Cell migration is essential for many physiological processes such as wound healing, immune response and morphogenesis, and plays a significant role in pathological processes such as cancer metastasis. In order for cells to migrate, they must actively and coordinately remodel their actin cytoskeleton on a time scale of seconds. The control of actin dynamics requires dozens of proteins, but two critical components are the Arp2/3 complex that nucleates new filaments in branched arrays and ADF/Cofilin proteins that promote actin filament turnover by severing and enhanced depolymerization. It has long been suspected that these two factors function in a coordinated manner, but the mechanism of this coordination was unknown. Recent data from our lab indicate that Coronins, highly conserved WD-repeat proteins, have a unique function as coordinators of Arp2/3 and Cofilin activity at the leading edge of motile cells. This proposal seeks to elucidate the mechanisms of this coordination and determine how this activity contributes to cell migration and cancer metastasis. To achieve this, we propose four specific aims: 1) The regulation of Arp2/3 function by Coronin 1B;2) The regulation of Cofilin activity by Coronin 1B via the Slingshot phosphatases;3) The spatial and temporal control of Coronin 1B activity by Ser2 phosphorylation;and 4) The comparative analysis of Coronin 1B and Coronin 1C regulation and function.
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