Measuring the multifaceted roles of mucin-domain glycoproteins in cancer

Abstract

Mucin-domain glycoproteins are highly O-glycosylated cell surface and secreted proteins that serve as both biochemical and biophysical modulators. Aberrant expression and glycosylation of mucins are known hallmarks in numerous malignancies, yet mucin-domain glycoproteins remain enigmatic in the broad landscape of cancer glycobiology. Here we review the multifaceted roles of mucins in cancer through the lens of the analytical and biochemical methods used to study them. We also describe a collection of emerging tools that are specifically equipped to characterize mucin-domain glycoproteins in complex biological backgrounds. These approaches are poised to further elucidate how mucin biology can be understood and subsequently targeted for the next generation of cancer therapeutics.

Keywords: Cancer; Chemical biology; Glycoproteomics; Mucin-domain glycoproteins; Mucins; O-glycosylation.

Fig. 1

Protein domains of canonical human mucins. Protein domains for membrane (top) and secreted (bottom) mucins are shown. All secreted mucins are gel forming, with the exception of MUC7 which is non-gel forming. Protein sequences not drawn to scale and the amino acid (aa) length of each protein is indicated. Protein domains include: signal sequence (SS), mucin domain (PTS), domain found in sea-urchin sperm protein, enterokinase and agrin (SEA), transmembrane domain (TM), adhesion-associated domain (AMOP), nidogen-like domain (NIDO), von Wilebrand factor type D domain (VWD), Cys-rich domain (CysD), cys-knot domain (CK), von Wilebrand factor type C domain (VWC). Protein domain information obtained from Lang et al. (2016). Protein sequences created using DOG 1.0 (Ren et al., 2009).

Fig. 2. Biosynthesis of common human O-glycan types.

Pathways to build core 1 through 4 of O-glycans are shown.