Biological and biochemical properties of two Xenopus laevis N-acetylgalactosaminyltransferases with contrasting roles in embryogenesis

Voglmeir, Josef; Laurent, Nicolas; Flitsch, Sabine L.; Oelgeschläger, Michael; Wilson, Iain B. H.

doi:10.1016/j.cbpb.2014.10.003

Cited by 9 publications

(4 citation statements)

References 61 publications

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“…O-GalNAc modification of vertebrate Notch can affect Notch signaling during development ( Boskovski et al, 2013 ); the Drosophila ortholog of the responsible GalNAc transferase is also essential for embryogenesis ( Bennett et al, 2010 ; Schwientek et al, 2002 ). A GalNAcT in Xenopus can glycosylate a peptide corresponding to the ActR IIB receptor and inhibit Activin and BMP type signaling ( Herr et al, 2008 ; Voglmeir et al, 2015 ). Thus the changed glycosylation we observe on components of the Notch and Dpp pathways could alter transcription ( Hamaratoglu et al, 2014 ; Ntziachristos et al, 2014 ), shifting protein levels and thereby changing the ratio of some glycopeptides in the mrva mutant relative to the wild type.…”

Section: Resultsmentioning

confidence: 99%

A conserved major facilitator superfamily member orchestrates a subset of O-glycosylation to aid macrophage tissue invasion

Valosková

Biebl

Roblek

et al. 2019

eLife

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Aberrant display of the truncated core1 O-glycan T-antigen is a common feature of human cancer cells that correlates with metastasis. Here we show that T-antigen in Drosophila melanogaster macrophages is involved in their developmentally programmed tissue invasion. Higher macrophage T-antigen levels require an atypical major facilitator superfamily (MFS) member that we named Minerva which enables macrophage dissemination and invasion. We characterize for the first time the T and Tn glycoform O-glycoproteome of the Drosophila melanogaster embryo, and determine that Minerva increases the presence of T-antigen on proteins in pathways previously linked to cancer, most strongly on the sulfhydryl oxidase Qsox1 which we show is required for macrophage tissue entry. Minerva’s vertebrate ortholog, MFSD1, rescues the minerva mutant’s migration and T-antigen glycosylation defects. We thus identify a key conserved regulator that orchestrates O-glycosylation on a protein subset to activate a program governing migration steps important for both development and cancer metastasis.

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Section: Resultsmentioning

confidence: 99%

A conserved major facilitator superfamily member orchestrates a subset of O-glycosylation to aid macrophage tissue invasion

Valosková

Biebl

Roblek

et al. 2019

eLife

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“…ppGalNAc-T14 plays a critical role in the invasion and migration of breast cancer cells by regulating the activity of MMP-2 and the expression of some EMT genes ( 29 ). xGalNAc-T6 and xGalNAc-T16 from the African clawed frog ( Xenopus laevis ), which show high homology to human ppGalNAc-T6 and ppGalNAc-T16, had contrasting roles in TGF-β/BMP signaling in embryogenesis ( 30 ). Recently, accumulating reports have demonstrated that ppGalNAc-T4 participates in numerous cellular processes, including tumorigenesis ( 31 , 32 , 33 ).…”

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confidence: 99%

ppGalNAc-T4-catalyzed O-Glycosylation of TGF-β type Ⅱ receptor regulates breast cancer cells metastasis potential

Zhang

et al. 2021

Journal of Biological Chemistry

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GalNAc-type O-glycosylation, initially catalyzed by polypeptide N-acetylgalactosaminyltransferases (ppGalNAc-Ts), is one of the most abundant and complex post-translational modifications of proteins. Emerging evidence has proven that aberrant ppGalNAc-Ts are involved in malignant tumor transformation. However, the exact molecular functions of ppGalNAc-Ts are still unclear. Here, the role of one isoform, ppGalNAc-T4, in breast cancer cell lines was investigated. The expression of ppGalNAc-T4 was found to be negatively associated with migration of breast cancer cells. Loss-of function studies revealed that ppGalNAc-T4 attenuated the migration and invasion of breast cancer cells by inhibiting the epithelial-mesenchymal transition (EMT) process. Correspondingly, transforming growth factor beta (TGF-β) signaling, which is the upstream pathway of EMT, was impaired by ppGalNAc-T4 expression. ppGalNAc-T4 knock-out decreased O-GalNAc modification of TGF-β type Ⅰ and Ⅱ receptor (TβR Ⅰ and Ⅱ) and led to the elevation of TGF-β receptor dimerization and activity. Importantly, a peptide from TβR Ⅱ was first identified as the naked peptide substrate of ppGalNAc-T4 with a higher affinity than ppGalNAc-T2. Further, Ser31, corresponding to the extracellular domain of TβR Ⅱ, was identified as the O-GalNAcylation site upon in vitro glycosylation by ppGalNAc-T4. The O-GalNAc-deficient S31A mutation enhanced TGF-β signaling activity and EMT in breast cancer cells. Together, these results identified a novel mechanism of ppGalNAc-T4-catalyzed TGF-β receptors O-GalNAcylation that suppresses breast cancer cell migration and invasion via the EMT process. Targeting ppGalNAc-T4 may be a potential therapeutic strategy for breast cancer treatment.

