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J. Biol. Chem., Vol. 281, Issue 29, 20148-20159, July 21, 2006

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The Adaptor Molecule Lnk Negatively Regulates Tumor Necrosis Factor--dependent VCAM-1 Expression in Endothelial Cells through Inhibition of the ERK1 and -2 Pathways^*

From the INSERM, U643, Nantes, France, Institut de Transplantation et de Recherche en Transplantation, Centre Hospitalier Universitaire, and Université de Nantes, Unité de Formation et de Recherche de Médecine, F-44093 Nantes, France

Lnk, with APS and SH2-B (Src homology 2-B), belongs to a family of SH2-containing proteins with potential adaptor functions. Lnk regulates growth factor and cytokine receptor-mediated pathways implicated in lymphoid, myeloid, and platelet homeostasis. We have previously shown that Lnk is expressed and up-regulated in vascular endothelial cells (ECs) in response to tumor necrosis factor- (TNF). In this study, we have shown that, in ECs, Lnk down-regulates the expression, at both mRNA and protein levels, of the proinflammatory molecules VCAM-1 and E-selectin induced by TNF. Mechanistically, our data indicated that, in response to TNF, NFB/p65 phosphorylation and translocation as well as IB phosphorylation and degradation were unchanged, suggesting that Lnk does not modulate NFB activity. However, Lnk activates phosphatidylinositol 3-kinase (PI3K) as reflected by Akt phosphorylation. Our results identify endothelial nitric-oxide synthase as a downstream target of Lnk-mediated activation of the PI3K/Akt pathway and HO-1 as a new substrate of Akt. We found that sustained Lnk-mediated activation of PI3K in TNF-activated ECs correlated with the inhibition of ERK1/2 phosphorylation, whereas phosphorylation of p38 and c-Jun NH₂-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) was unchanged. ERK1/2 inhibition decreases VCAM-1 expression in TNF-treated ECs. Collectively, our results identify the adaptor Lnk as a negative regulator in the TNF-signaling pathway mediating ERK inhibition and suggest a role for Lnk in the interplay between PI3K and ERK triggered by TNF in ECs.

Received for publication, October 7, 2005 , and in revised form, April 20, 2006.

^* 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.

¹ Supported by fellowships from La Société Francophone de Transplantation, La Société deNéphrologie and La Fondation ProGreffe.

² Supported by a fellowship from the Fondation pour la Recherche Médicale. Present address: Children's Hospital, Division of Nephrology, Boston, MA 02115.

³ To whom correspondence should be addressed: INSERM U643, ITERT, CHU Hôtel-Dieu, 30 Bd Jean Monnet, F-44093 Nantes, France. Tel.: 33-240-087-416; Fax: 33-240-087-411; E-mail: Beatrice.Charreau{at}univ-nantes.fr.

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