2nd Annual BMRP Investigator Meeting - Abstract

Does Phosphorylation Play a Role in the Function of the MUC3-Related Mucins?

Laurie L. Shekels

Department of Medicine, University of Minnesota and Veterans Affairs Medical Center (Minneapolis, U.S.A.)

It has been recognized that there is a genetic predisposition to inflammatory bowel disease (IBD).  Of particular interest to our lab is the demonstration via microsatellite marker studies that a predisposition to inflammatory bowel disease is carried on chromosome 7q22.  Several related genes are found within this region - the MUC3A, MUC3B, MUC12 and MUC17 mucin genes.  These genes encode for cell surface glycoproteins expressed along the intestinal tract that are characterized by two EGF-like domains in their extracellular domain and numerous serines, threonines and tyrosines in the cytoplasmic domain.  Alterations in mucin content and properties have been found in inflammatory bowel disease, however, these reports focused solely on changes in the type and quantity of mucin present.  This project investigates the functional properties of the MUC3 related mucins, focusing on interactions with other proteins, phosphorylation of the cytoplasmic domains and genetic alterations in the mucin DNA sequence that may alter their biological role.

Results:  No interaction of MUC3, MUC12 or MUC17 with the EGF receptor (ErbB1) or ErbB2 was detected.  Interactions with other proteins are continuing.  DNA from 25 individuals with ulcerative colitis and 25 individuals with Crohn’s disease was evaluated for gene polymorphisms of the carboxyl terminal exons and, more specifically, for differences in the sequence surrounding potential sites of phosphorylation.  No differences were found in the regions surrounding the tyrosine residues in the carboxyl terminal domain of MUC12 and MUC17.  Experiments examining the phosphorylation of the cytoplasmic domain of the MUC3-related mucins are in progress.

This project examines MUC3-related mucin function in a novel setting, suggesting that these proteins may actively play a role in the inflammatory and reparative process through signaling and protein-protein interactions.  Insight into the functional activities of these mucin proteins and genetic alterations will provide additional knowledge toward the susceptibility and pathogenesis of IBD.