title: Flt-1 regulates vascular endothelial cell migration via a protein tyrosine kinase-7-dependent pathway.
abstract: Protein tyrosine kinase 7 (PTK7) is a pseudokinase whose precise function in regulating angiogenesis remains unknown. The purpose of this study was to define the mechanisms by which PTK7 promotes vascular endothelial growth factor-A (VEGF-A)-induced angiogenesis in vivo and in vitro. Immunoblotting was used to measure PTK7 expression in several types of vascular endothelial cells. Using both immunoprecipitation and immunoblotting, PTK7 was found to join a receptor complex with Flt-1 (VEGFR1), but not with KDR/Flk-1 (VEGFR2) or with Flt-4 (VEGFR3). By surface plasmon resonance analysis, the interaction between Flt-1 and PTK7 was confirmed and found to be intensified by VEGF-A. Flt-1 phosphorylation and downstream signals of Akt, and focal adhesion kinase (FAK) thus induced were down-regulated by inhibition of PTK7 expression using siRNA. Moreover, PTK7 overexpression in endothelial cells resulted in enhanced angiogenesis in vitro. In contrast, neovascularization induced in vivo by VEGF-A pellets was significantly decreased by injection of siRNA targeting PTK7. These data suggest that PTK7 serves an essential role in Flt-1-mediated angiogenesis.
authors: Schepens Eye Research Institute and Department of Ophthalmology, MA Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors: Hyung Keun
authors: HK
authors: Lee
authors: Sunil K
authors: SK
authors: Chauhan
authors: Eunduk
authors: E
authors: Kay
authors: Reza
authors: R
authors: Dana
mesh_terms: D000818:Animals; D001158:Arteries / Q000166:cytology / Q000378:metabolism; D015153:Blotting, Western; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D016510:Corneal Neovascularization; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020349:Surface Plasmon Resonance; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing
chemical_list: D015815:Cell Adhesion Molecules; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C501162:FLT1 protein, human; C096905:PTK7 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3