Document Detail

R-Ras regulates migration through an interaction with filamin A in melanoma cells.
MedLine Citation:
PMID:  20585650     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Changes in cell adhesion and migration in the tumor microenvironment are key in the initiation and progression of metastasis. R-Ras is one of several small GTPases that regulate cell adhesion and migration on the extracellular matrix, however the mechanism has not been completely elucidated. Using a yeast two-hybrid approach we sought to identify novel R-Ras binding proteins that might mediate its effects on integrins.
METHODS AND FINDINGS: We identified Filamin A (FLNa) as a candidate interacting protein. FLNa is an actin-binding scaffold protein that also binds to integrin beta1, beta2 and beta7 tails and is associated with diverse cell processes including cell migration. Indeed, M2 melanoma cells require FLNa for motility. We further show that R-Ras and FLNa interact in co-immunoprecipitations and pull-down assays. Deletion of FLNa repeat 3 (FLNaDelta3) abrogated this interaction. In M2 melanoma cells active R-Ras co-localized with FLNa but did not co-localize with FLNa lacking repeat 3. Thus, activated R-Ras binds repeat 3 of FLNa. The functional consequence of this interaction was that active R-Ras and FLNa coordinately increased cell migration. In contrast, co-expression of R-Ras and FLNaDelta3 had a significantly reduced effect on migration. While there was enhancement of integrin activation and fibronectin matrix assembly, cell adhesion was not altered. Finally, siRNA knockdown of endogenous R-Ras impaired FLNa-dependent fibronectin matrix assembly.
CONCLUSIONS: These data support a model in which R-Ras functionally associates with FLNa and thereby regulates integrin-dependent migration. Thus in melanoma cells R-Ras and FLNa may cooperatively promote metastasis by enhancing cell migration.
Joanna E Gawecka; Genevieve S Griffiths; Barbro Ek-Rylander; Joe W Ramos; Michelle L Matter
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2010-06-23
Journal Detail:
Title:  PloS one     Volume:  5     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2010  
Date Detail:
Created Date:  2010-06-29     Completed Date:  2011-01-13     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e11269     Citation Subset:  IM    
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MeSH Terms
Base Sequence
Blotting, Western
Cell Movement / physiology*
Contractile Proteins / physiology*
DNA Primers
Melanoma / pathology*
Microfilament Proteins / physiology*
Microscopy, Fluorescence
ras Proteins / physiology*
Grant Support
P20RR016453/RR/NCRR NIH HHS; R01 CA093849/CA/NCI NIH HHS; R01 CA093849-06/CA/NCI NIH HHS
Reg. No./Substance:
0/Contractile Proteins; 0/DNA Primers; 0/Filamins; 0/Microfilament Proteins; EC 3.6.1.-/RRAS protein, human; EC Proteins

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