title: Muc4/sialomucin complex, the intramembrane ErbB2 ligand, in cancer and epithelia: to protect and to survive.
abstract: The membrane mucin Muc4, also called sialomucin complex (SMC), is a heterodimeric complex of two subunits, ASGP-1 and ASGP-2, derived from a single gene. It is produced by multiple epithelia in both membrane and soluble forms and serves as a protective agent for the epithelia. The membrane form of Muc4 acts as a steric barrier to the apical cell surface of epithelial or tumor cells. An important example is the uterus of the rat, in which Muc4 expression is downregulated for blastocyst implantation. The soluble form facilitates the protection and lubrication of epithelia by mucous gels composed of gel-forming mucins, as in the airway, where Muc4 is proposed to participate in mucociliary transport as a constituent of the periciliary fluid. The soluble form is also found in body fluids, such as milk, tears, and saliva. The transmembrane subunit ASGP-2 acts as an intramembrane ligand and activator for the receptor tyrosine kinase ErbB2. Formation of this ligand-receptor complex is proposed to repress apopotosis in epithelial and cancer cells in which the ligand-receptor complex is formed, providing a second type of cell protective mechanism. Muc4 expression is regulated in epithelial tissues in a cell- and tissue-specific manner during epithelial differentiation. In stratified epithelia, it is predominantly in the most superficial, differentiated layers, often coincident with ErbB2. Dysregulation of Muc4 expression may contribute to cell and tissue dysfunction, such as the proposed contribution of Muc4 to mammary tumor progression. These observations clearly show that Muc4 has multiple roles in epithelia, which may provide insights into aberrant behaviors of these tissues and their derivative carcinomas.
authors.affiliation: Department of Cell Biology and Anatomy, University of Miami School of Medicine, Florida 33101, USA.
authors.forename: Kermit L
authors.initials: KL
authors.lastname: Carraway
authors.forename: Aymee
authors.initials: A
authors.lastname: Perez
authors.forename: Nebila
authors.initials: N
authors.lastname: Idris
authors.forename: Scott
authors.initials: S
authors.lastname: Jepson
authors.forename: Maria
authors.initials: M
authors.lastname: Arango
authors.forename: Masanobu
authors.initials: M
authors.lastname: Komatsu
authors.forename: Bushra
authors.initials: B
authors.lastname: Haq
authors.forename: Shari A
authors.initials: SA
authors.lastname: Price-Schiavi
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Coralie A Carothers
authors.initials: CA
authors.lastname: Carraway
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004848:Epithelium / Q000378:metabolism; D005260:Female; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D008969:Molecular Sequence Data; D055264:Mucin-4; D009077:Mucins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D008024:Ligands; D055264:Mucin-4; D009077:Mucins; D018719:Erb-b2 Receptor Tyrosine Kinases; C524658:MUC4 protein, human; C524660:Muc4 protein, rat