ORGANIZATION OF THE GENE FOR HUMAN PLATELET ENDOTHELIAL-CELL ADHESION MOLECULE-1 SHOWS ALTERNATIVELY SPLICED ISOFORMS AND A FUNCTIONALLY COMPLEX CYTOPLASMIC DOMAIN

Platelet endothelial cell adhesion molecule-1 (PECAM-1) is a cell-cell adhesion molecule that is expressed on circulating platelets, on leukocytes, and at the intercellular junctions of vascular endothelial cells and mediates the interactions of these cells during the process of transendothelial cell migration. The cDNA for PECAM-1 encodes an open reading frame of 738 amino acids (aa) that is organized into a 27-aa signal peptide, a 574-aa extracellular domain composed of 6 lg homology units, and a relatively long cytoplasmic tail of 118 aa containing multiple sites for posttranslational modification and postreceptor signal transduction. To provide a molecular basis for the precise evaluation of the structure and function of th is transmembrane glycoprotein, we have determined the organization of the human PECAM-1 gene. The PECAM-1 gene, which has been localized to human chromosome 17, is a single-copy gene of approximately 65 hb in length and is broken into is exons by introns ranging in size from 86 to greater than 12,000 bp in length. Typical of other members of the lg superfamily, each of the extracellular lg homology domains is encoded by a separate exon, consistent with PECAM-1 having arisen by gene duplication and exon shuffling of ancestral lg superfamily genes. However, the cytoplasmic domain was found to be surprisingly complex, being encoded by seven short exons that may represent discrete functional entities, Alternative splicing of the cytoplasmic tail appears to generate multiple PECAM-1 isoforms that may regulate phosphorylation, cytoskeletal association, and affinity modulation of the mature protein, Finally, a processed pseudogene having 76% identity with PECAM-1 cDNA was identified and localized to human chromosome 3. These findings should have important implications for structure/function analysis of PECAM-1 and its role in vascular adhesive interactions. (C) 1994 by The American Society of Hematology.