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

Stanley S. Stylli, T. T I Stacey, Anne M. Verhagen, San San Xu, Ian Pass, Sara Courtneidge, Peter Lock

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2727-2740
Number of pages14
JournalJournal of Cell Science
Volume122
Issue number15
DOIs
StatePublished - Aug 1 2009
Externally publishedYes

Fingerprint

Extracellular Matrix
Actins
src Homology Domains
Proteins
src-Family Kinases
Proteolysis
Cluster Analysis
Podosomes
Nck protein
Peptide Hydrolases
Phosphorylation
Cell Membrane
Neoplasms

Keywords

  • ECM degradation
  • Invadopodia
  • Nck
  • Podosome
  • Src
  • Tks5

ASJC Scopus subject areas

  • Cell Biology

Cite this

Stylli, S. S., Stacey, T. T. I., Verhagen, A. M., Xu, S. S., Pass, I., Courtneidge, S., & Lock, P. (2009). Nck adaptor proteins link Tks5 to invadopodia actin regulation and ECM degradation. Journal of Cell Science, 122(15), 2727-2740. https://doi.org/10.1242/jcs.046680

Nck adaptor proteins link Tks5 to invadopodia actin regulation and ECM degradation. / Stylli, Stanley S.; Stacey, T. T I; Verhagen, Anne M.; Xu, San San; Pass, Ian; Courtneidge, Sara; Lock, Peter.

In: Journal of Cell Science, Vol. 122, No. 15, 01.08.2009, p. 2727-2740.

Research output: Contribution to journalArticle

Stylli, SS, Stacey, TTI, Verhagen, AM, Xu, SS, Pass, I, Courtneidge, S & Lock, P 2009, 'Nck adaptor proteins link Tks5 to invadopodia actin regulation and ECM degradation', Journal of Cell Science, vol. 122, no. 15, pp. 2727-2740. https://doi.org/10.1242/jcs.046680
Stylli, Stanley S. ; Stacey, T. T I ; Verhagen, Anne M. ; Xu, San San ; Pass, Ian ; Courtneidge, Sara ; Lock, Peter. / Nck adaptor proteins link Tks5 to invadopodia actin regulation and ECM degradation. In: Journal of Cell Science. 2009 ; Vol. 122, No. 15. pp. 2727-2740.
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