M-Ras induces Ral and JNK activation to regulate MEK/ERK-independent gene expression in MCF-7 breast cancer cells

Ariel F. Castro, Tania Campos, Justin T. Babcock, Marisol E. Armijo, Alfonso Martínez-Conde, Roxana Pincheira, Lawrence A. Quilliam

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Constitutive activation of M-Ras has previously been reported to cause morphologic and growth transformation of murine cells, suggesting that M-Ras plays a role in tumorigenesis. Cell transformation by M-Ras correlated with weak activation of the Raf/MEK/ERK pathway, although contributions from other downstream effectors were suggested. Recent studies indicate that signaling events distinct from the Raf/MEK/ERK cascade are critical for human tumorigenesis. However, it is unknown what signaling events M-Ras triggers in human cells. Using constitutively active M-Ras (Q71L) containing additional mutations within its effector-binding loop, we found that M-Ras induces MEK/ERK-dependent and -independent Elk1 activation as well as phosphatidylinositol 3 kinase (PI3K)/Akt and JNK/cJun activation in human MCF-7 breast cancer cells. Among several human cell lines examined, M-Ras-induced MEK/ERK-independent Elk1 activation was only detected in MCF-7 cells, and correlated with Rlf/M-Ras interaction and Ral/JNK activation. Supporting a role for M-Ras signaling in breast cancer, EGF activated M-Ras and promoted its interaction with endogenous Rlf. In addition, constitutive activation of M-Ras induced estrogen-independent growth of MCF-7 cells that was dependent on PI3K/Akt, MEK/ERK, and JNK activation. Thus, our studies demonstrate that M-Ras signaling activity differs between human cells, highlighting the importance of defining Ras protein signaling within each cell type, especially when designing treatments for Ras-induced cancer. These findings also demonstrate that M-Ras activity may be important for progression of EGFR-dependent tumors.

Original languageEnglish (US)
Pages (from-to)1253-1264
Number of pages12
JournalJournal of Cellular Biochemistry
Volume113
Issue number4
DOIs
StatePublished - Apr 1 2012

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Keywords

  • Elk1
  • ESTROGEN
  • JNK
  • M-Ras
  • Ral
  • Rlf/Rgl2

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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