Mena INV dysregulates cortactin phosphorylation to promote invadopodium maturation

• Published in: Scientific reports Vol. 6; p. 36142
• Main Authors: Weidmann, Maxwell D, Surve, Chinmay R, Eddy, Robert J, Chen, Xiaoming, Gertler, Frank B, Sharma, Ved P, Condeelis, John S
• Format: Journal Article
• Language: English
• Published: England 08-11-2016
• Subjects: Animals; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Movement; Cortactin - genetics; Cortactin - metabolism; Female; Humans; Mice; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; Neoplasm Invasiveness; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Phosphorylation - genetics; Podosomes - genetics; Podosomes - metabolism; Podosomes - pathology; Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism
• ISSN: 2045-2322

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
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
expression increases invadopodium maturation to a far greater extent than equivalent expression of other Mena isoforms. Mena
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
expression. We conclude that Mena
promotes invadopodium maturation by inhibiting normal dephosphorylation of cortactin at tyrosine 421 by the phosphatase PTP1B.