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The MEK-ERK pathway is necessary for serine phosphorylation of mitochondrial STAT3 and Ras-mediated transformation

Daniel J Gough1, Lisa Koetz, David E Levy

  • 1New York University Langone School of Medicine, New York, NY, United States of America.

Plos One
|December 7, 2013
PubMed

Insights

Activated Ras proteins utilize the MEK-ERK pathway to phosphorylate STAT3 on serine 727, promoting cancer cell growth. Inhibiting this pathway hinders Ras-driven transformation by targeting mitochondrial STAT3.

Area of Science:

  • Molecular Oncology
  • Signal Transduction Pathways

Background:

  • Activating Ras mutations are frequent oncogenic drivers in human cancers.
  • Elevated STAT3 signaling is implicated in numerous cancer types.
  • Previous work identified a requirement for mitochondrial STAT3 in Ras-driven transformation.

Purpose of the Study:

  • To elucidate the specific signaling pathways mediating Ras-induced STAT3 phosphorylation at serine 727 (S727).
  • To investigate the role of the MEK-ERK pathway in Ras-driven cellular transformation.
  • To determine the contribution of STAT3 S727 phosphorylation to the anti-oncogenic effects of MEK inhibitors.

Main Methods:

  • Utilized H-Ras oncoprotein to activate signaling pathways.
  • Employed pharmacological inhibitors targeting MEK, PI3K, and mTOR.
  • Generated mitochondrially restricted STAT3 mutants with phospho-mimetic S727 mutations.
  • Assessed anchorage-independent cell growth as a measure of transformation.

Main Results:

  • The MEK-ERK pathway, not PI3K or mTOR, drives H-Ras-induced STAT3 phosphorylation at S727.
  • Pharmacological MEK inhibition reduced transformation driven by H-, K-, and N-Ras.
  • Cells with mitochondrially localized, phospho-mimetic STAT3 showed partial resistance to MEK inhibition.

Conclusions:

  • The MEK-ERK pathway is essential for Ras-induced STAT3 S727 phosphorylation.
  • Inhibition of STAT3 S727 phosphorylation contributes to the anti-cancer activity of MEK inhibitors.
  • Mitochondrial STAT3 is a key substrate of the Ras-MEK-ERK axis in cellular transformation.

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