M‐Ras induces Ral and JNK activation to regulate MEK/ERK‐independent gene expression in MCF‐7 breast cancer cells
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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.
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MRAS may regulate other signaling pathways involving Rho, Ral or Rap GTPases, contributing to tumor cell migration adhesion, endocytosis or invasion.
“This suggests that MRAS may regulate other signaling pathways involving Rho, Ral or Rap GTPases38,53,54, contributing to tumor cell migration adhesion, endocytosis or invasion.”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [54]
The counteraction of oxidative phosphorylation, reactive oxygen species and Myc target gene upregulation may also be the result of MRAS modulation, as MRAS has previously been shown to activate JNK, a known regulator of MYC.
“which may also be the result of MRAS modulation, as MRAS has previously been shown to activate JNK54, a known regulator of MYC.”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [54]
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- Authors
- Castro, A. F., Campos, T., Babcock, J. T., Armijo, M. E., Martínez‐Conde, A., Pincheira, R., & Quilliam, L. A.
- Affiliations
- University of Concepción (CL)
- Indiana University School of Medicine (US)
- Corresponding author
- Castro, Ariel F.
- Venue
- Journal of Cellular Biochemistry
- Publisher
- Wiley
- Published
- 2012-02-23
- Volume
- 113
- Issue
- 4
- Pages
- 1253-1264
- ISSN
- 0730-2312 (ISSN-L)
- 1097-4644
- PMC
- PMC3303964
- OpenAlex
- W2071034573
- Cited by
- 22
- References
- 60
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 3 · 2020: 2 · 2019: 2 · 2018: 3 · 2017: 1 · 2016: 2 · 2015: 1 · 2012: 3
- FWCI
- 0.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Cellular Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- University of California, San Francisco
- National Cancer Institute (R01CA108647, CA108647)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- M-Ras, Ral, JNK, Elk-1, PI3K/Akt signaling, RalF, EGFR, epidermal growth factor, estrogen-independent growth, breast cancer, MCF-7 cells
- MeSH terms
- Enzyme Activation, Female, Humans, Signal Transduction, Gene Expression Regulation, Enzymologic, Monomeric GTP-Binding Proteins, ral GTP-Binding Proteins, Mitogen-Activated Protein Kinases, Cell Line, Tumor, Immunoprecipitation, MAP Kinase Kinase 4
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