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ORIGINAL RESEARCH ARTICLE

Direct Interaction of Tumor Suppressor CEACAM1 with Beta Catenin: Identification of Key Residues in the Long Cytoplasmic Domain

Lan Jin^*, Yun Li^*, Charng-Jui Chen^*, Mark A. Sherman, Keith Le^* and John E. Shively^*,1

^* Division of Immunology; and Division of Information Sciences, Beckman Research Institute of the City of Hope, Duarte, California 91010

To whom requests for reprints should be addressed at ¹ Division of Immunology, Beckman Research Institute of the City of Hope, 1450 E. Duarte Rd., Duarte, CA 91010. E-mail: jshively{at}coh.org

CEACAM1-4L (carcinoembryonic antigen cell adhesion molecule 1, with 4 extracellular Ig-like domains and a long, 71 amino acid cytoplasmic domain) is expressed in epithelial cells and activated T-cells, but is down-regulated in most epithelial cell cancers and T-cell leukemias. A highly conserved sequence within the cytoplasmic domain has ca 50% sequence homology with Tcf-3 and –4, transcription factors that bind β-catenin, and to a lesser extent (32% homology), with E-cadherin that also binds β-catenin. We show by quantitative yeast two-hybrid, BIAcore, GST-pull down, and confocal analyses that this domain directly interacts with β-catenin, and that H-469 and K-470 are key residues that interact with the armadillo repeats of β-catenin. Jurkat cells transfected with CEACAM1-4L have 2-fold less activity in the TOPFLASH reporter assay, and in MCF7 breast cancer cells that fail to express CEACAM1, transfection with CEACAM1 and growth in Ca²⁺ media causes redistribution of β-catenin from the cytoplasm to the cell membrane, demonstrating a functional role for the long cytoplasmic domain of CEACAM1 in regulation of β-catenin activity.

Key Words: CEACAM1 • β-catenin • tumor suppressor • cell-cell adhesion