Role of protein tyrosine phosphatase SHP2 in barrier function of pulmonary endothelium.
Pulmonary edema is mediated in part by disruption of interendothelial cell contacts. Protein tyrosine phosphatases (PTP) have been shown to affect both cell-extracellular matrix and cell-cell junctions. The SH2 domain-containing nonreceptor PTP, SHP2, is involved in intercellular signaling through direct interaction with adherens junction proteins. In this study, we examined the role of SHP2 in pulmonary endothelial barrier function. Inhibition of SHP2 promoted edema formation in rat lungs and increased monolayer permeability in cultured lung endothelial cells. In addition, pulmonary endothelial cells demonstrated a decreased level of p190RhoGAP activity following inhibition of SHP2, events that were accompanied by a concomitant increase in RhoA activity. Furthermore, immunofluorescence microscopy confirmed enhanced actin stress fiber formation and diminished interendothelial staining of adherens junction complex-associated proteins upon SHP2 inhibition. Finally, immunoprecipitation and immunoblot analyses demonstrated increased tyrosine phosphorylation of VE-cadherin, beta-catenin, and p190RhoGAP proteins, as well as decreased association between p120-catenin and VE-cadherin proteins. Our findings suggest that SHP2 supports basal pulmonary endothelial barrier function by coordinating the tyrosine phosphorylation profile of VE-cadherin, beta-catenin, and p190RhoGAP and the activity of RhoA, signaling molecules important in adherens junction complex integrity.
Grinnell
K L
KL
Vascular Research Laboratory, Providence VA Medical Center, 830 Chalkstone Ave., Providence, RI 02908, USA.
Casserly
B
B
Harrington
E O
EO
D022005:Adherens Junctions / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D055162:Biocatalysis / Q000187:drug effects; D015824:Blood-Air Barrier / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D051177:Catenins / Q000378:metabolism; D002417:Cattle; D004727:Endothelium / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011654:Pulmonary Edema / Q000201:enzymology / Q000473:pathology; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000095002:Delta Catenin; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D051177:Catenins; D004791:Enzyme Inhibitors; D019000:Phosphotyrosine; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D012097:Repressor Proteins; D020742:rhoA GTP-Binding Protein; D000095002:Delta Catenin; D000099152:Cadherin 5; C513040:Arhgap35 protein, rat