Expression of the UDP-GalNAc : polypeptide N-acetylgalactosaminyltransferase family is spatially and temporally regulated during Drosophila development

Tian, E; Hagen, Karl S.

doi:10.1093/glycob/cwj051

Cited by 55 publications

(67 citation statements)

References 27 publications

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“…Here we demonstrate that the expression of PGANT4 specifically in the secretory PR cells of the digestive tract confers increased stability to Tango1 by protecting it from Dfur2-mediated cleavage, thereby allowing the formation of large mucin-containing secretory vesicles within these cells. As the enzymes controlling the initiation of O-glycosylation are typically abundantly expressed in cells under high secretory burden (8,24), it raises the possibility that O-glycosylation may modulate the stability of Tango1 in other tissues, ensuring that Tango1 activity is commensurate with the secretory demands of the cell.…”

Section: Resultsmentioning

confidence: 99%

“…The concerted activity of these many members is thought to result in the elaborate glycosylation patterns typically seen in mucin-like molecules. As members of this family are abundantly expressed in many secretory cells and tissues (8,24), it raises the possibility that the yin/yang provided by the opposing forces of O-glycosylation and proteolytic cleavage may serve as a more widespread, dynamic system to regulate the stability and bioactivity of many proteins. In support of this theory, recent glycoproteomic studies performed in mammalian cell culture have mapped sites of O-glycosylation to be in close proximity to potential furin cleavage sites on many proteins (26).…”

Section: Resultsmentioning

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%

Section: Resultsmentioning

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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“…Here, we provide direct evidence for the role of mucin-type O-glycans in modulating proper secretion to this basal region in vivo by examining a specific substrate in a glycosyltransferase mutant background. Given that the multiple pgant genes responsible for initiating mucin-type O-glycosylation (22,39) have unique tissue-and stage-specific patterns of expression (23,(51)(52)(53), it is likely that specific pgant family members may be playing unique roles in the secretion and localization of proteins within diverse cell types.…”

Section: Discussionmentioning

confidence: 99%

An O-Glycosyltransferase Promotes Cell Adhesion during Development by Influencing Secretion of an Extracellular Matrix Integrin Ligand

Zhang

Tran

Hagen

2010

Journal of Biological Chemistry

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Protein secretion and localization are crucial during eukaryotic development, establishing local cell environments as well as mediating cell interactions, signaling, and adhesion. In this study, we demonstrate that the glycosyltransferase, pgant3, specifically modulates integrin-mediated cell adhesion by influencing the secretion and localization of the integrin ligand, Tiggrin. We demonstrate that Tiggrin is normally O-glycosylated and localized to the basal matrix where the dorsal and ventral cell layers adhere in wild type Drosophila wings. In pgant3 mutants, Tiggrin is no longer O-glycosylated and fails to be properly secreted to this basal cell layer interface, resulting in disruption of integrin-mediated cell adhesion in the wing. pgant3-mediated effects are dependent on enzymatic activity, as mutations that form a stable protein yet abrogate O-glycosyltransferase activity result in Tiggrin accumulation within the dorsal and ventral cells comprising the wing. Our results provide the first in vivo evidence for the role of O-glycosylation in the secretion of specific extracellular matrix proteins, thus altering the composition of the cellular "microenvironment" and thereby modulating developmentally regulated cell adhesion events. As alterations in cell adhesion are a hallmark of cancer progression, this work provides insight into the long-standing association between aberrant O-glycosylation and tumorigenesis.

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“…Rescue of the pgant35A lethality by btl-driven pgant35A expression was assessed by the presence of straight winged, Sb ϩ adult progeny. Whole Mount Antibody Staining and Lectin Staining-Embryos homozygous for pgant35A mutations were selected by lack of GFP fluorescence and fixed as previously described (30). Immunostaining was according to standard procedures.…”

Section: Methodsmentioning

confidence: 99%