Document Detail


Rap1-GTP-interacting adaptor molecule (RIAM) protein controls invasion and growth of melanoma cells.
MedLine Citation:
PMID:  21454517     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Pablo Hernández-Varas; Georgina P Coló; Ruben A Bartolomé; Andrew Paterson; Iria Medraño-Fernández; Nohemí Arellano-Sánchez; Carlos Cabañas; Paloma Sánchez-Mateos; Esther M Lafuente; Vassiliki A Boussiotis; Staffan Strömblad; Joaquin Teixidó
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-03-26
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-05-23     Completed Date:  2011-07-28     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  18492-504     Citation Subset:  IM    
Affiliation:
Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas, 28040 Madrid, Spain.
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / genetics,  metabolism*
Animals
Antigens, CD29 / genetics,  metabolism
Apoptosis / genetics
Cell Adhesion / genetics
Cell Line, Tumor
Cell Movement*
Cell Survival / genetics
GTPase-Activating Proteins / genetics,  metabolism
Gene Silencing
Humans
Melanoma / genetics,  metabolism*,  pathology
Membrane Proteins / genetics,  metabolism*
Mice
Mice, SCID
Mitogen-Activated Protein Kinase 1 / genetics,  metabolism
Mitogen-Activated Protein Kinase 3 / genetics,  metabolism
Neoplasm Invasiveness
Neoplasm Metastasis
Neoplasm Transplantation
Phosphatidylinositol 3-Kinases / genetics,  metabolism
Proto-Oncogene Proteins c-vav / genetics,  metabolism
Transplantation, Heterologous
rhoA GTP-Binding Protein / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
2R01 AI43552/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/APBB1IP protein, human; 0/Adaptor Proteins, Signal Transducing; 0/Antigens, CD29; 0/GTPase-Activating Proteins; 0/Membrane Proteins; 0/Proto-Oncogene Proteins c-vav; 0/RAP1GAP protein, human; 0/VAV2 protein, human; 124671-05-2/RHOA protein, human; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.24/MAPK1 protein, human; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3; EC 3.6.5.2/rhoA GTP-Binding Protein
Comments/Corrections

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