Altered Mucins (MUC) trafficking in benign and malignant conditions

Abstract

Mucins are high molecular weight O-glycoproteins that are predominantly expressed at the apical surface of epithelial cells and have wide range of functions. The functional diversity is attributed to their structure that comprises of a peptide chain with unique domains and multiple carbohydrate moieties added during posttranslational modifications. Tumor cells aberrantly overexpress mucins, and thereby promote proliferation, differentiation, motility, invasion and metastasis. Along with their aberrant expression, accumulating evidence suggest the critical role of altered subcellular localization of mucins under pathological conditions due to altered endocytic processes. The mislocalization of mucins and their interactions result in change in the density and activity of important cell membrane proteins (like, receptor tyrosine kinases) to facilitate various signaling, which help cancer cells to proliferate, survive and progress to more aggressive phenotype. In this review article, we summarize studies on mucins trafficking and provide a perspective on its importance to pathological conditions and to answer critical questions including its use for therapeutic interventions.

Figure 1. Diagrammatical representation of the intracellular transport of glycoproteins along endocytic and exocytic pathways

Internalization of cell surface glycoproteins occurs by clathrin-mediated, caveolin-mediated, or clathrin- & caveolinindependent pathways, followed by the fusion of internalized vesicles with early endosomes where the cargo is sorted and targeted for either recycling (from trans-Golgi, late endosome and recycling endosome) or for degradation (in lysosomes). The other exocytic route are representative of the secretory pathways, where glycoproteins are first synthesized and processed in the rough ER followed by their entry into the Golgi, where they are further modified, packaged into secretory vesicles (SV) and either targeted to the plasma membrane or secreted by the exocytic machinery. Abbreviations: EE, early endosome; RE, recycling endosome; MBMs, membrane bound mucins; SMs, secretory mucins; SV, secretory vesicles; SG, secretory granules; EC, extracellular

Figure 2. Mechanisms of intracellular transport and sorting of MUC1

MUC1 has demonstrated to be internalization by using clathrin and caveolin-mediated pathway, which is dependent on Rab5a, an early endosome marker. MUC1 has many interacting partners including EGFR family proteins, AP-2, Grb2 and β-catenin. MUC1 possesses a γ-secretase cleavage site and get cleaved in early endosome: (A) Cleaved MUC1-C, which is still in contact with β-catenin, travels to nucleus to increase the transcription of various genes that are regulated by the TCF promoter; MUC1-C interacts with heat shock proteins for mitochondrial (B) and lysosomal (C) translocation resulting in reduced cell death response to DNA damage and cathepsin mediated apoptosis, respectively; (D) MUC1, like other glycoproteins, undergoes multiple rounds of sialylation and glycosylation while continuing on the itinerary to the Golgi. MUC1 also has a CQCRRK sequence motif, which undergoes palmitoylation. These post-translational modifications and interacting protein partners play important roles in deciding the fate of MUC1.