Mucin-type O-Glycosylation during Development

Tran, Duy T.; Hagen, Karl S.

doi:10.1074/jbc.r112.418558

Cited by 234 publications

(191 citation statements)

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“…These family members are expressed in unique spatial and temporal patterns during development and in adult tissues (8,9). Additionally, these enzymes display unique substrate specificities, with some members preferring to add the initial GalNAc (peptide transferases) and others preferring to add GalNAc to previously glycosylated substrates (glycopeptide transferases).…”

Section: Resultsmentioning

confidence: 99%

“…O-glycosylation is an essential, evolutionarily conserved protein modification (8,9) that has direct medical relevance, as aberrations are responsible for the human diseases familial tumoral calcinosis (10,11) and Tn syndrome (12). Loss of this protein modification affected constitutive secretion and Golgi apparatus structure in Drosophila cell culture (7,13) and secretion in the developing respiratory system in vivo (14).…”

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confidence: 99%

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O-Glycosylation regulates polarized secretion by modulating Tango1 stability

Zhang

Syed

Härd

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Polarized secretion is crucial in many tissues. The conserved protein modification, O-glycosylation, plays a role in regulating secretion. However, the mechanisms by which this occurs are unknown. Here, we demonstrate that an O-glycosyltransferase functions as a novel regulator of secretion and secretory vesicle formation in vivo by glycosylating the essential Golgi/endoplasmic reticulum protein, Tango1 (Transport and Golgi organization 1), and conferring protection from furin-mediated proteolysis. Loss of the O-glycosyltransferase PGANT4 resulted in Tango1 cleavage, loss of secretory granules, and disrupted apical secretion. The secretory defects seen upon loss of pgant4 could be rescued either by overexpression of Tango1 or by knockdown of a specific furin (Dfur2) in vivo. Our studies elucidate a novel regulatory mechanism whereby secretion is influenced by the yin/yang of O-glycosylation and proteolytic cleavage. Moreover, our data have broader implications for the potential treatment of diseases resulting from the loss of O-glycosylation by modulating the activity of specific proteases.R egulation of secretory vesicle formation and polarized secretion in vivo is crucial to ensure the proper deposition of signaling molecules, morphogens, and matrix components that mediate growth and differentiation. Polarized secretion is also required in many differentiated tissues, such as the digestive tract, where secreted components along the apical surface form the mucous membrane that confers protection from mechanical and microbial insults (1) and provides immunoregulatory signals (2). Indeed, disruptions in the secreted mucous membrane are associated with diseases of the digestive tract, such as colitis and colon cancer (3-6).Recent studies aimed at identifying the factors that influence secretion have elucidated novel proteins that function in unique aspects of secretion, including the enzymes responsible for the addition of sugars to mucins and other proteins (mucin-type O-glycosylation) (7). O-glycosylation is an essential, evolutionarily conserved protein modification (8, 9) that has direct medical relevance, as aberrations are responsible for the human diseases familial tumoral calcinosis (10, 11) and Tn syndrome (12). Loss of this protein modification affected constitutive secretion and Golgi apparatus structure in Drosophila cell culture (7, 13) and secretion in the developing respiratory system in vivo (14). Additionally, loss of O-glycosylation also disrupted secretion of an extracellular matrix protein (Tiggrin) in the developing wing, resulting in aberrant basement membrane formation and disrupted integrin-mediated cell adhesion (15). Mammalian studies have confirmed the effects of O-glycosylation on secretion, as loss of a glycosyltransferase (ppGalNAcT-1) disrupted secretion of laminin and collagen during mammalian organogenesis, altering the composition of the basement membrane and disrupting proper FGF signaling and organ growth (16). Although these studies all point to a role for O-glycosylation in se...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

O-Glycosylation regulates polarized secretion by modulating Tango1 stability

Zhang

Syed

Härd

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…GalNAc-T6 is one of the 20 family members in mammals that are responsible for the initiation of O-linked glycosylation (2). Members of this family are essential in Drosophila and are involved in various cellular and developmental processes (6,7). Aberrant GALNT6 expression has previously been observed in several cancer types, but the biological role of GALNT6 in vivo is still unknown.…”

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confidence: 99%

Pleiotropic effects of O-glycosylation in colon cancer

Zhang

Hagen

2018

Journal of Biological Chemistry

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Edited by Eric R. Fearon Changes in the O-glycosylation of proteins have long been associated with the development of cancer, but establishing causal relationships between altered glycosylation and cancer progression remains incomplete. In this study, the authors perform comparative analyses of the cellular phenotypes, transcriptional changes, and alterations in the glycoproteome in colon cancer cells that differentially express one glycosyltransferase. Their results provide a wealth of data on which future studies can be based.The search for factors involved in the development and progression of cancer has revealed a multitude of genetic, epigenetic, and phenotypic changes that distinguish malignant cells from their normal counterparts. One such change typically seen in tumors is the alteration of protein glycosylation (1). In particular, changes in mucin-type O-linked glycosylation have been associated with cancer development and poor prognosis-and many diagnostic markers are based on these changes (1). Mucin-type O-linked glycosylation is initiated by a family of enzymes (known as the GalNAcTs 3 or ppGalNAcTs) that catalyze the addition of GalNAc onto the serine or threonine residues of proteins transiting the Golgi apparatus (Fig. 1A) (2). In mammals, other enzymes add additional sugars to the extant GalNAc in a stepwise process to form what are known as core structures, which can then be further elongated and branched by other glycosyltransferases (Fig. 1A) (2). However, in cancerous tissues, these structures are typically truncated, with many existing as only a single GalNAc (Tn antigen) or GalNAc capped with sialic acid (STn antigen) (1). The reasons for O-glycan truncation in cancerous tissues remain largely unknown, although many studies have implicated the enzymes involved in O-glycan extension in these alterations (1,3,4). Likewise, whether the changes in O-glycan structure are contributing to neoplastic transformation or are a by-product of the transformation process itself remains an ongoing area of inquiry.In this issue of JBC, Wandall and colleagues (5) report new insights into the potential role of one member of the enzyme family that initiates O-linked glycosylation (GalNAc-T6) in the cellular transformations typically seen in cancerous cells and tissues. GalNAc-T6 is one of the 20 family members in mammals that are responsible for the initiation of O-linked glycosylation (2). Members of this family are essential in Drosophila and are involved in various cellular and developmental processes (6, 7). Aberrant GALNT6 expression has previously been observed in several cancer types, but the biological role of GALNT6 in vivo is still unknown.To initiate their study, Wandall and colleagues (5) examined the expression profiles for all 20 GALNT isoforms in 288 colon adenocarcinomas and 41 healthy colon samples, observing that GALNT6 expression is largely absent in healthy colon tissue but up-regulated in many colon adenocarcinomas. The authors then used the colon adenocarcinoma cell line LS174T (which...

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“…N-glycans are critical for enabling efficient glycoprotein folding and for maintaining the structural and functional integrity of glycoproteins (16). Protein N-glycosylation is also intimately associated with development processes (23,24), with facilitating or preventing bacterial binding to the host (25) and with sustaining the normal function of individual cells, tissues, organs, and organisms (26). Finally, protein glycosylation is a strictly regulated modification process in healthy cells, and these biochemical processes are dysregulated in various pathologies including, but not restricted to, cancer (27,28), inflammation (29), Alzheimer's disease (30), multiple sclerosis (31), and cystic fibrosis (25).…”

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confidence: 99%