Fibroblast growth factor signaling potentiates VE-cadherin stability at adherens junctions by regulating SHP2.
BACKGROUND
The fibroblast growth factor (FGF) system plays a critical role in the maintenance of vascular integrity via enhancing the stability of VE-cadherin at adherens junctions. However, the precise molecular mechanism is not well understood. In the present study, we aimed to investigate the detailed mechanism of FGF regulation of VE-cadherin function that leads to endothelial junction stabilization.


RESULTS
In vitro studies demonstrated that the loss of FGF signaling disrupts the VE-cadherin-catenin complex at adherens junctions by increasing tyrosine phosphorylation levels of VE-cadherin. Among protein tyrosine phosphatases (PTPs) known to be involved in the maintenance of the VE-cadherin complex, suppression of FGF signaling reduces SHP2 expression levels and SHP2/VE-cadherin interaction due to accelerated SHP2 protein degradation. Increased endothelial permeability caused by FGF signaling inhibition was rescued by SHP2 overexpression, indicating the critical role of SHP2 in the maintenance of endothelial junction integrity.


CONCLUSIONS
These results identify FGF-dependent maintenance of SHP2 as an important new mechanism controlling the extent of VE-cadherin tyrosine phosphorylation, thereby regulating its presence in adherens junctions and endothelial permeability.
Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Kunihiko
K
Hatanaka
Anthony A
AA
Lanahan
Masahiro
M
Murakami
Michael
M
Simons
D022005:Adherens Junctions / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D002199:Capillary Permeability; D002417:Cattle; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D005346:Fibroblast Growth Factors; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D000099152:Cadherin 5