ORGANIZATION OF THE GENE FOR HUMAN PLATELET ENDOTHELIAL-CELL ADHESIONMOLECULE-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 leuk ocytes, and at the intercellular junctions of vascular endothelial cel ls 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 s ignal peptide, a 574-aa extracellular domain composed of 6 lg homology units, and a relatively long cytoplasmic tail of 118 aa containing mu ltiple sites for posttranslational modification and postreceptor signa l transduction. To provide a molecular basis for the precise evaluatio n of the structure and function of th is transmembrane glycoprotein, w e have determined the organization of the human PECAM-1 gene. The PECA M-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 exon s by introns ranging in size from 86 to greater than 12,000 bp in leng th. Typical of other members of the lg superfamily, each of the extrac ellular lg homology domains is encoded by a separate exon, consistent with PECAM-1 having arisen by gene duplication and exon shuffling of a ncestral lg superfamily genes. However, the cytoplasmic domain was fou nd to be surprisingly complex, being encoded by seven short exons that may represent discrete functional entities, Alternative splicing of t he 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 havi ng 76% identity with PECAM-1 cDNA was identified and localized to huma n chromosome 3. These findings should have important implications for structure/function analysis of PECAM-1 and its role in vascular adhesi ve interactions. (C) 1994 by The American Society of Hematology.