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Mol Cell. 2013 Dec 12;52(5):679-92. doi: 10.1016/j.molcel.2013.10.004. Epub 2013 Nov 7.

An MRAS, SHOC2, and SCRIB complex coordinates ERK pathway activation with polarity and tumorigenic growth.

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UCL Cancer Institute, University College London, London WC1E 6BT, UK.
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA.
European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, UK.
UCL Centre of Advanced Biomedical Imaging, Division of Medicine and Institute of Child Health, University College London, London WC1E 6BT, UK.
UCL Cancer Institute, University College London, London WC1E 6BT, UK. Electronic address:


SHOC2 is mutated in Noonan syndrome and plays a key role in the activation of the ERK-MAPK pathway, which is upregulated in the majority of human cancers. SHOC2 functions as a PP1-regulatory protein and as an effector of MRAS. Here we show that SHOC2 and MRAS form a complex with SCRIB, a polarity protein with tumor suppressor properties. SCRIB functions as a PP1-regulatory protein and antagonizes SHOC2-mediated RAF dephosphorylation through a mechanism involving competition for PP1 molecules within the same macromolecular complex. SHOC2 function is selectively required for the malignant properties of tumor cells with mutant RAS, and both MRAS and SHOC2 play a key role in polarized migration. We propose that MRAS, through its ability to recruit a complex with paradoxical components, coordinates ERK pathway spatiotemporal dynamics with polarity and that this complex plays a key role during tumorigenic growth.

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