Chronophin coordinates cell leading edge dynamics by controlling active cofilin levels.
Cofilin, a critical player of actin dynamics, is spatially and temporally regulated to control the direction and force of membrane extension required for cell locomotion. In carcinoma cells, although the signaling pathways regulating cofilin activity to control cell direction have been established, the molecular machinery required to generate the force of the protrusion remains unclear. We show that the cofilin phosphatase chronophin (CIN) spatiotemporally regulates cofilin activity at the cell edge to generate persistent membrane extension. We show that CIN translocates to the leading edge in a PI3-kinase-, Rac1-, and cofilin-dependent manner after EGF stimulation to activate cofilin, promotes actin free barbed end formation, accelerates actin turnover, and enhances membrane protrusion. In addition, we establish that CIN is crucial for the balance of protrusion/retraction events during cell migration. Thus, CIN coordinates the leading edge dynamics by controlling active cofilin levels to promote MTLn3 cell protrusion.
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037;
Violaine
V
Delorme-Walker
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037;
Ji-Yeon
JY
Seo
Department of Pharmacology, University of Würzburg, 97078 Wurzburg, Germany.
Antje
A
Gohla
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037;
Bruce
B
Fowler
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037;
Ben
B
Bohl
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037; dmceline@scripps.edu.
Céline
C
DerMardirossian
D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D051338:Cofilin 1 / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008840:Microfilament Proteins / Q000502:physiology; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction
D051339:Actin Depolymerizing Factors; D000199:Actins; C495810:CFL1 protein, human; C495812:Cfl1 protein, rat; D051338:Cofilin 1; D008840:Microfilament Proteins; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; C496428:PDXP protein, human; D010749:Phosphoprotein Phosphatases
actin dynamics; cancer cells; cell protrusion; chronophin; cofilin