β1 integrin regulates Arg to promote invadopodial maturation and matrix degradation

Brian T. Beaty, Ved P. Sharma, Jose J. Bravo-Cordero, Mark A. Simpson, Robert J. Eddy, Anthony J. Koleske, John S. Condeelis

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

β1 integrin has been shown to promote metastasis in a number of tumor models, including breast, ovarian, pancreatic, and skin cancer; however, the mechanism by which it does so is poorly understood. Invasive membrane protrusions called invadopodia are believed to facilitate extracellular matrix degradation and intravasation during metastasis. Previous work showed that β1 integrin localizes to invadopodia, but its role in regulating invadopodial function has not been well characterized. We find that β1 integrin is required for the formation of mature, degradation-competent invadopodia in both two- and three-dimensional matrices but is dispensable for invadopodium precursor formation in metastatic human breast cancer cells. β1 integrin is activated during invadopodium precursor maturation, and forced β1 integrin activation enhances the rate of invadopodial matrix proteolysis. Furthermore, β1 integrin interacts with the tyrosine kinase Arg and stimulates Arg-dependent phosphorylation of cortactin on tyrosine 421. Silencing β1 integrin with small interfering RNA completely abrogates Arg-dependent cortactin phosphorylation and cofilin-dependent barbed-end formation at invadopodia, leading to a significant decrease in the number and stability of mature invadopodia. These results describe a fundamental role for β1 integrin in controlling actin polymerization-dependent invadopodial maturation and matrix degradation in metastatic tumor cells.

Original languageEnglish (US)
Pages (from-to)1661-1675
Number of pages15
JournalMolecular Biology of the Cell
Volume24
Issue number11
DOIs
StatePublished - Jun 1 2013

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Integrins
Cortactin
Phosphorylation
Actin Depolymerizing Factors
Breast Neoplasms
Neoplasm Metastasis
Skin Neoplasms
Podosomes
Pancreatic Neoplasms
Polymerization
Ovarian Neoplasms
Protein-Tyrosine Kinases
Small Interfering RNA
Proteolysis
Extracellular Matrix
Tyrosine
Actins
Neoplasms
Membranes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

β1 integrin regulates Arg to promote invadopodial maturation and matrix degradation. / Beaty, Brian T.; Sharma, Ved P.; Bravo-Cordero, Jose J.; Simpson, Mark A.; Eddy, Robert J.; Koleske, Anthony J.; Condeelis, John S.

In: Molecular Biology of the Cell, Vol. 24, No. 11, 01.06.2013, p. 1661-1675.

Research output: Contribution to journalArticle

Beaty, Brian T. ; Sharma, Ved P. ; Bravo-Cordero, Jose J. ; Simpson, Mark A. ; Eddy, Robert J. ; Koleske, Anthony J. ; Condeelis, John S. / β1 integrin regulates Arg to promote invadopodial maturation and matrix degradation. In: Molecular Biology of the Cell. 2013 ; Vol. 24, No. 11. pp. 1661-1675.
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