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J. Biol. Chem., Vol. 280, Issue 33, 29620-29624, August 19, 2005

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Flow Activates ERK1/2 and Endothelial Nitric Oxide Synthase via a Pathway Involving PECAM1, SHP2, and Tie2^*

Lung-kuo Tai, Qinlei Zheng, Shi Pan, Zheng-Gen Jin, and Bradford C. Berk

From the Cardiovascular Research Institute and Department of Medicine, University of Rochester, Rochester, New York 14642

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 ERK1/2 phosphorylation depends on SHP2 phosphatase activity and SHP2 binding to phospho-PECAM1 (platelet endothelial adhesion molecule 1), suggesting that SHP2 forms a signaling module with PECAM1. 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 PECAM1 and their association with SHP2. To evaluate their functional roles, ECs were treated with Tie2 or PECAM1 small interfering RNA (siRNA). Tie2 and PECAM1 expression decreased >80% after siRNA treatment, and flow-stimulated phosphorylation of ERK1/2, Akt, and endothelial nitric oxide synthase was significantly inhibited by Tie2 and PECAM1 siRNA. Tie2 phosphorylation by flow was significantly inhibited by PECAM1 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.

Received for publication, February 2, 2005 , and in revised form, May 23, 2005.

^* This work was supported by National Institutes of Health Grant HL64839 (to B. C. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Table I, which provides information on proteins in SHP2 complexes.

To whom correspondence should be addressed: University of Rochester, Cardiovascular Research Inst., Box 679, 601 Elmwood Ave., Rochester, NY 14642. Tel.: 585-273-1946; Fax: 585-273-1497; E-mail: Bradford_Berk{at}urmc.rochester.edu.

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