Inside-out Signaling Promotes Dynamic Changes in the Carcinoembryonic Antigen-related Cellular Adhesion Molecule 1 (CEACAM1) Oligomeric State to Control Its Cell Adhesion Properties

Cell-cell contacts are fundamental to multicellular organisms and are subject to exquisite levels of control. The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) can engage in both cis -homophilic (parallel) oligomerization and trans -homophilic (anti-parallel) binding. In this study, we establish that the CEACAM1 transmembrane domain has a propensity to form cis- dimers via the transmembrane-embedded 432 G XXX G 436 motif and that this basal state is overcome when activated calmodulin binds to the CEACAM1 cytoplasmic domain. Although mutation of the 432 G XXX G 436 motif reduced CEACAM1 oligomerization, it did not affect surface localization of the receptor or influence CEACAM1-dependent cellular invasion by the pathogenic Neisseria . The mutation did, however, have a striking effect on CEACAM1-dependent cellular aggregation, increasing both the kinetics of cell-cell association and the size of cellular aggregates formed. CEACAM1 association with tyrosine kinase c-Src and tyrosine phosphatases SHP-1 and SHP-2 was not affected by the 432 G XXX G 436 mutation, consistent with their association with the monomeric form of wild type CEACAM1. Collectively, our results establish that a dynamic oligomer-to-monomer shift in surface-expressed CEACAM1 facilitates trans -homophilic binding and downstream effector signaling. Background: Carcinoembryonic antigen-related cellular adhesion molecules (CEACAMs) engage in intercellular binding and influence cellular growth and differentiation. Results: Calcium-dependent signals cause dissolution of the transmembrane domain-driven basal state CEACAM1 oligomers into monomers that mediate intercellular binding. Conclusion: Regulated switching in CEACAM1 oligomerization controls cell-cell adhesion and downstream effector recruitment. Significance: Inside-out signaling effects CEACAM1-dependent cell adhesion by controlling a reversible dimer-to-monomer transition.