Complete sequence of the human mucin MUC4: a putative cell membrane-associated mucin

Abstract

The MUC4 gene, which encodes a human epithelial mucin, is expressed in various epithelial tissues, just as well in adult as in poorly differentiated cells in the embryo and fetus. Its N-terminus and central sequences have previously been reported as comprising a 27-residue peptide signal, followed by a large domain varying in length from 3285 to 7285 amino acid residues. The present study establishes the whole coding sequence of MUC4 in which the C-terminus is 1156 amino acid residues long and shares a high degree of similarity with the rat sialomucin complex (SMC). SMC is a heterodimeric glycoprotein complex composed of mucin (ascites sialoglycoprotein 1, ASGP-1) and transmembrane (ASGP-2) subunits. The same organization is found in MUC4, where the presence of a GlyAspProHis proteolytic site may cleave the large precursor into two subunits, MUC4alpha and MUC4beta. Like ASGP-2, which binds the receptor tyrosine kinase p185(neu), MUC4beta possesses two epidermal growth factor-like domains, a transmembrane sequence and a potential phosphorylated site. MUC4, the human homologue of rat SMC, may be a heterodimeric bifunctional cell-surface glycoprotein of 2.12 micrometers. These results confer a new biological role for MUC4 as a ligand for ErbB2 in cell signalling.

Potentiation of metastasis by cell surface sialomucin complex (rat MUC4), a multifunctional anti-adhesive glycoprotein

“…The transmembrane subunit ASGP-2 contains 2 epidermal growth factor (EGF)-like domains (Sheng et al, 1992;, one of which can act as a ligand and modulator for the receptor tyrosine kinase ErbB2 . Recent work on the cloning and sequencing of the full-length human mucin gene MUC4 showed substantial similarities to rat SMC, including 60%-70% identity between the human MUC4 analog of ASGP-2 and rat ASGP-2 (Moniaux et al, 1999). These findings provide strong evidence that SMC is the rat homologue of MUC4.…”

“…These findings provide strong evidence that SMC is the rat homologue of MUC4. Up-regulation of MUC4 has been observed in several types of human adenocarcinomas (Moniaux et al, 1999), suggesting a role for this glycoprotein complex in tumorigenesis and/or tumor progression. However, despite its possible involvement in metastasis of human cancer, analyses of MUC4 have been limited.…”

“…Since the ErbB receptors play significant roles in the progression of many types of carcinomas (Tzahar and Yarden, 1998), these findings further implicate SMC in the progression of malignancy. Moreover, the strong similarity in the domain structures of MUC4 and rat SMC (Moniaux et al, 1999) suggests that this metastasis-promoting function of SMC is also relevant in human cancer.…”

Mucin gene expression and cell differentiation in human normal, premalignant and malignant esophagus

“…In these tissues, as in esophageal mucosa, MUC1 and MUC4 expression is not restricted to mucus-secreting cells and occurs, as seen with MUC3, in a wide variety of epithelial cells which are not specialized in mucus secretion (e.g., enterocytes and ciliated cells of airway epithelium) (Audie et al, 1993;Buisine et al, 1999). Recent studies of the cDNA sequences of MUC4 (Moniaux et al, 1999) andMUC3 (Crawley et al, 1999) revealed the presence of a putative transmembrane domain, as previously described for the structure of the MUC1 apomucin. MUC1, MUC3 and MUC4 genes are not located in the gene cluster, which is located in chromosome 11p15 and includes MUC2, MUC5AC, MUC5B and MUC6 genes.…”

Alternate splicing at the 3?-end of the human pancreatic tumor-associated mucin MUC4 cDNA

“…The COOH-terminal region can be divided into 12 domains (CT1 to CT12). The CT7, CT9 [25], and CT6 [24] are EGF-like domains, and CT11 corresponds to the transmembrane domain. A putative GDPH proteolytic cleavage site is situated between CT4 and CT5 domains may divide the precursor into a large mucin-type MUC4α subunit and a transmembrane growth factor like subunit MUC4β.…”