title: An MRAS, SHOC2, and SCRIB complex coordinates ERK pathway activation with polarity and tumorigenic growth.
abstract: 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.
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Lucy C
authors.initials: LC
authors.lastname: Young
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Nicole
authors.initials: N
authors.lastname: Hartig
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Muñoz-Alegre
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Oses-Prieto
authors.affiliation: European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
authors.forename: Sevi
authors.initials: S
authors.lastname: Durdu
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Sabine
authors.initials: S
authors.lastname: Bender
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, UK.
authors.forename: Vineetha
authors.initials: V
authors.lastname: Vijayakumar
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Matteo
authors.initials: M
authors.lastname: Vietri Rudan
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Christina
authors.initials: C
authors.lastname: Gewinner
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Henderson
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Amit P
authors.initials: AP
authors.lastname: Jathoul
authors.affiliation: UCL Centre of Advanced Biomedical Imaging, Division of Medicine and Institute of Child Health, University College London, London WC1E 6BT, UK.
authors.forename: Rupinder
authors.initials: R
authors.lastname: Ghatrora
authors.affiliation: UCL Centre of Advanced Biomedical Imaging, Division of Medicine and Institute of Child Health, University College London, London WC1E 6BT, UK.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Lythgoe
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Alma L
authors.initials: AL
authors.lastname: Burlingame
authors.affiliation: UCL Cancer Institute, University College London, London WC1E 6BT, UK. Electronic address: p.rodriguez-viciana@ucl.ac.uk.
authors.forename: Pablo
authors.initials: P
authors.lastname: Rodriguez-Viciana
mesh_terms: D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics*; D046911:Macromolecular Substances / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D017476:Receptors, Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C109523:MRAS protein, human; D046911:Macromolecular Substances; D008565:Membrane Proteins; D017476:Receptors, Neuropeptide Y; C480591:SCRIB protein, human; C112913:SHOC2 protein, human; D025521:Tumor Suppressor Proteins; C109491:neuropeptide Y4 receptor; D048490:raf Kinases; D018631:ras Proteins