title: A novel spatiotemporal RhoC activation pathway locally regulates cofilin activity at invadopodia.
abstract: BACKGROUND
  RhoGTPases have been implicated in the regulation of cancer metastasis. Invasive carcinoma cells form invadopodia, F-actin-rich matrix-degrading protrusions that are thought to be important for tumor cell invasion and intravasation. Regulation of actin dynamics at invadopodial protrusions is crucial to drive invasion. This process requires the severing activity of cofilin to generate actin-free barbed ends. Previous work demonstrates that cofilin's severing activity is tightly regulated through multiple mechanisms, including regulation of cofilin serine phosphorylation by Rho GTPases. However, it is not known which Rho GTPase is involved in regulating cofilin's phosphorylation status at invadopodia.
  
  
  RESULTS
  We show here, for the first time, how RhoC activation is controlled at invadopodia and how this activation regulates cofilin phosphorylation to control cofilin's generation of actin-free barbed ends. Live-cell imaging of fluorescent RhoC biosensor reveals that RhoC activity is spatially confined to areas surrounding invadopodia. This spatiotemporal restriction of RhoC activity is controlled by "spatially distinct regulatory elements" that confine RhoC activation within this compartment. p190RhoGEF localizes around invadopodia to activate RhoC, whereas p190RhoGAP localizes inside invadopodia to deactivate the GTPase within the structure. RhoC activation enhances cofilin phosphorylation outside invadopodia.
  
  
  CONCLUSIONS
  These results show how RhoC activity is spatially regulated at invadopodia by p190RhoGEF and p190RhoGAP. RhoC activation in areas surrounding invadopodia restricts cofilin activity to within the invadopodium core, resulting in a focused invadopodial protrusion. This mechanism likely enhances tumor cell invasion during metastasis.
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, USA. jose-javier.bravo@einstein.yu.edu
authors.forename: Jose Javier
authors.initials: JJ
authors.lastname: Bravo-Cordero
authors.forename: Matthew
authors.initials: M
authors.lastname: Oser
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Chen
authors.forename: Robert
authors.initials: R
authors.lastname: Eddy
authors.forename: Louis
authors.initials: L
authors.lastname: Hodgson
authors.forename: John
authors.initials: J
authors.lastname: Condeelis
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015374:Biosensing Techniques; D002465:Cell Movement; D022081:Cell Surface Extensions / Q000378:metabolism*; D015674:Mammary Neoplasms, Animal / Q000378:metabolism* / Q000473:pathology; D009362:Neoplasm Metastasis / Q000473:pathology*; D010766:Phosphorylation; D051381:Rats; D012694:Serine / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000075024:rhoC GTP-Binding Protein
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D012694:Serine; C560445:RhoC protein, rat; D020741:rho GTP-Binding Proteins; D000075024:rhoC GTP-Binding Protein