The Role of Mutant UDP-N-Acetyl-α-d-Galactosamine-Polypeptide N-Acetylgalactosaminyltransferase 3 in Regulating Serum Intact Fibroblast Growth Factor 23 and Matrix Extracellular Phosphoglycoprotein in Heritable Tumoral Calcinosis

Garringer, Holly J.; Fisher, Corinne; Larsson, Tobias E.; Davis, Siobhan I.; Koller, Daniel L.; Cullen, Michael J.; Draman, Mohd Shazli; Conlon, Niamh; Jain, Anuj; Fedarko, Neal S.; Dasgupta, Bhaskar; White, Kenneth E.

doi:10.1210/jc.2006-0305

Cited by 107 publications

(82 citation statements)

References 24 publications

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“…The Thr 171 site is also glycosylated by several other ppGalNAc-T isoforms (21). Our previous work (43) utilizing transferase specific preferences, obtained from random peptide studies, also suggests that Thr 171 would be a moderate to good substrate for ppGalNAc T1, T2, and T3, whereas Thr 178 would not be a substrate for ppGalNAc T1 or T2 and would be only a modest substrate for ppGalNAc T3 (see Table 2 , whose glycosylation is required to inhibit the proprotein convertase cleavage of FGF23 in vivo and in vitro (20,21,74).…”

Section: Discussionmentioning

confidence: 96%

“…8 Likewise, studies on the glycan binding requirements of the lectin domain of ppGalNAc T3 suggest that this transferase utilizes its lectin domain to glycosylate residues C-terminal of the site of prior glycosylation (55), again in keeping with our findings for ppGalNAc T3. ppGalNAc T3 was previously shown to be the only isoform capable of glycosylating the proprotein processing region of FGF23 (IHFNT 171 PIPR RHT 178 R2SAEDD) (21,25,74), and in unpublished work, 9 Kato et al have found that ppGalNAc T3 glycosylates the Thr 178 site in a lectin-dependent manner by first glycosylating Thr 171 in a lectin-independent manner, both in in vitro enzyme assays and ex vivo in CHO cells stably transfected with ppGalNAc T3 variants. The Thr 171 site is also glycosylated by several other ppGalNAc-T isoforms (21).…”

Section: Discussionmentioning

confidence: 97%

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The Lectin Domain of the Polypeptide GalNAc Transferase Family of Glycosyltransferases (ppGalNAc Ts) Acts as a Switch Directing Glycopeptide Substrate Glycosylation in an N- or C-terminal Direction, Further Controlling Mucin Type O-Glycosylation

Gerken

Revoredo

Thome³

et al. 2013

Journal of Biological Chemistry

119

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Background: ppGalNAc transferases, which initiate O-glycosylation, possess a poorly understood lectin domain. Results:The lectin domain directs glycosylation in an N-or C-terminal direction in an isoform-specific manner. Conclusion: Unanticipated isoform-specific directionality was revealed for modification of glycopeptide substrates. Significance: A novel mechanism of controlling of mucin type O-glycosylation has been discovered based on tethered lectin domains specifying N-or C-terminal modification of glycopeptide substrates.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 97%

The Lectin Domain of the Polypeptide GalNAc Transferase Family of Glycosyltransferases (ppGalNAc Ts) Acts as a Switch Directing Glycopeptide Substrate Glycosylation in an N- or C-terminal Direction, Further Controlling Mucin Type O-Glycosylation

Gerken

Revoredo

Thome³

et al. 2013

Journal of Biological Chemistry

119

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“…This gene encodes a protein called UDP-N-acetyl-a-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase-3 (ppGaNTase-T3) and is involved in post-translational modifications of serine or threonine residues by O-glycation; patients with FTC that (Garringer et al 2006). Circulatory FGF23 levels are also extremely high in patients with CKD , Imanishi et al 2004.…”

Section: Fgf23mentioning

confidence: 99%

The emerging role of the fibroblast growth factor-23–klotho axis in renal regulation of phosphate homeostasis

