title: RasGRF suppresses Cdc42-mediated tumour cell movement, cytoskeletal dynamics and transformation.
abstract: Individual tumour cells move in three-dimensional environments with either a rounded or an elongated 'mesenchymal' morphology. These two modes of movement are tightly regulated by Rho family GTPases: elongated movement requires activation of Rac1, whereas rounded/amoeboid movement engages specific Cdc42 and Rho signalling pathways. In siRNA screens targeting the genes encoding guanine nucleotide exchange factors (GEFs), we found that the Ras GEF RasGRF2 regulates conversion between elongated- and rounded-type movement. RasGRF2 suppresses rounded movement by inhibiting the activation of Cdc42 independently of its capacity to activate Ras. RasGRF2 and RasGRF1 directly bind to Cdc42, outcompeting Cdc42 GEFs, thereby preventing Cdc42 activation. By this mechanism, RasGRFs regulate other Cdc42-mediated cellular processes such as the formation of actin spikes, transformation and invasion in vitro and in vivo. These results demonstrate a role for RasGRF GEFs as negative regulators of Cdc42 activation.
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas-IDICAN-Universidad de Cantabria, Departamento de Biología Molecular, Facultad de Medicina, Santander, 39011, Cantabria, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Calvo
authors.forename: Victoria
authors.initials: V
authors.lastname: Sanz-Moreno
authors.forename: Lorena
authors.initials: L
authors.lastname: Agudo-Ibáñez
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wallberg
authors.forename: Erik
authors.initials: E
authors.lastname: Sahai
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Marshall
authors.forename: Piero
authors.initials: P
authors.lastname: Crespo
mesh_terms: D000818:Animals; D019556:COS Cells; D002465:Cell Movement; D048430:Cell Shape; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D003599:Cytoskeleton / Q000378:metabolism*; D015536:Down-Regulation; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D018715:Microscopy, Video; D009154:Mutation; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D020663:ras Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D020666:ras-GRF1 / Q000378:metabolism
chemical_list: D051567:Proto-Oncogene Proteins c-vav; C513039:RASGRF1 protein, human; C504490:RASGRF2 protein, human; C513037:Rasgrf1 protein, mouse; C504491:Rasgrf2 protein, mouse; D011993:Recombinant Fusion Proteins; D020663:ras Guanine Nucleotide Exchange Factors; D020666:ras-GRF1; D020764:cdc42 GTP-Binding Protein