cis-Determinants in the cytoplasmic domain of CEACAM1 responsible for its tumor inhibitory function

CEACAM1, also known as C-CAM, BGP and CD66a, is a member of the carcinoembr yonic antigen (CEA) family which is itself part of the immunoglobulin super gene family, CEACAM1 is involved in intercellular adhesion, signal transduc tion and tumor cell growth regulation, CEACAM1 is down-regulated in colon a nd prostate carcinomas, as well as in endometrial, bladder and hepatic tumo rs, and 30% of breast cancers, We have shown in a mouse colon tumor model t hat CEACAM1 with a long cytoplasmic domain inhibited the development of tum ors whereas a splice variant lacking the cytoplasmic domain did not, In thi s study, we define the subregions of the long cytoplasmic domain participat ing in the tumor inhibition phenotype of CEACAM1, We show that a single poi nt mutation of Tyr488, conforming to an Immune-receptor Tyrosine Inhibition Motif (ITIM), was sufficient to reverse the in vivo tumor cell growth inhi bition, Substitution or deletion of residues in the C-terminal region of th e CEACAM1 cytoplasmic domain also led to reversal of tumor cell growth inhi bition. This result is in agreement with our previous studies demonstrating the C-terminal region of the cytoplasmic domain influences the levels of C EACAM1 Tyr phosphorylation and its association with the protein Tyr phospha tases SHP-1 and SHP-2, Furthermore, removal of the N-terminal domain of CEA CAM1, essential for intercellular adhesion, did not impair the tumor inhibi tory effect. These results suggest that Tyr phosphorylation or dephosphoryl ation of the CEACAM1 cytoplasmic domain represents a crucial step in the co ntrol of epithelial cell proliferation.