title: Stimulus-dependent phosphorylation of profilin-1 in angiogenesis.
abstract: Angiogenesis, the formation of new blood vessels, is fundamental to development and post-injury tissue repair. Vascular endothelial growth factor (VEGF)-A guides and enhances endothelial cell migration to initiate angiogenesis. Profilin-1 (Pfn-1) is an actin-binding protein that enhances actin filament formation and cell migration, but stimulus-dependent regulation of Pfn-1 has not been observed. Here, we show that VEGF-A-inducible phosphorylation of Pfn-1 at Tyr 129 is critical for endothelial cell migration and angiogenesis. Chemotactic activation of VEGF receptor kinase-2 (VEGFR2) and Src induces Pfn-1 phosphorylation in the cell leading edge, promoting Pfn-1 binding to actin and actin polymerization. Conditional endothelial knock-in of phosphorylation-deficient Pfn1(Y129F) in mice reveals that Pfn-1 phosphorylation is critical for angiogenesis in response to wounding and ischaemic injury, but not for developmental angiogenesis. Thus, VEGFR2/Src-mediated phosphorylation of Pfn-1 bypasses canonical, multistep intracellular signalling events to initiate endothelial cell migration and angiogenesis, and might serve as a selective therapeutic target for anti-angiogenic therapy.
authors.affiliation: Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fan
authors.forename: Abul
authors.initials: A
authors.lastname: Arif
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Gong
authors.forename: Jie
authors.initials: J
authors.lastname: Jia
authors.forename: Sandeepa M
authors.initials: SM
authors.lastname: Eswarappa
authors.forename: Belinda
authors.initials: B
authors.lastname: Willard
authors.forename: Arie
authors.initials: A
authors.lastname: Horowitz
authors.forename: Linda M
authors.initials: LM
authors.lastname: Graham
authors.forename: Marc S
authors.initials: MS
authors.lastname: Penn
authors.forename: Paul L
authors.initials: PL
authors.lastname: Fox
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D055879:Gene Knock-In Techniques; D007511:Ischemia / Q000378:metabolism; D008297:Male; D051379:Mice; D055806:Microvessels / Q000166:cytology / Q000378:metabolism; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D051304:Profilins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014947:Wounds and Injuries / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C495739:Pfn1 protein, mouse; D051304:Profilins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D019061:src-Family Kinases