Razzaque

Lanske

2007

Journal of Endocrinology

206

156

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Normal mineral ion homeostasis is tightly controlled by numerous endocrine factors that coordinately exert effects on intestine, kidney, and bone to maintain physiological balance. The importance of the fibroblast growth factor (FGF)-23-klotho axis in regulating mineral ion homeostasis has been proposed from recent research observations. Experimental studies suggest that 1) FGF23 is an important in vivo regulator of phosphate homeostasis, 2) FGF23 acts as a counter regulatory hormone to modulate the renal 1a-hydroxylase and sodium-phosphate cotransporter activities, 3) there is a trend of interrelationship between FGF23 and parathyroid hormone activities, 4) most of the FGF23 functions are conducted through the activation of FGF receptors, and 5) such receptor activation needs klotho, as a cofactor to generate downstream signaling events. These observations clearly suggest the emerging roles of the FGF23-klotho axis in maintaining mineral ion homeostasis. In this brief article, we will summarize how the FGF23-klotho axis might coordinately regulate normal mineral ion homeostasis, and how their abnormal regulation could severely disrupt such homeostasis to induce disease pathology.

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“…[9][10][11][12][13][14] Indeed, the importance of the interactions between these factors is highlighted by the findings that loss of function mutations in aKL 15 and FGF23 [16][17][18][19] lead to the Mendelian disorder hyperphosphatemic familial tumoral calcinosis. In the reciprocal setting, gain of function mutations in FGF23 result in increased blood FGF23 and autosomal dominant hypophosphatemic rickets.…”

mentioning

confidence: 99%

Chronic Hyperphosphatemia and Vascular Calcification Are Reduced by Stable Delivery of Soluble Klotho

Hum

O’Bryan²,

Tatiparthi

et al. 2016

JASN

Self Cite

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aKlotho (aKL) regulates mineral metabolism, and diseases associated with aKL deficiency are characterized by hyperphosphatemia and vascular calcification (VC). aKL is expressed as a membrane-bound protein (mKL) and recognized as the coreceptor for fibroblast growth factor-23 (FGF23) and a circulating soluble form (cKL) created by endoproteolytic cleavage of mKL. The functions of cKL with regard to phosphate metabolism are unclear. We tested the ability of cKL to regulate pathways and phenotypes associated with hyperphosphatemia in a mouse model of CKD-mineral bone disorder and aKL-null mice. Stable delivery of adeno-associated virus (AAV) expressing cKL to diabetic endothelial nitric oxide synthase-deficient mice or aKL-null mice reduced serum phosphate levels. Acute injection of recombinant cKL downregulated the renal sodium-phosphate cotransporter Npt2a in aKL-null mice supporting direct actions of cKL in the absence of mKL. aKL-null mice with sustained AAV-cKL expression had a 74%-78% reduction in aorta mineral content and a 72%-77% reduction in mineral volume compared with control-treated counterparts (P,0.01). Treatment of UMR-106 osteoblastic cells with cKL + FGF23 increased the phosphorylation of extracellular signal-regulated kinase 1/2 and induced Fgf23 expression. CRISPR/Cas9-mediated deletion of fibroblast growth factor receptor 1 (FGFR1) or pretreatment with inhibitors of mitogen-activated kinase kinase 1 or FGFR ablated these responses. In summary, sustained cKL treatment reduced hyperphosphatemia in a mouse model of CKD-mineral bone disorder, and it reduced hyperphosphatemia and prevented VC in mice without endogenous aKL. Furthermore, cKL stimulated Fgf23 in an FGFR1-dependent manner in bone cells. Collectively, these findings indicate that cKL has mKL-independent activity and suggest the potential for enhancing cKL activity in diseases of hyperphosphatemia with associated VC.

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The Role of Mutant UDP-N-Acetyl-α-d-Galactosamine-Polypeptide N-Acetylgalactosaminyltransferase 3 in Regulating Serum Intact Fibroblast Growth Factor 23 and Matrix Extracellular Phosphoglycoprotein in Heritable Tumoral Calcinosis

Cited by 107 publications

References 24 publications

The Lectin Domain of the Polypeptide GalNAc Transferase Family of Glycosyltransferases (ppGalNAc Ts) Acts as a Switch Directing Glycopeptide Substrate Glycosylation in an N- or C-terminal Direction, Further Controlling Mucin Type O-Glycosylation

The Lectin Domain of the Polypeptide GalNAc Transferase Family of Glycosyltransferases (ppGalNAc Ts) Acts as a Switch Directing Glycopeptide Substrate Glycosylation in an N- or C-terminal Direction, Further Controlling Mucin Type O-Glycosylation

The emerging role of the fibroblast growth factor-23–klotho axis in renal regulation of phosphate homeostasis

Chronic Hyperphosphatemia and Vascular Calcification Are Reduced by Stable Delivery of Soluble Klotho

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