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Regular Manuscript

Direct interaction of tumor suppressor CEACAM1 with beta-catenin: identification of key residues in the long cytoplasmic domain

¹ City of Hope

^* To whom correspondence should be addressed. E-mail: jshively{at}coh.org.

	Abstract

CEACAM1-4L (carcinoembryonic antigen cell adhesion molecule 1, with 4 ectodomains and a long, 71 amino acid cytoplasmic domain) is expressed in epithelial cells and activated T-cells, but is down-regulated in 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 -catenin, and to a lesser extent (32% homology), with E-cadherin that also binds -catenin. We show by quantitative yeast two-hybrid, BIAcore, GST-pull down, and confocal analyses that this domain directly interacts with -catenin, and that H-469 and K-470 are key residues that interact with the armadillo repeats of -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 -catenin from the cytoplasm to the cell membrane, demonstrating a functional role for the long cytoplasmic domain of CEACAM1 in regulation of -catenin activity.

Key Words: CEACAM1, beta-catenin, cell-cell adhesion, tumor suppressor