Identification of a Novel Protein Binding Motif within the T-synthase for the Molecular Chaperone Cosmc

Aryal, Rajindra P.; Ju, Tongzhong; Cummings, Richard D.

doi:10.1074/jbc.m114.555870

Cited by 20 publications

(17 citation statements)

References 68 publications

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“…Cosmc is present in the ER of animal cells and has a single client protein, the T-synthase, to which it binds cotranslationally in the ER to prevent oligomerization and destruction in the proteasome. Successful binding of Cosmc to the T-synthase requires the presence of a novel CBRT (297), which is exposed in non-native T-synthase but becomes buried and inaccessible in the folded T-synthase. Once folded properly, the T-synthase moves to the Golgi apparatus, where it acts quantitatively on the products of the ppGalNAcTs to generate normal O -glycans (102).…”

Section: Figurementioning

confidence: 99%

Protein Glycosylation in Cancer

Stowell¹,

Cummings

2015

Annu. Rev. Pathol. Mech. Dis.

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693

589

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Neoplastic transformation results in a wide variety of cellular alterations that impact the growth, survival, and general behavior of affected tissue. Although genetic alterations underpin the development of neoplastic disease, epigenetic changes can exert an equally significant effect on neoplastic transformation. Among neoplasia-associated epigenetic alterations, changes in cellular glycosylation have recently received attention as a key component of neoplastic progression. Alterations in glycosylation appear to not only directly impact cell growth and survival but also facilitate tumor-induced immunomodulation and eventual metastasis. Many of these changes may support neoplastic progression, and unique alterations in tumor-associated glycosylation may also serve as a distinct feature of cancer cells and therefore provide novel diagnostic and even therapeutic targets.

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Section: Figurementioning

confidence: 99%

Protein Glycosylation in Cancer

Stowell¹,

Cummings

2015

Annu. Rev. Pathol. Mech. Dis.

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693

589

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“…C. elegans and Drosophila T-synthase orthologs do not require Cosmc for proper folding, presumably due to the presence of N-glycans that were lost in mammalian T-synthase but may facilitate interaction with calnexin/calreticulin in the ER (Ju, Zheng, & Cummings, 2006). Mammalian Cosmc interacts with unfolded T-synthase, perhaps cotranslationally in the RER via a unique peptide region in T-synthase called the CBRT (Cosmc Binding Region of T-synthase; Aryal, Ju, & Cummings, 2014; Narimatsu et al, 2011). This results in proper folding of the T-synthase and production of an active enzyme, which is transported to the Golgi, preventing nonproductive aggregation, ubiquitination, retrotranslocation to the proteasome, and degradation (Ju, Aryal, et al, 2008).…”

Section: O-glycan Biosynthesismentioning

confidence: 99%

Simple Sugars to Complex Disease—Mucin-Type O-Glycans in Cancer

Kudelka¹,

Ju²,

Heimburg-Molinaro³

et al. 2015

Advances in Cancer Research

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209

192

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Mucin-type O-glycans are a class of glycans initiated with N-acetylgalactosamine (GalNAc) α-linked primarily to Ser/Thr residues within glycoproteins and often extended or branched by sugars or saccharides. Most secretory and membrane-bound proteins receive this modification, which is important in regulating many biological processes. Alterations in mucin-type O-glycans have been described across tumor types and include expression of relatively small-sized, truncated O-glycans and altered terminal structures, both of which are associated with patient prognosis. New discoveries in the identity and expression of tumor-associated O-glycans are providing new avenues for tumor detection and treatment. This chapter describes mucin-type O-glycan biosynthesis, altered mucin-type O-glycans in primary tumors, including mechanisms for structural changes and contributions to the tumor phenotype, and clinical approaches to detect and target altered O-glycans for cancer treatment and management.

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“…Previously, we found that hypermethylation of COSMC is one of the prevalent causes for the expression of the immature truncated O‐glycans (Tn and STn antigens) in ~40% of the PDAC tumours . Further, COSMC is the molecular chaperone for Core 1 synthase (C1GalT1) that stabilizes the enzyme . Loss of COSMC and aberrant expression of truncated O‐glycans induce oncogenic features, including compromised adhesion, increased cell migration, reduced apoptosis, loss of tissue architecture, invasive growth and metastasis .…”

Section: Introductionmentioning

confidence: 99%

“…7 Further, COSMC is the molecular chaperone for Core 1 synthase (C1GalT1) that stabilizes the enzyme. 8 Loss of COSMC and aberrant expression of truncated O-glycans induce oncogenic features, including compromised adhesion, increased cell migration, reduced apoptosis, loss of tissue architecture, invasive growth and metastasis. 7,9 However, the molecular mechanism whereby these truncated O-glycans enhance the tumorigenic properties of PDAC cells remains elusive.…”

Section: Introductionmentioning

confidence: 99%

Truncated O‐glycans promote epithelial‐to‐mesenchymal transition and stemness properties of pancreatic cancer cells

Thomas

Sagar

Caffrey

et al. 2019

J Cellular Molecular Medi

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Aberrant expression of Sialyl‐Tn (STn) antigen correlates with poor prognosis and reduced patient survival. We demonstrated that expression of Tn and STn in pancreatic ductal adenocarcinoma (PDAC) is due to hypermethylation of Core 1 synthase specific molecular chaperone (COSMC) and enhanced the malignant properties of PDAC cells with an unknown mechanism. To explore the mechanism, we have genetically deleted COSMC in PDAC cells to express truncated O‐glycans (SimpleCells, SC) which enhanced cell migration and invasion. Since epithelial‐to‐mesenchymal transition (EMT) play a vital role in metastasis, we have analysed the induction of EMT in SC cells. Expressions of the mesenchymal markers were significantly high in SC cells as compared to WT cells. Equally, we found reduced expressions of the epithelial markers in SC cells. Re‐expression of COSMC in SC cells reversed the induction of EMT. In addition to this, we also observed an increased cancer stem cell population in SC cells. Furthermore, orthotopic implantation of T3M4 SC cells into athymic nude mice resulted in significantly larger tumours and reduced animal survival. Altogether, these results suggest that aberrant expression of truncated O‐glycans in PDAC cells enhances the tumour aggressiveness through the induction of EMT and stemness properties.

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Identification of a Novel Protein Binding Motif within the T-synthase for the Molecular Chaperone Cosmc

Cited by 20 publications

References 68 publications

Protein Glycosylation in Cancer

Protein Glycosylation in Cancer

Simple Sugars to Complex Disease—Mucin-Type O-Glycans in Cancer

Truncated O‐glycans promote epithelial‐to‐mesenchymal transition and stemness properties of pancreatic cancer cells

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