpose of the Study:

  • To investigate the distinct roles of Mek1 and Mek2 in epidermal signaling.
  • To determine the extent to which Mek kinases mediate Ras/Raf-driven epidermal hyperplasia.
  • To elucidate the mechanism by which Mek1 promotes epidermal proliferation.

Main Methods:

  • Expression of inducible Mek1 and Mek2 in transgenic murine and human epidermis.
  • Analysis of ERK phosphorylation levels.
  • Assessment of epidermal proliferation, differentiation, and integrin expression.
  • Utilizing a kinase-dead Mek1 mutant.

Main Results:

  • Both Mek1 and Mek2 induced ERK phosphorylation.
  • Mek1, but not Mek2, replicated Ras/Raf effects: increased proliferation, integrin expression, and suppressed differentiation.
  • A kinase-dead Mek1 mutant retained the ability to promote epidermal proliferation, independent of ERK phosphorylation.

Conclusions:

  • Mek1 is sufficient to induce the proliferative epithelial phenotype characteristic of neoplasia.
  • Mek1-driven epidermal proliferation can occur independently of its kinase activity.
  • Mek1 possesses functions beyond ERK activation that contribute to epidermal hyperplasia.

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