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First published online 13 July 2009
doi: 10.1242/jcs.046680

Journal of Cell Science 122, 2727-2740 (2009)
Published by The Company of Biologists 2009
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Research Article

Nck adaptor proteins link Tks5 to invadopodia actin regulation and ECM degradation

Stanley S. Stylli1, Stacey T. T. I1, Anne M. Verhagen2, San San Xu1, Ian Pass3, Sara A. Courtneidge3 and Peter Lock1,*,{ddagger}

1 Department of Surgery, University of Melbourne, Level 5, Clinical Sciences Building, Royal Melbourne Hospital, Parkville, Victoria 3052, Australia
2 Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
3 Burnham Institute for Medical Research, Torrey Pines Road, La Jolla, CA 92037, USA

{ddagger} Author for correspondence (e-mail: peteralanlock{at}gmail.com)

Accepted 5 May 2009

Invadopodia are actin-based projections enriched with proteases, which invasive cancer cells use to degrade the extracellular matrix (ECM). The Phox homology (PX)-Src homology (SH)3 domain adaptor protein Tks5 (also known as SH3PXD2A) cooperates with Src tyrosine kinase to promote invadopodia formation but the underlying pathway is not clear. Here we show that Src phosphorylates Tks5 at Y557, inducing it to associate directly with the SH3-SH2 domain adaptor proteins Nck1 and Nck2 in invadopodia. Tks5 mutants unable to bind Nck show reduced matrix degradation-promoting activity and recruit actin to invadopodia inefficiently. Conversely, Src- and Tks5-driven matrix proteolysis and actin assembly in invadopodia are enhanced by Nck1 or Nck2 overexpression and inhibited by Nck1 depletion. We show that clustering at the plasma membrane of the Tks5 inter-SH3 region containing Y557 triggers phosphorylation at this site, facilitating Nck recruitment and F-actin assembly. These results identify a Src-Tks5-Nck pathway in ECM-degrading invadopodia that shows parallels with pathways linking several mammalian and pathogen-derived proteins to local actin regulation.

Key words: Invadopodia, Podosome, Src, Tks5, Nck, ECM degradation


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This article has been cited by other articles:


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B. Diaz, G. Shani, I. Pass, D. Anderson, M. Quintavalle, and S. A. Courtneidge
Tks5-Dependent, Nox-Mediated Generation of Reactive Oxygen Species Is Necessary for Invadopodia Formation
Sci. Signal., September 15, 2009; 2(88): ra53 - ra53.
[Abstract] [Full Text] [PDF]


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