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J. Biol. Chem., Vol. 282, Issue 2, 968-975, January 12, 2007

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Phosphorylation of the LFA-1 Integrin 2-Chain on Thr-758 Leads to Adhesion, Rac-1/Cdc42 Activation, and Stimulation of CD69 Expression in Human T Cells^*

From the Division of Biochemistry, Faculty of Biosciences, University of Helsinki, 00014 Helsinki, Finland

Phosphorylation of the leukocyte function-associated antigen-1 (LFA-1) integrin 2-chain on Thr-758 occurs after T cell receptor stimulation and leads to 14-3-3 recruitment to the integrin, actin cytoskeleton reorganization, and increased adhesion. Here, we have investigated the signaling effects of 2 integrin Thr-758 phosphorylation. A penetratin-coupled phospho-Thr-758-2 peptide (mimicking the part of the integrin -chain surrounding Thr-758) stimulated adhesion of human T cells to the LFA-1 ligand intercellular adhesion molecule-1 (ICAM-1). Additionally, the peptide activated the small GTPases Rac-1 and Cdc42 in T cells. Constitutively active forms of Rac-1 and Cdc42, but not Rho, could compensate for the reduction of cell adhesion to ICAM-1 caused by the T758A mutation in the 2 integrin. Additionally, the active GTPases salvaged the cell-spreading defect of T758A integrin-transfected cells on coated ICAM-1. A dominant negative form of Cdc42, on the other hand, significantly reduced wild-type 2 integrin-mediated cell adhesion and spreading. In a T cell stimulation system, the pThr-758 penetratin peptide acted in a similar manner to coated ICAM-1 to increase T cell receptor-induced CD69 expression. These results show that Thr-758-phosphorylated LFA-1 is upstream of Rac-1/Cdc42, cell adhesion, and costimulatory activation of human T cells, thus identifying phosphorylation of Thr-758 in 2 as a proximal element in LFA-1 signaling.

Received for publication, September 5, 2006 , and in revised form, October 23, 2006.

^* This work was supported by the Academy of Finland, the Magnus Ehrnrooth Foundation, the Ruth and Nils-Erik Stenbäck Foundation, the Liv och Hälsa Foundation, the Sigrid Juselius Foundation, and the Finnish Cancer Society. 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 To whom correspondence should be addressed. Tel.: 358-9-19159604; Fax: 358-9-19159068; E-mail: susanna.fagerholm{at}helsinki.fi.

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