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    Analysis of the Biochemical Mechanisms for the Endocrine Actions of FGF23

    Author
    Yu, X.; Ibrahimi, O.A.; Zhang, F.; Davis, S.I.; Garringer, H.J.; Linhardt, Robert J.; Ornitz, D.M.; Mohammadi, M.; White, K.E.
    ORCID
    https://orcid.org/0000-0003-2219-5833
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    ANALYSIS OF THE BIOCHEMICAL MECHANISMS FOR THE ENDOCRINE.pdf (2.059Mb)
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    Date Issued
    2005
    Subject
    Biology; Chemistry and chemical biology; Chemical and biological engineering; Biomedical engineering
    Degree
    Terms of Use
    In Copyright : this Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). https://rightsstatements.org/page/InC/1.0/;
    Full Citation
    Analysis of the Biochemical Mechanisms for the Endocrine Actions of FGF23, X. Yu, O. A. Ibrahimi, F. Zhang, S. I. Davis, H. J. Garringer, R. J. Linhardt, D. M. Ornitz, M. Mohammadi, K. E. White, Endocrinology, 146, 4647-4656, 2005.
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    URI
    https://hdl.handle.net/20.500.13015/5187; https://doi.org/10.1210/en.2005-0670
    Abstract
    Fibroblast growth factor (FGF)-23 has emerged as an endocrine regulator of phosphate and of vitamin D metabolism. It is produced in bone and, unlike other FGFs, circulates in the bloodstream to ultimately regulate phosphate handling and vitamin D production in the kidney. Presently, it is unknown which of the seven principal FGF receptors (FGFRs) transmits FGF23 biological activity. Furthermore, the molecular basis for the endocrine mode of FGF23 action is unclear. Herein, we performed surface plasmon resonance and mitogenesis experiments to comprehensively characterize receptor binding specificity. Our data demonstrate that FGF23 binds and activates the c splice isoforms of FGFR1-3, as well as FGFR4, but not the b splice isoforms of FGFR1-3. Interestingly, highly sulfated and longer glycosaminoglycan (GAG) species were capable of promoting FGF23 mitogenic activity. We also show that FGF23 induces tyrosine phosphorylation and inhibits sodium-phosphate cotransporter Npt2a mRNA expression using opossum kidney cells, a model kidney proximal tubule cell line. Removal of cell surface GAGs abolishes the effects of FGF23, and exogenous highly sulfated GAG is capable of restoring FGF23 activity, suggesting that proximal tubule cells naturally express GAGs that are permissive for FGF23 action. We propose that FGF23 signals through multiple FGFRs and that the unique endocrine actions of FGF23 involve escape from FGF23-producing cells and circulation to the kidney, where highly sulfated GAGs most likely act as cofactors for FGF23 activity. Our biochemical findings provide important insights into the molecular mechanisms by which dysregulated FGF23 signaling leads to disorders of hyper- and hypophosphatemia.;
    Description
    Endocrinology, 146, 4647-4656; Note : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.
    Department
    The Linhardt Research Labs.; The Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS);
    Publisher
    Oxford
    Relationships
    The Linhardt Research Labs Online Collection; Rensselaer Polytechnic Institute, Troy, NY; https://harc.rpi.edu/;
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