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Activation of Vav/Rho GTPase signalling by CXCL12 controls MT1-MMP -dependent melanoma cell invasion

AuthorsBartolomé, Rubén Álvaro ; Molina-Ortiz, Isabel; Samaniego, Rafael ; Sánchez-Mateos, Paloma; Bustelo, Xosé R. ; Teixidó, Joaquín
Issue DateJan-2006
PublisherAmerican Association for Cancer Research
CitationCancer Research 66(1): 248-258(2006)
AbstractMelanoma cells express the chemokine receptor CXCR4, which confers invasive signals on binding to its ligand CXCL12. We show here that knocking down membrane-type matrix metalloproteinase (MT1-MMP) expression translates into a blockade of invasion across reconstituted basement membranes and type I collagen gels in response to CXCL12, which is the result of lack of MMP-2 activation. Interference with MMP-2 expression further confirms its important role during this invasion. Vav proteins are guanine-nucleotide exchange factors for Rho GTPases that regulate actin dynamics and gene expression. We show that melanoma cells express Vav1 and Vav2, which are activated by CXCL12 involving Jak activity. Blocking Vav expression by RNA interference results in impaired activation of Rac and Rho by CXCL12 and in a remarkable inhibition of CXCL12-promoted invasion. Importantly, up-regulation of MT1-MMP expression by CXCL12, a mechanism contributing to melanoma cell invasion, is blocked by knocking down Vav expression or by inhibiting Jak. Together, these data indicate that activation of Jak/Vav/Rho GTPase pathway by CXCL12 is a key signaling event for MT1-MMP/MMP-2–dependent melanoma cell invasion
Description11 páginas, 7 figuras, 1 tabla -- PAGS nros. 248-258
Publisher version (URL)http://dx.doi.org/10.1158/0008-5472.CAN-05-2489
Appears in Collections:(CIB) Artículos
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