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Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Inhibits Proximal TCR Signaling by Targeting ZAP-70¹

Gastroenterology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115

The long cytoplasmic tail (CT) isoforms of carcinoembryonic Ag-related cell adhesion molecule 1 (CEACAM1) are expressed on activated human T cells and possess two ITIM motifs in the CT. These isoforms of CEACAM1 are inhibitory for T cell responses initiated by the TCR/CD3 complex with the inhibition dependent upon the ITIMs of CEACAM1 and Src homology 2 domain-containing phosphatase 1 (SHP-1). However, the mechanism by which this inhibition occurs in T cells is unknown. We demonstrate here that the Src family kinase, Lck, and the ability of CEACAM1 to bind homophilically are required for the ITIM phosphorylation of CEACAM1 that is a prerequisite for CEACAM1 association with SHP-1. We further show that CEACAM1 associates with and recruits SHP-1 to the TCR/CD3 complex leading to decreased phosphorylation of CD3- and ZAP-70 and consequently decreased activation of the elements downstream of ZAP-70. This is physiologically relevant because extinction of SHP-1 expression or blockade of homophilic binding by CEACAM1 using a Fab that specifically recognizes the homophilic binding region of human CEACAM1 increases the cytolytic function initiated by the TCR/CD3 complex. These studies show that long CT isoforms of CEACAM1 orchestrate an inhibitory program that abrogates extremely proximal events downstream of the TCR/CD3 complex by focusing on the activation of ZAP-70.

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 This work was supported by National Institutes of Health Grants R01 DK53056, R01 DK51362, R01 DK44319, and P30 DK034854 (Harvard Digestive Diseases Center; to R.S.B.).

² Address correspondence and reprint requests to Dr. Richard S. Blumberg, Thorn Research Building Room 1419, Gastroenterology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115. E-mail address: rblumberg{at}partners.org

³ Abbreviations used in this paper: CEA, carcinoembryonic Ag; CEACAM1, CEA Ag-related cell adhesion molecule 1; CT, cytoplasmic tail; cyt, cytoplasmic; SHP-1, Src homology 2 domain-containing phosphatase 1; S, short; L, long; H, human; siRNA, short interfering RNA; p, phospho; IP, immunoprecipitation; PBT, peripheral blood T; IEL, intraepithelial lymphocyte; IB, immunoblotted; WT, wild type; LAT, linker for activation of T cells.

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				Z. Chen, L. Chen, and R. S. Blumberg Editorial: CEACAM1: fine-tuned for fine-tuning J. Leukoc. Biol., August 1, 2009; 86(2): 195 - 197. [Full Text] [PDF]