|Institution:||Case Western Reserve University|
|Keywords:||Cellular Biology; Pathology; cell migration; endothelial cell; polarization; thymosin; profilin; myosin 1c|
|Full text PDF:||http://rave.ohiolink.edu/etdc/view?acc_num=case1247148451|
Cell migration is crucial for various physiological and pathologicalprocesses, including embryonic morphogenesis, wound healing, immuneresponses, cancer progression, and atherosclerosis development. Particularly,endothelial cell (EC) migration is a fundamental process in angiogenesis andvascular immune responses. Cell migration is driven by actin polymerization-mediatedlamellipodia protrusion, and proceeds by repeated cycles of protrusion,adhesion, and contraction. Intensive studies have shown that these processesare subjected to spatiotemporal regulation by signalling molecules, e.g. PI(3)Kand Rho GTPases, and by actin-binding proteins, e.g. Arp2/3 and cofilin. Hereour data show that 1) spatially restricted dissociation of G-actin–Tß4 complexesat the leading edge liberates actin for filament assembly, and simultaneouslyfacilitates Tß4 binding to integrin-linked kinase in the lamellipodia, followed byAkt2-mediated matrix metalloproteinase-2 production, providing a coordinationmechanism that couples actin polymerization to matrix degradation; 2) Myo1cdelivers lamellipodial G-actin to the leading edge to facilitate local actinpolymerization, indicating a mechanism for G-actin transport-mediatedpolarization of actin polymerization; 3) During VEGF-induced endothelial cellchemotaxis migration, profilin phosphorylation at Tyr129 preferentially occurs atthe leading edge to increase local actin polymerization, suggesting a mechanismfor establishment and maintenance of cell polarity during chemotaxis. Takentogether, these findings elucidate novel molecular mechanisms underlyingcoordination of actin polymerization and matrix degradation, as well aspolarization of actin polymerization during EC migration, which contributes tobetter molecular resolution of cell movement and may lead to the development oftherapeutic strategies for EC migration-related diseases.