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Focal adhesion disassembly is regulated by a RIAM to MEK-1 pathway
Georgina P. Coló, Pablo Hernández-Varas, John Lock, Rubén A. Bartolomé, Nohemí Arellano-Sánchez, Staffan Strömblad, Joaquin Teixidó


Cell migration and invasion require regulated turnover of integrin-dependent adhesion complexes. Rap1-GTP-interacting adaptor molecule (RIAM) is an adaptor protein that mediates talin recruitment to the cell membrane, and whose depletion leads to defective melanoma cell migration and invasion. In this study, we investigated the potential involvement of RIAM in focal adhesion (FA) dynamics. RIAM-depleted melanoma and breast carcinoma cells displayed an increased number, size and stability of FAs, which accumulated centrally at the ventral cell surface, a phenotype caused by defective FA disassembly. Impairment in FA disassembly resulting from RIAM knockdown correlated with deficient integrin-dependent mitogen-activated protein kinase kinase (MEK)–Erk1/2 activation and, importantly, overexpression of constitutively active MEK resulted in rescue of FA disassembly and recovery of cell invasion. Furthermore, RIAM-promoted Ras homologue gene family, member A (RhoA) activation following integrin engagement was needed for subsequent Erk1/2 activation. In addition, RhoA overexpression partially rescued the FA phenotype in RIAM-depleted cells, also suggesting a functional role for RhoA downstream of RIAM, but upstream of Erk1/2. RIAM knockdown also led to enhanced phosphorylation of paxillin Tyr118 and Tyr31. However, expression of phosphomimetic and nonphosphorylatable mutants at these paxillin residues indicated that paxillin hyperphosphorylation is a subsequent consequence of the blockade of FA disassembly, but does not cause the FA phenotype. RIAM depletion also weakened the association between FA proteins, suggesting that it has important adaptor roles in the correct assembly of adhesion complexes. Our data suggest that integrin-triggered, RIAM-dependent MEK activation represents a key feedback event required for efficient FA disassembly, which could help explain the role of RIAM in cell migration and invasion.


  • ‡Present address: Karolinska Institutet, Center for Biosciences, Department of Biosciences and Nutrition, SE-141 83 Huddinge, Sweden

  • Funding

    This work was supported by the Ministerio de Ciencia e Innovación [grant numbers SAF2008-00479, SAF2011-24022 and RETICS RD06/0020/0011 to J.T.]; the European Union (EU) FP7 MetaFight project [grant number HEALTH-2007-201862 to J.T. and S.S.]; and the EU FP7-Systems Microscopy NoE and the Center for Biosciences (to S.S.); The Swedish Cancer Society; The Swedish Research Council; and the Fundación de Investigación Científica de la Asociación Española contra el Cáncer (to R.A.B.). Imaging was partly supported by grants from the Knut and Alice Wallenberg foundation, the Swedish Research Council and the Center for Biosciences.

  • Supplementary material available online at

  • Accepted July 24, 2012.
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