Cortactin phosphorylation regulates cell invasion through a pH-dependent pathway

Marco A O Magalhaes, Daniel R. Larson, Christopher C. Mader, Jose Javier Bravo-Cordero, Hava Gil-Henn, Matthew Oser, Xiaoming Chen, Anthony J. Koleske, John S. Condeelis

Research output: Contribution to journalArticle

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Abstract

Invadopodia are invasive protrusions with proteolytic activity uniquely found in tumor cells. Cortactin phosphorylation is a key step during invadopodia maturation, regulating Nck1 binding and cofilin activity. The precise mechanism of cortactin-dependent cofilin regulation and the roles of this pathway in invadopodia maturation and cell invasion are not fully understood. We provide evidence that cortactin-cofilin binding is regulated by local pH changes at invadopodia that are mediated by the sodium-hydrogen exchanger NHE1. Furthermore, cortactin tyrosine phosphorylation mediates the recruitment of NHE1 to the invadopodium compartment, where it locally increases the pH to cause the release of cofilin from cortactin. We show that this mechanism involving cortactin phosphorylation, local pH increase, and cofilin activation regulates the dynamic cycles of invadopodium protrusion and retraction and is essential for cell invasion in 3D. Together, these findings identify a novel pH-dependent regulation of cell invasion.

Original languageEnglish (US)
Pages (from-to)903-920
Number of pages18
JournalJournal of Cell Biology
Volume195
Issue number5
DOIs
StatePublished - Nov 2011

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Cortactin
Actin Depolymerizing Factors
Phosphorylation
Sodium-Hydrogen Antiporter
Tyrosine
Podosomes

ASJC Scopus subject areas

  • Cell Biology

Cite this

Magalhaes, M. A. O., Larson, D. R., Mader, C. C., Bravo-Cordero, J. J., Gil-Henn, H., Oser, M., ... Condeelis, J. S. (2011). Cortactin phosphorylation regulates cell invasion through a pH-dependent pathway. Journal of Cell Biology, 195(5), 903-920. https://doi.org/10.1083/jcb.201103045

Cortactin phosphorylation regulates cell invasion through a pH-dependent pathway. / Magalhaes, Marco A O; Larson, Daniel R.; Mader, Christopher C.; Bravo-Cordero, Jose Javier; Gil-Henn, Hava; Oser, Matthew; Chen, Xiaoming; Koleske, Anthony J.; Condeelis, John S.

In: Journal of Cell Biology, Vol. 195, No. 5, 11.2011, p. 903-920.

Research output: Contribution to journalArticle

Magalhaes, MAO, Larson, DR, Mader, CC, Bravo-Cordero, JJ, Gil-Henn, H, Oser, M, Chen, X, Koleske, AJ & Condeelis, JS 2011, 'Cortactin phosphorylation regulates cell invasion through a pH-dependent pathway', Journal of Cell Biology, vol. 195, no. 5, pp. 903-920. https://doi.org/10.1083/jcb.201103045
Magalhaes MAO, Larson DR, Mader CC, Bravo-Cordero JJ, Gil-Henn H, Oser M et al. Cortactin phosphorylation regulates cell invasion through a pH-dependent pathway. Journal of Cell Biology. 2011 Nov;195(5):903-920. https://doi.org/10.1083/jcb.201103045
Magalhaes, Marco A O ; Larson, Daniel R. ; Mader, Christopher C. ; Bravo-Cordero, Jose Javier ; Gil-Henn, Hava ; Oser, Matthew ; Chen, Xiaoming ; Koleske, Anthony J. ; Condeelis, John S. / Cortactin phosphorylation regulates cell invasion through a pH-dependent pathway. In: Journal of Cell Biology. 2011 ; Vol. 195, No. 5. pp. 903-920.
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