Cited by 345Fibroblast Growth Factor ResearchParathyroid Disorders and TreatmentsFluoride Effects and Removal

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βKlotho Is Required for Fibroblast Growth Factor (FGF) 21 Signaling through FGF Receptor (FGFR) 1c and FGFR3c

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Suzuki, Masashi, Uehara, Yuriko, Motomura-Matsuzaka, Kaori, Oki, Junko, Koyama, Yoshinori, Kimura, Miho, Asada, Masahiro, Komi-Kuramochi, Akiko, Oka, Syuichi, Toru, Toru·2008·Molecular Endocrinology

DOI 10.1210/me.2007-0313PMC PMC5419549

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Abstract

Fibroblast growth factor (FGF) 21, a structural relative of FGF23 that regulates phosphate homeostasis, is a regulator of insulin-independent glucose transport in adipocytes and plays a role in the regulation of body weight. It also regulates ketogenesis and adaptive responses to starvation. We report that in a reconstituted receptor activation assay system using BaF3 cells, which do not endogenously express any type of FGF receptor (FGFR) or heparan sulfate proteoglycan, FGF21 alone does not activate FGFRs and that betaKlotho is required for FGF21 to activate two specific FGFR subtypes: FGFR1c and FGFR3c. Coexpression of betaKlotho and FGFR1c on BaF3 cells enabled FGF21, but not FGF23, to activate receptor signaling. Conversely, coexpression of FGFR1c and Klotho, a protein related to betaKlotho, enabled FGF23 but not FGF21 to activate receptor signaling, indicating that expression of betaKlotho/Klotho confers target cell specificity on FGF21/FGF23. In all of these cases, heparin enhanced the activation but was not essential. In 3T3-L1 adipocytes, up-regulation of glucose transporter (GLUT) expression by FGF21 was associated with expression of betaKlotho, which was absent in undifferentiated 3T3-L1 fibroblasts. It is thus suggested that betaKlotho expression is a crucial determinant of the FGF21 specificity of the target cells upon which it acts in an endocrine fashion.

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Authors: Suzuki, M., Uehara, Y., Motomura-Matsuzaka, K., Oki, J., Koyama, Y., Kimura, M., Asada, M., Komi-Kuramochi, A., Oka, S., & Toru, T.
Affiliations: National Institute of Advanced Industrial Science and Technology (JP)
Tokyo University of Science (JP)
Signaling Molecules Research Laboratory (M.S., Y.U., K.M.-M., J.O., M.K., M.A., A.K.-K., S.O., T.I.), Ibaraki 305-8566, Japan
ORCID: Asada, Masahiro
Venue: Molecular Endocrinology
Publisher: The Endocrine Society
Published: 2008-04-01
Volume: 22
Issue: 4
Pages: 1006-1014
ISSN: 0888-8809 (ISSN-L)
1944-9917
DOI: 10.1210/me.2007-0313
PMC: PMC5419549
OpenAlex: W2110534048
Cited by: 345
References: 34
Citations by year: 2026: 17 · 2025: 16 · 2024: 18 · 2023: 11 · 2022: 18 · 2021: 18 · 2020: 19 · 2019: 19 · 2018: 13 · 2017: 25 · 2016: 26 · 2015: 25 · 2014: 16 · 2013: 20 · 2012: 27
FWCI: 7.82
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Molecular Endocrinology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
Physical Sciences › Environmental Science › Water Science and Technology › Fluoride Effects and Removal
Keywords: β-Klotho, FGF21, fibroblast growth factor 23, FGFR1c, FGF receptor signaling, target cell specificity, heparan sulfate proteoglycans, adipocytes, insulin-independent glucose transport, Ba/F3 cells, 3T3-L1 adipocytes, phosphate homeostasis, ketogenesis, starvation adaptation
MeSH terms: Fibroblast Growth Factor-23, Klotho Proteins, Animals, Fibroblast Growth Factors, Glucuronidase, Protein Binding, RNA, Messenger, Immunoblotting, Signal Transduction, Gene Expression, Reverse Transcriptase Polymerase Chain Reaction, 3T3-L1 Cells, Glucose Transport Proteins, Facilitative, Mice, Receptor, Fibroblast Growth Factor, Type 1, Receptor, Fibroblast Growth Factor, Type 3

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βKlotho Is Required for Fibroblast Growth Factor (FGF) 21 Signaling through FGF Receptor (FGFR) 1c and FGFR3c

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