MenaINV dysregulates cortactin phosphorylation to promote invadopodium maturation

Maxwell D. Weidmann, Chinmay R. Surve, Robert J. Eddy, Xiaoming Chen, Frank B. Gertler, Ved P. Sharma, John S. Condeelis

Research output: Contribution to journalArticle

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Abstract

Invadopodia, actin-based protrusions of invasive carcinoma cells that focally activate extracellular matrix-degrading proteases, are essential for the migration and intravasation of tumor cells during dissemination from the primary tumor. We have previously shown that cortactin phosphorylation at tyrosine residues, in particular tyrosine 421, promotes actin polymerization at newly-forming invadopodia, promoting their maturation to matrix-degrading structures. However, the mechanism by which cells regulate the cortactin tyrosine phosphorylation-dephosphorylation cycle at invadopodia is unknown. Mena, an actin barbed-end capping protein antagonist, is expressed as various splice-isoforms. The Mena INV isoform is upregulated in migratory and invasive sub-populations of breast carcinoma cells, and is involved in tumor cell intravasation. Here we show that forced Mena INV expression increases invadopodium maturation to a far greater extent than equivalent expression of other Mena isoforms. Mena INV is recruited to invadopodium precursors just after their initial assembly at the plasma membrane, and promotes the phosphorylation of cortactin tyrosine 421 at invadopodia. In addition, we show that cortactin phosphorylation at tyrosine 421 is suppressed by the phosphatase PTP1B, and that PTP1B localization to the invadopodium is reduced by Mena INV expression. We conclude that Mena INV promotes invadopodium maturation by inhibiting normal dephosphorylation of cortactin at tyrosine 421 by the phosphatase PTP1B.

Original languageEnglish (US)
Article number36142
JournalScientific Reports
Volume6
DOIs
StatePublished - Nov 8 2016

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Cortactin
Phosphorylation
Tyrosine
Actins
Protein Isoforms
Phosphoric Monoester Hydrolases
Neoplasms
Podosomes
Polymerization
Extracellular Matrix
Peptide Hydrolases
Cell Membrane
Breast Neoplasms
Carcinoma

ASJC Scopus subject areas

  • General

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MenaINV dysregulates cortactin phosphorylation to promote invadopodium maturation. / Weidmann, Maxwell D.; Surve, Chinmay R.; Eddy, Robert J.; Chen, Xiaoming; Gertler, Frank B.; Sharma, Ved P.; Condeelis, John S.

In: Scientific Reports, Vol. 6, 36142, 08.11.2016.

Research output: Contribution to journalArticle

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AU - Gertler, Frank B.

AU - Sharma, Ved P.

AU - Condeelis, John S.

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