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Gab1 and SHP-2 promote Ras/MAPK regulation of epidermal growth and differentiation

Ti Cai1, Keigo Nishida, Toshio Hirano

  • 1Veterans Affairs Palo Alto Healthcare System and the Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.

The Journal of Cell Biology
|October 9, 2002
PubMed

Insights

Regulators of epidermal Ras function, Gab1 and SHP-2, promote undifferentiated skin cells by facilitating Ras/MAPK signaling. Gab1 and SHP-2 are key to maintaining skin cell proliferation and differentiation.

Area of Science:

  • Dermatology
  • Cell Biology
  • Molecular Biology

Background:

  • Ras signaling pathways are critical regulators of epidermal cell proliferation and differentiation.
  • The precise mechanisms and regulators of epidermal Ras function remain incompletely understood, with controversial effects on growth and differentiation.

Purpose of the Study:

  • To investigate the roles of Gab1 and SHP-2 as regulators of epidermal Ras function.
  • To elucidate the contribution of Gab1 and SHP-2 to Ras/MAPK signaling in epidermal homeostasis.

Main Methods:

  • Utilized mutant Gab1 (Gab1Y627F) and dominant-negative SHP-2 (SHP-2C459S) to disrupt SHP-2 binding to Gab1.
  • Generated transgenic human epidermis overexpressing active Gab1 and SHP-2.
  • Created Gab1 knockout (Gab1-/-) murine epidermis.
  • Assessed levels of active Ras and MAPK proteins, and evaluated epidermal proliferation and differentiation.

Main Results:

  • Disruption of Gab1-SHP-2 interaction (Gab1Y627F, SHP-2C459S) reduced active Ras and MAPK, initiating epidermal differentiation.
  • Overexpression of active Gab1 and SHP-2 stimulated epidermal proliferation.
  • Gab1-/- epidermis exhibited reduced active Ras and MAPK, with hypoplasia and enhanced differentiation.
  • Ras activation blocked differentiation induced by Gab1Y627F and SHP-2C459S, indicating Gab1 and SHP-2 act upstream of Ras.

Conclusions:

  • Gab1 and SHP-2 facilitate Ras/MAPK signaling, promoting an undifferentiated epidermal cell state.
  • These findings support a role for Ras in promoting epidermal proliferation and inhibiting differentiation.
  • Gab1 and SHP-2 are crucial upstream regulators of Ras/MAPK signaling in the epidermis.

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