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Flow Activates ERK1/2 and Endothelial Nitric Oxide Synthase via a Pathway Involving PECAM1, SHP2, and Tie2.
- Source :
-
Journal of Biological Chemistry . 8/19/2005, Vol. 280 Issue 33, p29620-29624. 5p. - Publication Year :
- 2005
-
Abstract
- Blood flow modulates endothelial cell (EC) functions through specific signaling events. Previous data show that flow stimulates SHP2 translocation to cell membranes and binding to phosphotyrosine proteins. Flow-induced ERK½ phosphorylation depends on SHP2 phosphatase activity and SHP2 binding to phospho-PE-CAM1 (platelet endothelial adhesion molecule 1), suggesting that SHP2 forms a signaling module with PE-CAM1. We hypothesized that flow induces assembly of the multi-protein complexes with SHP2 that are required for downstream signaling. ECs were exposed to flow for 10 min, and endogenous SHP2 was immunoprecipitated. SHP2-associated proteins were analyzed by SDS-PAGE and identified by mass spectrometry. Tie2 and several known SHP2-binding proteins were identified in flow-induced SHP2 complexes. Flow significantly increased tyrosine phosphorylation of both Tie2 and PE-CAM1 and their association with SHP2. To evaluate their functional roles, ECs were treated with Tie2 or PECAM1 small interfering RNA (siRNA). Tie2 and PE-CAM1 expression decreased >80% after siRNA treatment, and flow-stimulated phosphorylation of ERK½, Akt, and endothelial nitric oxide synthase was significantly inhibited by Tie2 and PECAM1 siRNA. Tie2 phosphorylation by flow was significantly inhibited by PE-CAM1 siRNA treatment. These results establish Tie2 transactivation via PECAM1 as an early event in flow-mediated mechanotransduction and suggest an important role for a PECAM1-SHP2-Tie2 pathway in flow-mediated signal transduction. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00219258
- Volume :
- 280
- Issue :
- 33
- Database :
- Academic Search Index
- Journal :
- Journal of Biological Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 18121125
- Full Text :
- https://doi.org/10.1074/jbc.M501243200