CLONING OF THE MUCOSAL ADDRESSIN MADCAM-1 FROM HUMAN BRAIN - IDENTIFICATION OF NOVEL ALTERNATIVELY SPLICED TRANSCRIPTS

The mucosal addressin cell adhesion molecule-1 (MAdCAM-1), expressed s electively on high endothelial venules (HEY) and lamina propria venule s, directs lymphocyte traffic by binding the lymphocyte Peyer's patch adhesion molecule-1 (LPAM-1, alpha 4 beta 7). Full-length DNA encoding human MAdCAM-1 was obtained by combining sequences from an expressed sequence tag (EST) identified in an early stage human brain cDNA libra ry, a polymerase chain reaction-derived clone? and a MAdCAM-1 genomic clone. The deduced amino acid sequence revealed an 18 amino acid signa l peptide, two N-terminal immunoglobulin (Ig)-like domains conserved ( 59-65%) in sequence with those of the mouse homologue. an 86 amino aci d mucin-like region rich in serine-threonine residues, a 20 amino acid transmembrane domain and a 43 amino acid charged cytoplasmic domain. No counterpart to the third IgA-like domain of mouse MAdCAM-1 was pres ent: however, the serine-threonine-rich mucin domain was extended as t wo distinguishable major and minor mucin regions unrelated to the mous e mucin domain. The major domain is formed from six tandem repeats of an eight amino acid sequence having the MUC-2-related consensus DTTSPE P/SP. Human MAdCAM-1 mRNA transcripts were restricted to small intesti ne, colon, spleen, pancreas and brain. Alternatively spliced MAdCAM-1 variants were identified that lack parts of the second Ig domain and a ll or part of the major mucin domain, indicating that the function of this vascular addressin is regulated by extensive modifications to its multi-domain structure.