The O-Mannosylation Pathway: Glycosyltransferases and Proteins Implicated in Congenital Muscular Dystrophy

Wells, Lance

doi:10.1074/jbc.r112.438978

Cited by 77 publications

(54 citation statements)

References 79 publications

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“…Stress-and nutrient-dependent changes in oligosaccharide levels can trigger the UPR (83)(84)(85)(86). Given that highly specific changes in glycosylation regulate diverse proteins like Notch (130), dystroglycan (131)(132)(133), amyloid precursor protein (134,135), and MUC1 (136), one can speculate that UPR regulates these proteins under some conditions. For example, in cancer cells, the global glycosylation of proteins is impacted (137,138), which includes MUC1, a major activator of the proliferative RAS-MEK-ERK MAPK pathway (9,139,140).…”

Section: Discussionmentioning

confidence: 99%

Role of the Unfolded Protein Response in Regulating the Mucin-Dependent Filamentous-Growth Mitogen-Activated Protein Kinase Pathway

Adhikari

Vadaie

Chow

et al. 2015

Molecular and Cellular Biology

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bSignaling mucins are evolutionarily conserved regulators of signal transduction pathways. The signaling mucin Msb2p regulates the Cdc42p-dependent mitogen-activated protein kinase (MAPK) pathway that controls filamentous growth in yeast. The cleavage and release of the glycosylated inhibitory domain of Msb2p is required for MAPK activation. We show here that proteolytic processing of Msb2p was induced by underglycosylation of its extracellular domain. Cleavage of underglycosylated Msb2p required the unfolded protein response (UPR), a quality control (QC) pathway that operates in the endoplasmic reticulum (ER). The UPR regulator Ire1p, which detects misfolded/underglycosylated proteins in the ER, controlled Msb2p cleavage by regulating transcriptional induction of Yps1p, the major protease that processes Msb2p. Accordingly, the UPR was required for differentiation to the filamentous cell type. Cleavage of Msb2p occurred in conditional trafficking mutants that trap secretory cargo in the endomembrane system. Processed Msb2p was delivered to the plasma membrane, and its turnover by the ubiquitin ligase Rsp5p and ESCRT attenuated the filamentous-growth pathway. We speculate that the QC pathways broadly regulate signaling glycoproteins and their cognate pathways by recognizing altered glycosylation patterns that can occur in response to extrinsic cues. Signaling mucins are evolutionarily conserved regulators of signal transduction pathways (1-4). Signaling mucins are composed of a highly glycosylated extracellular domain that contains a mucin homology domain (MHD), which is defined by tandem repeats rich in Ser/Thr/Pro residues. The extracellular domain is connected by a single-pass transmembrane (TM) alpha helix to a cytosolic signaling domain, which associates with a diverse array of proteins that regulate mitogen-activated protein kinase (MAPK) pathways, Akt, ␤-catenin, and other pathways (5-8). Signaling mucins are overexpressed in different cancers, where they contribute to cell proliferation and metastasis (6). They are diagnostic biomarkers for cancers (9) and targets for immunotherapies (10,11). Therefore, the mechanisms by which signaling mucins and related glycoproteins are regulated is of intense interest.In the budding yeast Saccharomyces cerevisiae, the mucin-like glycoprotein Msb2p regulates the MAPK pathway that controls filamentous growth, a cell differentiation behavior that occurs in response to nutrient limitation (12-14). The extracellular domain of Msb2p is extensively glycosylated. Msb2p is modified by Nlinked and O-linked glycosylation and contains a canonical MHD that is itself highly glycosylated (15, 16). In a landmark study, Yang et al. identified Pmt4p as the major O-mannosyltransferase for Msb2p (17). Pmt4p is a member of an evolutionarily conserved protein mannosyl transferase (Pmt) gene family (2, 18). Msb2p also contains a cytosolic signaling domain. The cytosolic domain of Msb2p associates with the Rho GTPase Cdc42p (15), which is a ubiquitous regulator of cell polarity and signaling...

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Section: Discussionmentioning

confidence: 99%

Role of the Unfolded Protein Response in Regulating the Mucin-Dependent Filamentous-Growth Mitogen-Activated Protein Kinase Pathway

Adhikari

Vadaie

Chow

et al. 2015

Molecular and Cellular Biology

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“…Given the known pathology of hypoglycosylated ␣DG resulting in a loss of laminin binding in a subset of muscular dystrophies, which can have associated cardiomyopathies (79,80), we examined the glycosylation of ␣DG specifically. We did not detect differences in ␣DG glycosylation or laminin binding between Pompe and control iPSC-CMs, suggesting that this specific glycosylation pathway is intact in Pompe disease and unlikely to be central to the pathophysiology.…”

Section: Discussionmentioning

confidence: 99%

Pompe Disease Results in a Golgi-based Glycosylation Deficit in Human Induced Pluripotent Stem Cell-derived Cardiomyocytes

Raval

Tao

White

et al. 2015

Journal of Biological Chemistry

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“…In particular, Tmem2 may be relevant to the set of congenital muscular dystrophies known as dystroglycanopathies, which feature aberrant glycosylation of αDG (Muntoni et al, 2008;Wells, 2013). Mutations in 18 genes have been shown to cause dystroglycanopathies and several of these genes encode characterized or putative glycosyltransferases (Bouchet-Séraphin et al, 2015; Godfrey et al, 2011).…”

Section: Tmem2 Promotes Cell-matrix Interactions By Influencing Ecm Omentioning

confidence: 99%

Tmem2 regulates cell-matrix interactions that are essential for muscle fiber attachment

Ryckebüsch¹,

Hernandez²,

Wang³

et al. 2016

Journal of Cell Science

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Skeletal muscle morphogenesis depends upon interactions between developing muscle fibers and the extracellular matrix (ECM) that anchors fibers to the myotendinous junction (MTJ). The pathways that organize the ECM and regulate its engagement by cell-matrix adhesion complexes (CMACs) are therefore essential for muscle integrity. Here, we demonstrate the impact of transmembrane protein 2 (tmem2) on cell-matrix interactions during muscle morphogenesis in zebrafish. Maternal-zygotic tmem2 mutants (MZtmem2) exhibit muscle fiber detachment, in association with impaired laminin organization and ineffective fibronectin degradation at the MTJ. Similarly, disorganized laminin and fibronectin surround MZtmem2 cardiomyocytes, which could account for their hindered movement during cardiac morphogenesis. In addition to ECM defects, MZtmem2 mutants display hypoglycosylation of α-dystroglycan within the CMAC, which could contribute to the observed fiber detachment. Expression of the Tmem2 ectodomain can rescue aspects of the MZtmem2 phenotype, consistent with a possible extracellular function of Tmem2. Together, our results suggest that Tmem2 regulates cell-matrix interactions by affecting both ECM organization and CMAC activity. These findings evoke possible connections between the functions of Tmem2 and the etiologies of congenital muscular dystrophies, particularly dystroglycanopathies.

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The O-Mannosylation Pathway: Glycosyltransferases and Proteins Implicated in Congenital Muscular Dystrophy

Cited by 77 publications

References 79 publications

Role of the Unfolded Protein Response in Regulating the Mucin-Dependent Filamentous-Growth Mitogen-Activated Protein Kinase Pathway

Role of the Unfolded Protein Response in Regulating the Mucin-Dependent Filamentous-Growth Mitogen-Activated Protein Kinase Pathway

Pompe Disease Results in a Golgi-based Glycosylation Deficit in Human Induced Pluripotent Stem Cell-derived Cardiomyocytes

Tmem2 regulates cell-matrix interactions that are essential for muscle fiber attachment

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