Role of Mucin‐1 in Carcinomas

Abstract

Mucin 1 (MUC1) is a large, heavy O‐glycosylated mucin glycoprotein with a molecular weight of 250 to 500 kDa, depending on the level of glycosylation, and extends 200–500 nm from the cell surface. MUC1 spans the cell membrane at the apical surface of normal simple epithelia and the surfaces of some hematopoietic cells. MUC1 is comprised of three major domains: the cytoplasmic tail, transmembrane, and extracellular domains. The cytoplasmic tail (CT) domain is highly conserved across species and interacts with various cell signaling networks. The transmembrane domain is composed of hydrophobic amino acids to anchor MUC1 in the membrane. The extracellular domain is not strictly conserved, but always consists of a series of 20–100 tandem repeats enriched in serine, threonine and proline residues providing sites for the heavy O‐linked glycosylation characteristic of mucin‐type glycoproteins. The extracellular domain contributes MUC1’s function as an inhibitor of cell‐cell and cell‐extracellular matrix adhesion. The heavy glycosylation of MUC1 normally serves to protect cells from infection and also lubricates the cell surface. In normal biology, MUC1 serves as an inhibitor of embryo attachment to the uterine cell surface and controls early aspects of the reproductive process. In cancer, carcinomas often overexpress MUC1 due to a combination of gene duplication events as well as stimulation of MUC gene expression by cytokines produced by cells of the immune system in their efforts to destroy the cancer cells. Cancer cells also lose their normally polarized distribution of MUC1 and instead express the glycoprotein over their entire surface, MUC1 protects tumor cells from the immune system in two ways. First, by inhibiting the cell contact required for cell‐mediated immunity, e.g. by NK cells. In addition MUC1 expressed at tumor cell surfaces or shed by the action of cell surface proteases is immunosuppressive, presumably by interacting with immune checkpoint inhibitors. Various mouse models have been used to conduct research about MUC1, showing the connection between MUC1 overexpression in mouse mammary glands and cancer development and other processes. MUC1 serves as a commonly used serum marker for various cancers and is being explored as a target for certain therapeutic approaches. The Walton SMART team has designed a 3D model of MUC1 to investigate the relationship between its structure and function.Support or Funding InformationMSOE Center for Biomolecular Modeling