title: Rap1-GTP-interacting adaptor molecule (RIAM) protein controls invasion and growth of melanoma cells.
abstract: The Mig-10/RIAM/lamellipodin (MRL) family member Rap1-GTP-interacting adaptor molecule (RIAM) interacts with active Rap1, a small GTPase that is frequently activated in tumors such as melanoma and prostate cancer. We show here that RIAM is expressed in metastatic human melanoma cells and that both RIAM and Rap1 are required for BLM melanoma cell invasion. RIAM silencing in melanoma cells led to inhibition of tumor growth and to delayed metastasis in a severe combined immunodeficiency xenograft model. Defective invasion of RIAM-silenced melanoma cells arose from impairment in persistent cell migration directionality, which was associated with deficient activation of a Vav2-RhoA-ROCK-myosin light chain pathway. Expression of constitutively active Vav2 and RhoA in cells depleted for RIAM partially rescued their invasion, indicating that Vav2 and RhoA mediate RIAM function. These results suggest that inhibition of cell invasion in RIAM-silenced melanoma cells is likely based on altered cell contractility and cell polarization. Furthermore, we show that RIAM depletion reduces β1 integrin-dependent melanoma cell adhesion, which correlates with decreased activation of both Erk1/2 MAPK and phosphatidylinositol 3-kinase, two central molecules controlling cell growth and cell survival. In addition to causing inhibition of cell proliferation, RIAM silencing led to higher susceptibility to cell apoptosis. Together, these data suggest that defective activation of these kinases in RIAM-silenced cells could account for inhibition of melanoma cell growth and that RIAM might contribute to the dissemination of melanoma cells.
authors: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas, 28040 Madrid, Spain.
authors: Pablo
authors: P
authors: Hernández-Varas
authors: Georgina P
authors: GP
authors: Coló
authors: Ruben A
authors: RA
authors: Bartolomé
authors: Andrew
authors: A
authors: Paterson
authors: Iria
authors: I
authors: Medraño-Fernández
authors: Nohemí
authors: N
authors: Arellano-Sánchez
authors: Carlos
authors: C
authors: Cabañas
authors: Paloma
authors: P
authors: Sánchez-Mateos
authors: Esther M
authors: EM
authors: Lafuente
authors: Vassiliki A
authors: VA
authors: Boussiotis
authors: Staffan
authors: S
authors: Strömblad
authors: Joaquin
authors: J
authors: Teixidó
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C493340:APBB1IP protein, human; D048868:Adaptor Proteins, Signal Transducing; D020690:GTPase-Activating Proteins; D019012:Integrin beta1; D008565:Membrane Proteins; D051567:Proto-Oncogene Proteins c-vav; C484658:RAP1GAP protein, human; C093651:VAV2 protein, human; C066737:RHOA protein, human; D019869:Phosphatidylinositol 3-Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020742:rhoA GTP-Binding Protein