title: ERK1/2-induced phosphorylation of R-Ras GTPases stimulates their oncogenic potential.
abstract: The Ras-related (R-Ras) isoforms TC21, R-Ras and M-Ras are members of the Ras superfamily of small GTPases. R-Ras family proteins are frequently overexpressed in human cancers, and expression of activated mutants of these GTPases is sufficient to induce cell transformation. Unlike Ras, few activating mutations of R-Ras proteins have been reported in human cancer, and very little is known about the regulation of their activity. In this study, we report that TC21 and R-Ras are phosphorylated on a conserved serine, Ser186 and Ser201, respectively, in intact cells. This residue is located in the C-terminal hypervariable region of the proteins and is not conserved in M-Ras. We show that the MAP kinases ERK1/2 phosphorylate TC21 and R-Ras on this C-terminal serine residue both in vitro and in vivo. Phosphorylation of R-Ras proteins does not affect their subcellular localization or stability but rather stimulates their activation. Phosphorylation-defective mutants of R-Ras and TC21 are compromised in their ability to promote cancer cell adhesion and migration/invasion, respectively. Importantly, we show that phosphorylation of TC21 and R-Ras potentiates their tumorigenic activity in immunodeficient mice. Our results identify a novel regulatory mechanism of the small GTPases TC21 and R-Ras that controls their oncogenic potential.
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Frémin
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: J-P
authors.initials: JP
authors.lastname: Guégan
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Plutoni
authors.affiliation: Departments of Medicine, Cell Biology and Pharmacology, Perlmutter Cancer Institute, New York University, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Mahaffey
authors.affiliation: Departments of Medicine, Cell Biology and Pharmacology, Perlmutter Cancer Institute, New York University, New York, NY, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Philips
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.|Molecular Biology Program, Université de Montréal, Montreal, Quebec, Canada.|Department of Pathology and Cell Biology, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Emery
authors.affiliation: Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.|Molecular Biology Program, Université de Montréal, Montreal, Quebec, Canada.|Department of Pharmacology, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Meloche
mesh_terms: D000595:Amino Acid Sequence; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D020559:Monomeric GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport
chemical_list: D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C087360:RRAS2 protein, human; D020559:Monomeric GTP-Binding Proteins