期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：37
页码：E5150-E5159
DOI：10.1073/pnas.1510945112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceCell motility plays important roles in normal physiology and numerous disease states, including cancers. Cofilin, a key player in cell locomotion, controls the direction and the force of cell protrusion. Our study establishes the cofilin phosphatase chronophin (CIN) as a major component of a PI3-kinase-mediated, Rac1-dependent signaling mechanism that activates cofilin downstream of EGF receptor in mammary carcinoma cells. During EGF stimulation, CIN redistributes to the cell edge, where it regulates cofilin-dependent actin turnover and coordinates cell protrusion and retraction dynamics. Our data uncover previously unidentified molecular mechanisms regulating cofilin in time and space in tumor cells and expand our understanding of cancer cell movement, a critical step in the process of metastasis. 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.
