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An attempt to promote neo‐vascularization by employing a newly synthesized inhibitor of protein tyrosine phosphatase
Author(s) -
Soeda Shinji,
Shimada Takuji,
Koyanagi Satoru,
Yokomatsu Tsutomu,
Murano Tetsuo,
Shibuya Shiroshi,
Shimeno Hiroshi
Publication year - 2002
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(02)03002-8
Subject(s) - angiogenesis , phosphorylation , umbilical vein , protein tyrosine phosphatase , matrigel , microbiology and biotechnology , vascular endothelial growth factor , tyrosine phosphorylation , dephosphorylation , chemistry , kinase insert domain receptor , tyrosine kinase inhibitor , signal transduction , human umbilical vein endothelial cell , cancer research , receptor tyrosine kinase , phosphatase , vascular endothelial growth factor a , biology , biochemistry , vegf receptors , cancer , in vitro , genetics
Vascular endothelial growth factor (VEGF) and its receptors play a key role in angiogenesis. VEGF receptor‐2 (VEGFR‐2) has a tyrosine kinase domain, and, once activated, induces the phosphorylation of cytoplasmic signaling proteins. The phosphorylated VEGFR‐2 may be a substrate for intracellular protein tyrosine phosphatases (PTPs) which prevent VEGF signaling. We synthesized a series of α,α‐difluoro(phenyl)methylphosphonic acids (DFPMPAs) which inhibit the action of PTP. In this study, we test their effects on VEGF‐induced angiogenesis. DFPMPA‐3, the most effective inhibitor of human PTP‐1B, promoted tube formation by human umbilical vein endothelial cells (HUVEC) on Matrigel more effectively than any other DFPMPAs. The inhibitor promoted the VEGF‐induced proliferation and migration of HUVEC by inhibiting the dephosphorylation of VEGFR‐2. Its effectiveness was proven through neo‐vascularization in mice. The present findings suggest that targeting PTP to promote therapeutic neo‐vascularization may be a potential strategy.