MRAS and SHOC2 Coordinate ERK Activation with Cell Polarity

Although it is rarely mutated in human cancer, the RAS family member MRAS shares some regulatory and effector proteins with HRAS, KRAS, and NRAS and can promote oncogenic transformation. MRAS activates the RAF–MEK–ERK signaling cascade by inducing the dephosphorylation of a conserved inhibitory site on RAF proteins as part of a ternary complex containing protein phosphatase 1 (PP1) and soc-2 suppressor of clear homolog (SHOC2). Because SHOC2 is almost entirely comprised of leucine-rich repeat (LRR) domains, Young and colleagues hypothesized that a shared function of LRR-containing proteins may be to regulate substrate specificity of PP1. A screen of LRR proteins for the ability to coimmunoprecipitate with PP1 identified SCRIB, the Drosophila Scribble protein human homolog and putative tumor suppressor that controls polarized cell migration. SCRIB also was found to directly bind SHOC2 and indirectly interact with MRAS in a SHOC2-dependent manner. Unlike SHOC2, which binds PP1 and stimulates ERK phosphorylation downstream of active MRAS, SCRIB overexpression inhibited ERK activation. Mechanistically, SCRIB competes with SHOC2 for binding to PP1 within an MRAS-bound complex and prevents SHOC2–PP1-mediated dephosphorylation of BRAF serine 365 or CRAF serine 259. In cancer cells with constitutive RAS activity, SHOC2 was required for anchorage-independent growth, colony formation on soft agar, and growth in nude mice in a cell-type–specific manner, whereas SCRIB overexpression reduced the tumorigenicity of these cells, further indicating that SHOC2 and SCRIB have antagonistic effects on RAF–MEK–ERK signaling. However, like SCRIB, MRAS and SHOC2 were also required for polarized cell migration, suggesting that MRAS links ERK pathway regulation with control of cell polarity through its recruitment of SHOC2 and SCRIB.

Young LC, Hartig N, Muñoz-Alegre M, Oses-Prieto JA, Durdu S, Bender S, et al. An MRAS, SHOC2, and SCRIB complex coordinates ERK pathway activation with polarity and tumorigenic growth. Mol Cell 2013 Nov 7 [Epub ahead of print].