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Review
. 2016 Jul 30;6(3):34.
doi: 10.3390/biom6030034.

Functional Consequences of Differential O-glycosylation of MUC1, MUC4, and MUC16 (Downstream Effects on Signaling)

Ryan L Hanson  1 , Michael A Hollingsworth  2
Affiliations
Review

Functional Consequences of Differential O-glycosylation of MUC1, MUC4, and MUC16 (Downstream Effects on Signaling)

Ryan L Hanson et al. Biomolecules. .

Abstract

Glycosylation is one of the most abundant post-translational modifications that occur within the cell. Under normal physiological conditions, O-linked glycosylation of extracellular proteins is critical for both structure and function. During the progression of cancer, however, the expression of aberrant and truncated glycans is commonly observed. Mucins are high molecular weight glycoproteins that contain numerous sites of O-glycosylation within their extracellular domains. Transmembrane mucins also play a functional role in monitoring the surrounding microenvironment and transducing these signals into the cell. In cancer, these mucins often take on an oncogenic role and promote a number of pro-tumorigenic effects, including pro-survival, migratory, and invasive behaviors. Within this review, we highlight both the processes involved in the expression of aberrant glycan structures on mucins, as well as the potential downstream impacts on cellular signaling.

Keywords: MUC1; MUC16; MUC4; O-glycosylation; cancer; mucin; signaling.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
O-type glycosylation of mucins. Schematic representation of mucin O-type glycosylation. Initiation occurs through addition of N-acetylgalactosamine (GalNAc) to serine or threonine residues present in the mucin backbone. These structures are then extended into Core 1, Core 2, Core 3, and Core 4 structures through the addition of the indicated sugar. The enzyme involved in each reaction is indicated with the arrow and linkage lines indicate the attachment for each sugar. The cancer associated epitopes T, Tn, and sialyl-Tn (STn) are highlighted within the box. Gal: galactose; GalNAc-T: GalNAc-transferase; C1GalT: Core 1 Gal-transferase; C2GnT: Core 2 N-acetylglucosamine transferase; C3GnT: Core 3 N-acetylglucosamine transferase; C4GnT: Core 4 N-acetylglucosamine transferase.
Figure 2
Figure 2
Structure of MUC1, MUC4, and MUC16. General domain structures for MUC1 (A); MUC4 (B); and MUC16 (C). Cleavage sites are represented by dashed lines and the sequence of the cytoplasmic tail is presented for each mucin. Confirmed phosphorylated residues are indicated by red asterisks (*). Proteins are not drawn to scale. VNTR: variable number tandem repeat domain; SEA: sperm protein, enterokinase, agrin domain; TM: transmembrane domain; CT: cytoplasmic tail; NIDO: nidogen-like domain; AMOP: adhesion-associated domain in MUC4 and other proteins; VWD: Von Willebrand factor type D domain; EGF: epidermal growth factor-like domain.
Figure 3
Figure 3
Impact of O-glycosylation on MUC1 signaling. In fully glycosylated state (A), the interaction of MUC1 with signaling partners, such as epidermal growth factor receptor (EGFR), may be enabled or inhibited either through steric effects or by masking of interaction domains. Glycosylation may also sequester growth signals and decrease availability for receptor mediated signaling. Branched glycans may also promote adhesive effects of MUC1 and inhibit migration. Loss of glycosylation (B) can promote association between MUC1 and signaling partners, either through direct interactions or those mediated by adaptor partners, like galectin-3 (Gal-3). These interactions can promote downstream signaling from the surface, or internalization of the complexes to compartmentalize signaling. Loss of glycosylation also promotes anti-adhesive behavior through interactions in the microenvironment and may result in loss of capacity to sequester growth signals. RTK: receptor tyrosine kinase; TF: transcription factor.
Figure 4
Figure 4
Impact of O-glycosylation on MUC4 signaling. In fully glycosylated state (A), MUC4 may not interact with Erb-B2 receptor tyrosine kinase (ErbB) family members, due to masking of epidermal growth factor (EGF)-like domains. Masking of nidogen-like (NIDO) domain also results in maintenance of basement membrane integrity. With loss of glycosylation (B), EGF-like domains may be exposed resulting in stabilization of ErbB signaling complexes and promotion of extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K), and focal adhesion kinase (FAK) signaling. Exposure of the NIDO domain can also result in loss of basement membrane integrity through disruption of fibulin-2/nidogen complexes and promote invasive behavior.
Figure 5
Figure 5
Impact of O-glycosylation on tumor cells. Aberrant O-glycosylation can induce a wide range of effects, including (1) alterations to interactions with microenvironment, such as increased association with endothelial cells and invasive behavior; (2) immune modulation through interaction with receptors expressed on antigen presenting cells, or other immune effector cells; (3) alterations to signaling complexes through the unmasking of domains critical for interaction with receptor tyrosine kinases or other effectors. This can result in either signaling at the surface or (4) alterations to cellular localization through endocytosis or translocation to the nucleus; (5) increased shedding of extracellular domains through exposure of cleavage sites. These events may also promote morphogenetic signaling; (6) disruption of interactions with extracellular matrix and basement membrane proteins resulting in migratory and invasive behaviors. APC: antigen-presenting cell; NK: natural killer.
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