title: Cortactin phosphorylation regulates cell invasion through a pH-dependent pathway.
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.
authors: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, USA.
authors: Marco A O
authors: MA
authors: Magalhaes
authors: Daniel R
authors: DR
authors: Larson
authors: Christopher C
authors: CC
authors: Mader
authors: Jose Javier
authors: JJ
authors: Bravo-Cordero
authors: Hava
authors: H
authors: Gil-Henn
authors: Matthew
authors: M
authors: Oser
authors: Xiaoming
authors: X
authors: Chen
authors: Anthony J
authors: AJ
authors: Koleske
authors: John
authors: J
authors: Condeelis
mesh_terms: D051339:Actin Depolymerizing Factors / Q000235:genetics / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism / Q000502:physiology; D045744:Cell Line, Tumor; D022081:Cell Surface Extensions / Q000378:metabolism / Q000502:physiology; D051356:Cortactin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008954:Models, Biological; D009361:Neoplasm Invasiveness / Q000235:genetics; D015513:Oncogene Proteins / Q000378:metabolism; D010766:Phosphorylation; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism / Q000502:physiology
chemical_list: D051339:Actin Depolymerizing Factors; D048868:Adaptor Proteins, Signal Transducing; D027682:Cation Transport Proteins; D051356:Cortactin; C078332:Nck protein; D015513:Oncogene Proteins; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers