Targeted inhibition of Klotho binding to fibroblast growth factor 23 prevents hypophosphetemia

Fakhar, Muhammad; Rashid, Sajid

doi:10.1016/j.jmgm.2017.04.024

Cited by 9 publications

(5 citation statements)

References 57 publications

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“…Of course, further experiments were needed to verify this hypothesis. This proximity is clinically relevant since lesions to this nerve may typically produce symptoms in both the glomerular and auditory components (Barilyak et al, 2018;Fakhar & Rashid, 2017;Quarles, 2019).…”

Section: Discussionmentioning

confidence: 99%

The correlation between fibroblast growth factor-23 and ESRD patients with hearing impairment

Nie

Guo

et al. 2021

PeerJ

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Background End-stage renal disease (ESRD) patients often experience hearing impairment, resulting in a high rate of disability and a decline in their quality of life. Fibroblast growth factor-23 (FGF23) is a diagnostic biomarker for chronic kidney disease (CKD) and a pathogenic contributor to CKD progression. However, the correlation between FGF23 level and CKD patients with hearing impairment remains elusive. This study aimed to investigate the relationship between the FGF23 and ESRD accompanied with hearing impairment. Methods A total of 144 ESRD patients, who were admitted to the First Affiliated Hospital of Kunming Medical University from November to December 2020, were enrolled in this study. Firstly, 144 ESRD patients underwent pure-tone audiometry (PTA). Secondly, it was attempted to randomly select 20 ESRD patients with normal hearing, and 20 ESRD patients with hearing impairment (match ratio, 1:1). Age- and gender-matched healthy people (n = 20) were also recruited as controls group. The expression levels of FGF23 was detected by enzyme-linked immunosorbent assay (ELISA). Results The results of pure-tone audiometry showed that the prevalence of hearing impairment in ESRD patients was 80.5%. Male ESRD patients were more likely to develop hearing impairment compared to female patients. The incidence rate of hearing impairment at a high frequency was significantly higher than that at a low frequency (P < 0.01). The serum levels of FGF23, phosphorus, and parathyroid hormone (PTH) in ESRD patients with hearing impairment significantly increased compared with those with normal hearing and healthy controls. Conclusion ESRD patients had a higher risk of hearing loss, especially high-frequency hearing impairment. As FGF23 level increased, the risk of hearing loss was also elevated. The hearing impairment in ESRD patients was associated with the degree of kidney injury, and serum FGF23 level.

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Section: Discussionmentioning

confidence: 99%

The correlation between fibroblast growth factor-23 and ESRD patients with hearing impairment

Nie

Guo

et al. 2021

PeerJ

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“…4B). A higher Rg value implies lower compactness of a system 43–47 . Consequently, βTrCP1-GLI3-β1–4 exhibited minor compactness than apo-form.…”

Section: Resultsmentioning

confidence: 99%

Structural basis of βTrCP1-associated GLI3 processing

Shafique

Rashid

2019

Sci Rep

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Controlled ubiquitin-mediated protein degradation is essential for various cellular processes. GLI family regulates the transcriptional events of the sonic hedgehog pathway genes that are implicated in almost one fourth of human tumors. GLI3 phosphorylation by Ser/Thr kinases is a primary factor for their transcriptional activity that incurs the formation of both GLI3 repressor and activator forms. GLI3 processing is triggered in an ubiquitin-dependent manner via SCF βTrCP1 complex; however, structural characterization, mode of action based on sequence of phosphorylation signatures and induced conformational readjustments remain elusive. Here, through structural analysis and molecular dynamics simulation assays, we explored comparative binding pattern of GLI3 phosphopeptides against βTrCP1. A comprehensive and thorough analysis demarcated GLI3 presence in the binding cleft shared by inter-bladed binding grooves of β-propeller. Our results revealed the involvement of all seven WD40 repeats of βTrCP1 in GLI3 interaction. Conversely, GLI3 phosphorylation pattern at primary protein kinase A (PKA) sites and secondary casein kinase 1 (CK1) or glycogen synthase kinase 3 (GSK3) sites was carefully evaluated. Our results indicated that GLI3 processing depends on the 19 phosphorylation sites (849, 852, 855, 856, 860, 861, 864, 865, 868, 872, 873, 876, 877, 880, 899, 903, 906, 907 and 910 positions) by a cascade of PKA, GSK3β and CSKI kinases. The presence of a sequential phosphorylation in the binding induction of GLI3 and βTrCP1 may be a hallmark to authenticate GLI3 processing. We speculate that mechanistic information of the individual residual contributions through structure-guided approaches may be pivotal for the rational design of specific and more potent inhibitors against activated GLI3 with a special emphasis on the anticancer activity.

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“…One of the most successful treatments has been the direct inhibition of FGF23 using monoclonal antibodies (burosumab) [169,170]. Another approach would be the inhibition of FGF23 binding to the Klotho coreceptor by binding small molecules to the glycosyl hydrolase (GS1 and GS2) domains of Klotho [173]. Additionally, there is another strategy that proposes the inhibition of the FGF receptor to increase blood phosphate and calcitriol levels.…”

Section: Fgf23 As a Therapeutic Targetmentioning

confidence: 99%

Non-Classical Effects of FGF23: Molecular and Clinical Features

Martínez-Heredia,

Canelo-Moreno,

García-Fontana

et al. 2024

IJMS

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This article reviews the role of fibroblast growth factor 23 (FGF23) protein in phosphate metabolism, highlighting its regulation of vitamin D, parathyroid hormone, and bone metabolism. Although it was traditionally thought that phosphate–calcium homeostasis was controlled exclusively by parathyroid hormone (PTH) and calcitriol, pathophysiological studies revealed the influence of FGF23. This protein, expressed mainly in bone, inhibits the renal reabsorption of phosphate and calcitriol formation, mediated by the α-klotho co-receptor. In addition to its role in phosphate metabolism, FGF23 exhibits pleiotropic effects in non-renal systems such as the cardiovascular, immune, and metabolic systems, including the regulation of gene expression and cardiac fibrosis. Although it has been proposed as a biomarker and therapeutic target, the inhibition of FGF23 poses challenges due to its potential side effects. However, the approval of drugs such as burosumab represents a milestone in the treatment of FGF23-related diseases.

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Targeted inhibition of Klotho binding to fibroblast growth factor 23 prevents hypophosphetemia

Cited by 9 publications

References 57 publications

The correlation between fibroblast growth factor-23 and ESRD patients with hearing impairment

The correlation between fibroblast growth factor-23 and ESRD patients with hearing impairment

Structural basis of βTrCP1-associated GLI3 processing

Non-Classical Effects of FGF23: Molecular and Clinical Features

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