The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index.
Tissue-specific Expression of βKlotho and Fibroblast Growth Factor (FGF) Receptor Isoforms Determines Metabolic Activity of FGF19 and FGF21
Open accessAbstract
The fibroblast growth factor (FGF) 19 subfamily of ligands, FGF19, FGF21, and FGF23, function as hormones that regulate bile acid, fatty acid, glucose, and phosphate metabolism in target organs through activating FGF receptors (FGFR1-4). We demonstrated that Klotho and betaKlotho, homologous single-pass transmembrane proteins that bind to FGFRs, are required for metabolic activity of FGF23 and FGF21, respectively. Here we show that, like FGF21, FGF19 also requires betaKlotho. Both FGF19 and FGF21 can signal through FGFR1-3 bound by betaKlotho and increase glucose uptake in adipocytes expressing FGFR1. Additionally, both FGF19 and FGF21 bind to the betaKlotho-FGFR4 complex; however, only FGF19 signals efficiently through FGFR4. Accordingly, FGF19, but not FGF21, activates FGF signaling in hepatocytes that primarily express FGFR4 and reduces transcription of CYP7A1 that encodes the rate-limiting enzyme for bile acid synthesis. We conclude that the expression of betaKlotho, in combination with particular FGFR isoforms, determines the tissue-specific metabolic activities of FGF19 and FGF21.
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In the citing paper
“loss of KLB abolishes all effects of FGF21 in vitro and in vivo46,53–56.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [46]
In the citing paper
“FGF21 binding promotes the formation of a dimeric FGFR1c–KLB signalling complex, which activates the intracellular tyrosine kinase domains of FGFR1c and propagates signalling through phosphorylation by the kinase ERK46,53,58,59”
From Metabolic messengers: FGF21 (2021) · cites this paper as [46]
In the citing paper
“FGF21 elicits its biological effects by binding and activating a receptor complex composed of the co-receptor KLB and a traditional FGF receptor, fibroblast growth factor receptor 1c (FGFR1c)46,47.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [46]
In the citing paper
“Interestingly, both FGF21 and another endocrine FGF, FGF15/19, share a requirement for KLB for signaling46,54, but what cross-talk, if any, exists between these signalling pathways in both physiological and pharmacological settings is unclear.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [46]
In the citing paper
“FGF21 signals to a receptor complex comprised of FGF receptor 1c (FGFR1c) and its co-receptor β-klotho (KLB) [[143], [144], [145], [146]].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [143]
In the citing paper
“Importantly, since FGF receptors are ubiquitously expressed, endocrine FGFs require a coreceptor to provide signaling specificity, which for FGF21 and FGF19 is the coreceptor β-klotho (71, 99, 140).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [71]
In the citing paper
“FGF21 functions in target tissues that express the traditional FGF receptor FGFR1c and the obligate coreceptor β-klotho (2, 27, 71, 99, 124, 140).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [71]
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Citations
Cites
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837
Self-citationFGF-21 as a novel metabolic regulator
Kharitonenkov, A., Shiyanova, T. L., Koester, A., Ford, A. M., Micanovic, R., Galbreath, E. J., Sandusky, G. E., Hammond, L. J., Moyers, J. S., Owens, R. A., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23606 · Cited by 2,125
Suppression of Aging in Mice by the Hormone Klotho
Kurosu, H., Yamamoto, M., Clark, J. D., Pastor, J. V., Nandi, A., Gurnani, P., McGuinness, O. P., Chikuda, H., Yamaguchi, M., Kawaguchi, H., et al. (2005) · Science · doi:10.1126/science.1112766 · Cited by 1,935
Self-citationReceptor Specificity of the Fibroblast Growth Factor Family
Ornitz, D. M., Xu, J., Colvin, J. S., McEwen, D. G., MacArthur, C. A., Coulier, F., Gao, G., & Goldfarb, M. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.25.15292 · Cited by 1,871
Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis
Inagaki, T., Choi, M., Moschetta, A., Peng, L., Cummins, C. L., McDonald, J. G., Luo, G., Jones, S. A., Goodwin, B., Richardson, J. A., et al. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.09.001 · Cited by 1,865
Self-citationKlotho converts canonical FGF receptor into a specific receptor for FGF23
Urakawa, I., Yamazaki, Y., Shimada, T., Iijima, K., Hasegawa, H., Okawa, K., Fujita, T., Fukumoto, S., & Yamashita, T. (2006) · Nature · doi:10.1038/nature05315 · Cited by 1,865
Inagaki, T., Dutchak, P., Zhao, G., Ding, X., Gautron, L., Parameswara, V., Li, Y., Goetz, R., Mohammadi, M., Esser, V., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.05.003 · Cited by 1,504
Self-citationShimada, T., Kakitani, M., Yamazaki, Y., Hasegawa, H., Takeuchi, Y., Fujita, T., Fukumoto, S., Tomizuka, K., & Yamashita, T. (2004) · Journal of Clinical Investigation · doi:10.1172/jci19081 · Cited by 1,503
Badman, M. K., Pissios, P., Kennedy, A. R., Koukos, G., Flier, J. S., & Maratos-Flier, E. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.05.002 · Cited by 1,495
Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23
White, K., Evans, W. E., O'Riordan, J., Speer, M., Econs, M., Lorenz-Depiereux, B., Grabowski, M., Meitinger, T., & Strom, T. (2000) · Nature Genetics · doi:10.1038/81664 · Cited by 1,467
Cited by
Sorted by citations
The FGF family: biology, pathophysiology and therapy
Beenken, A., & Mohammadi, M. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2792 · Cited by 1,945
Self-citationRole of Bile Acids and Bile Acid Receptors in Metabolic Regulation
Lefebvre, P., Cariou, B., Lien, F., Kuipers, F., & Staels, B. (2009) · Physiological Reviews · doi:10.1152/physrev.00010.2008 · Cited by 1,678
Xu, J., Lloyd, D. J., Hale, C., Stanislaus, S., Chen, M., Sivits, G., Vonderfecht, S., Hecht, R., Li, Y.-S., Lindberg, R. A., et al. (2009) · Diabetes · doi:10.2337/db08-0392 · Cited by 1,151
Understanding the Physiology of FGF21
Fisher, F. M., & Maratos-Flier, E. (2016) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021115-105339 · Cited by 912
Bile Acids: Chemistry, Pathochemistry, Biology, Pathobiology, and Therapeutics
Hofmann, A. F., & Hagey, L. R. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-7568-6 · Cited by 873
Metadata
- Authors
- Kurosu, H., Choi, M., Ogawa, Y., Dickson, A. S., Goetz, R., Eliseenkova, A. V., Mohammadi, M., Rosenblatt, K. P., Kliewer, S. A., & Kuro-o, M.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- New York University (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-09
- Volume
- 282
- Issue
- 37
- Pages
- 26687-26695
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2496965
- OpenAlex
- W2048411348
- Cited by
- 748
- References
- 35
- Citations by year
- 2026: 37 · 2025: 24 · 2024: 33 · 2023: 31 · 2022: 55 · 2021: 46 · 2020: 44 · 2019: 48 · 2018: 52 · 2017: 47 · 2016: 38 · 2015: 40 · 2014: 43 · 2013: 43 · 2012: 51
- FWCI
- 10.87
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Ellison Medical Foundation
- Welch Foundation
- Ted Nash Long Life Foundation
- Eisai
- National Institutes of Health (1r01ag015326-01, DK067158)
- National Institute on Aging (R01AG19712, R01AG025326, R01 AG 15326, R01AG019712)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-067158, R01DK067158)
- National Institute of Dental and Craniofacial Research (R01DE13686, R01DE013686)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- β-Klotho, Klotho, FGF19, FGF21, fibroblast growth factor 23, fibroblast growth factor receptor, FGFR4, FGFR1, tissue-specific signaling, bile acid metabolism, CYP7A1, hepatocytes, metabolic hormones
- MeSH terms
- Fibroblast Growth Factor-23, Klotho Proteins, Animals, Cholesterol 7-alpha-Hydroxylase, Fibroblast Growth Factors, Humans, Membrane Proteins, Organ Specificity, Phosphorylation, Signal Transduction, Adipocytes, Protein Isoforms, Hepatocytes, 3T3-L1 Cells, Extracellular Signal-Regulated MAP Kinases, Mice, Rats, ErbB Receptors
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