The Cell Adhesion Receptor Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 Regulates Nucleocytoplasmic Trafficking of DNA Polymerase δ-Interacting Protein 38

Abstract

The homophilic cell-cell adhesion receptor CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1, CD66a) acts as a regulator of contact-dependent cell survival, differentiation, and growth. It is involved in the control of proliferation in hematopoietic and epithelial cells and can act as a tumor suppressor. In this study, we identify DNA polymerase ␦-interacting protein 38 (PDIP38) as a novel binding partner for CEACAM1-L and CEACAM1-S. We show that PDIP38 can occur in the nucleus, in the cytoplasm and at the plasma membrane in NBT-II, IEC18, RBE, and HeLa cells and that the distribution in NBT-II cells is influenced by the confluency of the cells. We also demonstrate that the interaction of CEACAM1 and PDIP38 is of functional importance in NBT-II cells, which co-express the long and the short CEACAM1 isoform. In subconfluent, proliferating NBT-II cells, perturbation of CEACAM1 by antibody clustering induces increased binding to PDIP38 and results in rapid recruitment of PDIP38 to the plasma membrane. The same treatment of confluent, quiescent NBT-II cells leads to a different response, i.e. translocation of PDIP38 to the nucleus. Together, our data show that PDIP38 can shuttle between the cytoplasmic and the nuclear compartments and that its subcellular localization is regulated by CEACAM1, implicating that PDIP38 may constitute a novel downstream target of CEACAM1 signaling.The fate of a cell is controlled by its environment, including the extracellular matrix, neighboring cells, and soluble factors. The signals mediated by this environment frequently are transduced by components of cell-matrix or cell-cell adhesion complexes, like integrins, Ig-cell adhesion molecules, or cadherins (1). CEACAM1 3 (carcinoembryonic antigen-related cell adhesion molecule 1) is a cell-cell adhesion receptor belonging to the CEA family within the Ig-like cell adhesion molecules. CEACAM1 acts as an important regulator of contactdependent control of cell survival, differentiation, and growth in various normal and transformed/cancerous cells of epithelial, endothelial, and hematopoietic origin, as reviewed previously (2, 3).The two major CEACAM1 isoforms are co-expressed in most cells and consist of four extracellular Ig-like domains, a transmembrane domain, and, as a result of differential splicing, a long (L, 71 aa) or a short (S, 10 aa) cytoplasmic domain. Both isoforms mediate cell-cell adhesion via homophilic binding (4, 5). CEACAM1 can also bind to other CEA family members (6) and is used as a receptor by viral and bacterial pathogens (7-9). Recent studies show that there is an important role for CEACAM1 in modulating the immune responses associated with infection, inflammation, and cancer, as reviewed previously (10, 11). CEACAM1 controls differentiation processes (12-14) and apoptosis (13,(15)(16)(17) and can act as a tumor suppressor, as reviewed before (2, 18). We have previously demonstrated that CEACAM1 is implicated in the regulation of proliferation and contact inhibition in epithelial NBT-II cells (19, *...

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