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“…In contrast to the growing evidence for the importance of O-glycosylation in organ development and various diseases (12,17,23,41), there is a particular dearth of information regarding its roles in neural development. Previously, our group found that ppGalNAc-T13 is restrictively expressed at a high level in the brain (28).…”

Section: Discussionmentioning

confidence: 99%

Polypeptide N-Acetylgalactosaminyltransferase 13 Contributes to Neurogenesis via Stabilizing the Mucin-type O-Glycoprotein Podoplanin

Pang

et al. 2016

Journal of Biological Chemistry

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Mucin-type O-glycosylation is initiated by an evolutionarily conserved family of polypeptide N-acetylgalactosaminyltransferases (ppGalNAc-Ts). Previously, it was reported that ppGalNAc-T13 is restrictively expressed at a high level in the brain. Here we provide evidence for the critical role of ppGalNAc-T13 in neural differentiation. In detail, we show that the expression of ppGalNAc-T13 was dramatically up-regulated during early neurogenesis in mouse embryonic brains. Similar changes were also observed in cell models of neuronal differentiation by using either primary mouse cortical neural precursor cells or murine embryonal carcinoma P19 cells. Knockout of ppGalNAc-T13 in P19 cells suppressed not only neural induction but also neuronal differentiation. These effects are at least partly mediated by the mucin-type O-glycoprotein podoplanin (PDPN), as knockdown of PDPN led to a similar inhibition of neuronal differentiation and PDPN was significantly reduced at the posttranscriptional level after ppGalNAc-T13 knockout. Further data demonstrate that PDPN acts as a substrate of ppGalNAc-T13 and that the ppGalNAc-T13-mediated O-glycosylation on PDPN is important for its stability. Taken together, this study suggests that ppGalNAc-T13 contributes to neuronal differentiation through glycosylating and stabilizing PDPN, which provides insights into the regulatory roles of O-glycosylation in mammalian neural development.Development of the CNS involves a well ordered generation of a variety of distinct neural cell types with progressive restriction in fate potential of neural progenitors (1). This process is precisely regulated by a large set of transcriptional factors (2, 3) and occurs with the reorchestration of molecule expression on the cell surface. These molecules, as indicated by many previous reports, include not only various glycoproteins or glycolipids but also the glycans on them (4 -6). Accumulating evidence shows that cell surface glycans play crucial roles in CNS development, where they do not function independently but via regulating the functions of their carrier proteins or lipids. It has been reported that N-glycans modulate neural cell adhesion, axonal targeting, neural transmission, and neurite outgrowth by affecting the folding or trafficking of certain carrier glycoproteins such as synaptic vesicle protein 2 (SV2) and ionotropic glutamate receptors (7). Also, genetic inactivation of ST8Sia II and ST8Sia IV sialyltransferases, which catalyze polysialic acid structures on neural cell adhesion molecule, leads to severe defects in neurite outgrowth, synaptic plasticity, etc. (7). In contrast to the increasing evidence for the significance of sialylation and N-glycosylation, there is very limited information regarding the mechanistic roles of O-glycosylation in neural development (8).Mucin type O-glycosylation is an evolutionarily conserved protein modification that plays important roles in protein processing, secretion, stability, and ligand binding (9, 10). In mammals, it is initiated by a family of 20 ...

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Biological and biochemical properties of two Xenopus laevis N-acetylgalactosaminyltransferases with contrasting roles in embryogenesis

Cited by 9 publications

References 61 publications

A conserved major facilitator superfamily member orchestrates a subset of O-glycosylation to aid macrophage tissue invasion

A conserved major facilitator superfamily member orchestrates a subset of O-glycosylation to aid macrophage tissue invasion

ppGalNAc-T4-catalyzed O-Glycosylation of TGF-β type Ⅱ receptor regulates breast cancer cells metastasis potential

Polypeptide N-Acetylgalactosaminyltransferase 13 Contributes to Neurogenesis via Stabilizing the Mucin-type O-Glycoprotein Podoplanin

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