Role of protein tyrosine phosphatase ib in vascular endothelial growth factor signaling and cell-cell adhesions in endothelial cells

Yoshimasa Nakamura, Nikolay Patrushev, Hyoe Inomata, Dolly Mehta, Norifumi Urao, Ha Won Kim, Masooma Razvi, Vidisha Kini, Kalyankar Mahadev, Barry J. Goldstein, Ronald McKinney, Tohru Fukai, Masuko Fukai

Research output: Contribution to journalArticle

132 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1182-1191
Number of pages10
JournalCirculation research
Volume102
Issue number10
DOIs
StatePublished - May 23 2008

Fingerprint

Protein Tyrosine Phosphatases
Cell Adhesion
Vascular Endothelial Growth Factor A
Endothelial Cells
Phosphorylation
Tyrosine
Hindlimb
Small Interfering RNA
Cell Movement
Ischemia
Cell Proliferation
Vascular Endothelial Growth Factor Receptor-2
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Human Umbilical Vein Endothelial Cells
p38 Mitogen-Activated Protein Kinases
Electric Impedance
Protein-Tyrosine Kinases
Permeability
cadherin 5

Keywords

  • Angiogenesis
  • Cell-cell adhesions
  • Endothelial cell
  • Protein tyrosine phosphatase IB
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Role of protein tyrosine phosphatase ib in vascular endothelial growth factor signaling and cell-cell adhesions in endothelial cells. / Nakamura, Yoshimasa; Patrushev, Nikolay; Inomata, Hyoe; Mehta, Dolly; Urao, Norifumi; Kim, Ha Won; Razvi, Masooma; Kini, Vidisha; Mahadev, Kalyankar; Goldstein, Barry J.; McKinney, Ronald; Fukai, Tohru; Fukai, Masuko.

In: Circulation research, Vol. 102, No. 10, 23.05.2008, p. 1182-1191.

Research output: Contribution to journalArticle

Nakamura, Y, Patrushev, N, Inomata, H, Mehta, D, Urao, N, Kim, HW, Razvi, M, Kini, V, Mahadev, K, Goldstein, BJ, McKinney, R, Fukai, T & Fukai, M 2008, 'Role of protein tyrosine phosphatase ib in vascular endothelial growth factor signaling and cell-cell adhesions in endothelial cells', Circulation research, vol. 102, no. 10, pp. 1182-1191. https://doi.org/10.1161/CIRCRESAHA.107.167080
Nakamura, Yoshimasa ; Patrushev, Nikolay ; Inomata, Hyoe ; Mehta, Dolly ; Urao, Norifumi ; Kim, Ha Won ; Razvi, Masooma ; Kini, Vidisha ; Mahadev, Kalyankar ; Goldstein, Barry J. ; McKinney, Ronald ; Fukai, Tohru ; Fukai, Masuko. / Role of protein tyrosine phosphatase ib in vascular endothelial growth factor signaling and cell-cell adhesions in endothelial cells. In: Circulation research. 2008 ; Vol. 102, No. 10. pp. 1182-1191.
@article{a6c4b5daad4e471d9a39944ead2ec509,
title = "Role of protein tyrosine phosphatase ib 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.",
keywords = "Angiogenesis, Cell-cell adhesions, Endothelial cell, Protein tyrosine phosphatase IB, Vascular endothelial growth factor",
author = "Yoshimasa Nakamura and Nikolay Patrushev and Hyoe Inomata and Dolly Mehta and Norifumi Urao and Kim, {Ha Won} and Masooma Razvi and Vidisha Kini and Kalyankar Mahadev and Goldstein, {Barry J.} and Ronald McKinney and Tohru Fukai and Masuko Fukai",
year = "2008",
month = "5",
day = "23",
doi = "10.1161/CIRCRESAHA.107.167080",
language = "English (US)",
volume = "102",
pages = "1182--1191",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "10",

}

TY - JOUR

T1 - Role of protein tyrosine phosphatase ib in vascular endothelial growth factor signaling and cell-cell adhesions in endothelial cells

AU - Nakamura, Yoshimasa

AU - Patrushev, Nikolay

AU - Inomata, Hyoe

AU - Mehta, Dolly

AU - Urao, Norifumi

AU - Kim, Ha Won

AU - Razvi, Masooma

AU - Kini, Vidisha

AU - Mahadev, Kalyankar

AU - Goldstein, Barry J.

AU - McKinney, Ronald

AU - Fukai, Tohru

AU - Fukai, Masuko

PY - 2008/5/23

Y1 - 2008/5/23

N2 - 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.

AB - 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.

KW - Angiogenesis

KW - Cell-cell adhesions

KW - Endothelial cell

KW - Protein tyrosine phosphatase IB

KW - Vascular endothelial growth factor

UR - http://www.scopus.com/inward/record.url?scp=45149107474&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=45149107474&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.107.167080

DO - 10.1161/CIRCRESAHA.107.167080

M3 - Article

C2 - 18451337

AN - SCOPUS:45149107474

VL - 102

SP - 1182

EP - 1191

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 10

ER -