• Kenneth J Dery, Sonia M Najjar, Nicole Beauchemin, John E Shively, and Jerzy W Kupiec-Weglinski.
• Department of Surgery, University of California Los Angeles, Los Angeles, California, USA.
• Eur. J. Clin. Invest. 2024 Dec 1; 54 Suppl 2 (Suppl 2): e14350e14350.

BackgroundAlternative splicing is a fundamental mechanism in the post-transcriptional regulation of genes. The multifunctional transmembrane glycoprotein receptor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) undergoes extensive alternative splicing to allow for tunable functions in cell signalling, adhesion and modulation of immune and metabolic responses. Splice isoforms that differ in their ectodomain and short or long cytoplasmic tail (CEACAM1-S/CEACAM1-L) have distinct functional roles. The mechanisms that regulate CEACAM1 RNA splicing remain elusive.MethodsThis narrative review summarizes the current knowledge of the mechanism and function of CEACAM1 splice isoforms. Historical perspectives address the biological significance of the glycosylated Ig domains, the variable exon 7, and phosphorylation events that dictate its signal transduction pathways. The use of small antisense molecules to target mis-spliced variable exon 7 is discussed.ResultsThe Ig variable-like N domain mediates cell adhesion and immune checkpoint inhibitory functions. Gly and Tyr residues in the transmembrane (TM) domain are essential for dimerization. Calmodulin, Calcium/Calmodulin-dependent protein kinase II delta (CamK2D), Actin and Annexin A2 are binding partners of CEACAM1-S. Homology studies of the muCEACAM1-S and huCEACAM1-S TM predict differences in their signal transduction pathways. Hypoxia-inducible factor 1-α (HIF-1-α) induces alternative splicing to produce CEACAM1-S under limited oxygen conditions. Antisense small molecules directed to exon 7 may correct faulty expression of the short and long cytoplasmic tail splicing isoforms.ConclusionMore pre-clinical and clinical studies are needed to elucidate the precise mechanisms by which CEACAM1 RNA splicing may be exploited to develop targeted interventions towards novel therapeutic strategies.© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.

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