Document Detail

Wnt5A activates the calpain-mediated cleavage of filamin A.
MedLine Citation:
PMID:  19177143     Owner:  NLM     Status:  MEDLINE    
We have previously shown that Wnt5A and ROR2, an orphan tyrosine kinase receptor, interact to mediate melanoma cell motility. In other cell types, this can occur through the interaction of ROR2 with the cytoskeletal protein filamin A. Here, we found that filamin A protein levels correlated with Wnt5A levels in melanoma cells. Small interfering RNA (siRNA) knockdown of WNT5A decreased filamin A expression. Knockdown of filamin A also corresponded to a decrease in melanoma cell motility. In metastatic cells, filamin A expression was predominant in the cytoplasm, which western analysis indicated was due to the cleavage of filamin A in these cells. Treatment of nonmetastatic melanoma cells with recombinant Wnt5A increased filamin A cleavage, and this could be prevented by the knockdown of ROR2 expression. Further, BAPTA-AM chelation of intracellular calcium also inhibited filamin A cleavage, leading to the hypothesis that Wnt5A/ROR2 signaling could cleave filamin A through activation of calcium-activated proteases, such as calpains. Indeed, WNT5A knockdown decreased calpain 1 expression, and by inhibiting calpain 1 either pharmacologically or using siRNA, it decreased cell motility. Our results indicate that Wnt5A activates calpain-1, leading to the cleavage of filamin A, which results in a remodeling of the cytoskeleton and an increase in melanoma cell motility.
Michael P O'Connell; Jennifer L Fiori; Katherine M Baugher; Fred E Indig; Amanda D French; Tura C Camilli; Brittany P Frank; Rachel Earley; Keith S Hoek; Joanne H Hasskamp; E George Elias; Dennis D Taub; Michel Bernier; Ashani T Weeraratna
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2009-01-29
Journal Detail:
Title:  The Journal of investigative dermatology     Volume:  129     ISSN:  1523-1747     ISO Abbreviation:  J. Invest. Dermatol.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-06-12     Completed Date:  2009-07-20     Revised Date:  2010-09-23    
Medline Journal Info:
Nlm Unique ID:  0426720     Medline TA:  J Invest Dermatol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1782-9     Citation Subset:  IM    
Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
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MeSH Terms
Calpain / genetics,  metabolism*
Cell Line, Tumor
Cell Movement / physiology
Chelating Agents / pharmacology
Contractile Proteins / metabolism*
Cytoskeleton / physiology
Egtazic Acid / analogs & derivatives,  pharmacology
Gene Expression Regulation, Neoplastic
Melanoma / metabolism*,  pathology,  physiopathology
Microfilament Proteins / metabolism*
Proto-Oncogene Proteins / genetics,  metabolism*
RNA, Small Interfering
Receptor Tyrosine Kinase-like Orphan Receptors
Receptors, Cell Surface / genetics,  metabolism
Skin Neoplasms / metabolism*,  pathology,  physiopathology
Wnt Proteins / genetics,  metabolism*
Grant Support
Z01 AG000442-04/AG/NIA NIH HHS
Reg. No./Substance:
0/CAPN1 protein, human; 0/Chelating Agents; 0/Contractile Proteins; 0/Microfilament Proteins; 0/Proto-Oncogene Proteins; 0/RNA, Small Interfering; 0/ROR2 protein, human; 0/Receptors, Cell Surface; 0/WNT5A protein, human; 0/Wnt Proteins; 0/filamins; 139890-68-9/1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; 67-42-5/Egtazic Acid; EC Tyrosine Kinase-like Orphan Receptors; EC 3.4.22.-/Calpain

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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