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

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 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.

M-Ras/Shoc2 signaling modulates E-cadherin turnover and cell–cell adhesion during collective cell migration

“…1 B and SI Appendix , Fig. S1 A ), and the interaction between active M-Ras and Shoc2 could be disrupted by mutations known to impair M-Ras effector interactions (T45S, E47G, and Y50C) (25) (Fig. 1 B ).…”

Human Ribosomal Proteins RPeL27, RPeL43, and RPeL41 Are Upregulated in Nasopharyngeal Carcinoma Cell Lines

“…As activator of other protooncogenes such as Rapidly Accelerated Fibrosarcoma (RAF) kinases [21], Phosphoinositide-3-Kinase (P13K) [22], Afadin (AF6) [23], and Guanine Nucleotide Exchange Factors (GEFs) [24], MRAS also triggers Mitogen-Activated Protein Kinases/Extracellular Signal-Regulated Kinases- (MAPK/ERK-) independent gene expression in breast cancer cells [25]. Our studies are the first to identify possible association between an RP and the MRAS protein in the NPC context.…”

MRAS: A Close but Understudied Member of the RAS Family

“…to ER-positive in three independent studies (van de Vijver et al 2002;Chin et al 2006;Hess et al 2006), and overexpression of constitutively active MRAS enables MCF-7 breast carcinoma cells to proliferate in the absence of oestrogen (Castro et al 2012). MRAS is part of the epithelial to mesenchymal signature (Huang et al 2012) and expression of active mutants causes EMT and oncogenic transformation in mouse scp-2 cells.…”

“…Given its sequence similarity and identical effector domain ( Figure 2B), it is unsurprising that MRAS can bind many of the same effectors as RAS such as A-, B-, and CRAF, AFDN/AF6, RASSF5, RalGEFs and PI3K (Quilliam et al 2001;Ortiz-Vega et al 2002;Rodriguez-Viciana et al 2004) . Through binding RGL2/RLF, MRAS activates RAL and ELK1 in MCF-7 cells, in an ERK-independent manner (Ehrhardt et al 2001;Castro et al 2012). MRAS also controls activation of RAP activity through binding MR-GEF/RAPGEF5 (Rebhun et al 2000) and RA-GEF2/RAPGEF6 (Gao et al 2001), the latter being specifically linked to control of cell adhesion through TNFα-triggered integrin activation in haematopoietic cells (Yoshikawa et al 2007).…”