title: Role of protein tyrosine phosphatase 1B in vascular endothelial growth factor signaling and cell-cell adhesions in endothelial cells.
abstract: Vascular endothelial growth factor (VEGF) binding induces phosphorylation of VEGF receptor (VEGFR)2 in tyrosine, which is followed by disruption of VE-cadherin-mediated cell-cell contacts of endothelial cells (ECs), thereby stimulating EC proliferation and migration to promote angiogenesis. Tyrosine phosphorylation events are controlled by the balance of activation of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Little is known about the role of endogenous PTPs in VEGF signaling in ECs. In this study, we found that PTP1B expression and activity are markedly increased in mice hindlimb ischemia model of angiogenesis. In ECs, overexpression of PTP1B, but not catalytically inactive mutant PTP1B-C/S, inhibits VEGF-induced phosphorylation of VEGFR2 and extracellular signal-regulated kinase 1/2, as well as EC proliferation, whereas knockdown of PTP1B by small interfering RNA enhances these responses, suggesting that PTP1B negatively regulates VEGFR2 signaling in ECs. VEGF-induced p38 mitogen-activated protein kinase phosphorylation and EC migration are not affected by PTP1B overexpression or knockdown. In vivo dephosphorylation and cotransfection assays reveal that PTP1B binds to VEGFR2 cytoplasmic domain in vivo and directly dephosphorylates activated VEGFR2 immunoprecipitates from human umbilical vein endothelial cells. Overexpression of PTP1B stabilizes VE-cadherin-mediated cell-cell adhesions by reducing VE-cadherin tyrosine phosphorylation, whereas PTP1B small interfering RNA causes opposite effects with increasing endothelial permeability, as measured by transendothelial electric resistance. In summary, PTP1B negatively regulates VEGFR2 receptor activation via binding to the VEGFR2, as well as stabilizes cell-cell adhesions through reducing tyrosine phosphorylation of VE-cadherin. Induction of PTP1B by hindlimb ischemia may represent an important counterregulatory mechanism that blunts overactivation of VEGFR2 during angiogenesis in vivo.
authors.affiliation: Department of Pharmacology, Center for Lung and Vascular Biology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Nikolay
authors.initials: N
authors.lastname: Patrushev
authors.forename: Hyoe
authors.initials: H
authors.lastname: Inomata
authors.forename: Dolly
authors.initials: D
authors.lastname: Mehta
authors.forename: Norifumi
authors.initials: N
authors.lastname: Urao
authors.forename: Ha Won
authors.initials: HW
authors.lastname: Kim
authors.forename: Masooma
authors.initials: M
authors.lastname: Razvi
authors.forename: Vidisha
authors.initials: V
authors.lastname: Kini
authors.forename: Kalyankar
authors.initials: K
authors.lastname: Mahadev
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Goldstein
authors.forename: Ronald
authors.initials: R
authors.lastname: McKinney
authors.forename: Tohru
authors.initials: T
authors.lastname: Fukai
authors.forename: Masuko
authors.initials: M
authors.lastname: Ushio-Fukai
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D016466:CHO Cells; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / 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; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D048051:p38 Mitogen-Activated Protein Kinases; D000099152:Cadherin 5; C467480:vascular endothelial growth factor A, mouse; C516609:Ptpn1 protein, mouse