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M‐Ras induces Ral and JNK activation to regulate MEK/ERK‐independent gene expression in MCF‐7 breast cancer cells
Author(s) -
Castro Ariel F.,
Campos Tania,
Babcock Justin T.,
Armijo Marisol E.,
MartínezConde Alfonso,
Pincheira Roxana,
Quilliam Lawrence A.
Publication year - 2012
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.23458
Subject(s) - anti apoptotic ras signalling cascade , mapk/erk pathway , carcinogenesis , protein kinase b , pi3k/akt/mtor pathway , cancer research , effector , microbiology and biotechnology , kinase , signal transduction , cancer cell , biology , mek inhibitor , cell growth , chemistry , cancer , biochemistry , genetics
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. J. Cell. Biochem. 113: 1253–1264, 2012. © 2011 Wiley Periodicals, Inc.