MenaINVdysregulates cortactin phosphorylation to promote invadopodium maturation.
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 MenaINVisoform is upregulated in migratory and invasive sub-populations of breast carcinoma cells, and is involved in tumor cell intravasation. Here we show that forced MenaINVexpression increases invadopodium maturation to a far greater extent than equivalent expression of other Mena isoforms. MenaINVis 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 MenaINVexpression. We conclude that MenaINVpromotes invadopodium maturation by inhibiting normal dephosphorylation of cortactin at tyrosine 421 by the phosphatase PTP1B.
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
Maxwell D
MD
Weidmann
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.|Integrated Imaging Program, Albert Einstein College of Medicine, Bronx, NY, USA.
Chinmay R
CR
Surve
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
Robert J
RJ
Eddy
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
Xiaoming
X
Chen
Department of Biology and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
Frank B
FB
Gertler
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.|Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, USA.
Ved P
VP
Sharma
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.|Integrated Imaging Program, Albert Einstein College of Medicine, Bronx, NY, USA.|Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, USA.
John S
JS
Condeelis
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D051356:Cortactin / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D000069261:Podosomes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism
C495868:CTTN protein, human; D051356:Cortactin; C511939:Enah protein, human; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D020033:Protein Isoforms; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1