Fibroblast Activation Protein Cleaves and Inactivates Fibroblast Growth Factor 21
Open accessAbstract
FGF21 is a stress-induced hormone with potent anti-obesity, insulin-sensitizing, and hepatoprotective properties. Although proteolytic cleavage of recombinant human FGF21 in preclinical species has been observed previously, the regulation of endogenously produced FGF21 is not well understood. Here we identify fibroblast activation protein (FAP) as the enzyme that cleaves and inactivates human FGF21. A selective chemical inhibitor, immunodepletion, or genetic deletion of Fap stabilized recombinant human FGF21 in serum. In addition, administration of a selective FAP inhibitor acutely increased circulating intact FGF21 levels in cynomolgus monkeys. On the basis of our findings, we propose selective FAP inhibition as a potential therapeutic approach to increase endogenous FGF21 activity for the treatment of obesity, type 2 diabetes, non-alcoholic steatohepatitis, and related metabolic disorders.
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Human but not mouse FGF21 is cleaved and processed by FAP.
“Notably, human but not mouse FGF21 is cleaved and processed by FAP, because mouse FGF21 possesses a single–amino acid difference in the stringent FAP-recognition motif42,43.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [42]
FGF21 is cleaved by FAP and DPP-IV; cleavage at residue 171 inactivates FGF21 because the last ten residues are critical for KLB interaction.
“FGF21 is also subject to proteolytic cleavage by the serine proteases fibroblast activation protein (FAP) and dipeptidyl peptidase IV (DPP-IV)42,43.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [42]
Mouse FGF21 is neither cleaved nor inactivated by FAP because mouse FGF21 has a glutamate residue at the corresponding glycine residue at position 170, which disrupts the stringent glycine-proline sequence required for FAP-mediated cleavage.
“Interestingly, mouse FGF21 is neither cleaved nor inactivated by FAP because mouse FGF21 has a glutamate residue at the corresponding glycine residue at position 170, which disrupts the stringent glycine–proline sequence required for FAP-mediated cleavage (29, 150).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [29]
Circulating human FGF21 is composed of 181 amino acids and is proteolytically cleaved, and inactivated, between Pro-171 and Ser-172 by the endopeptidase fibroblast activation protein (FAP).
“Circulating human FGF21 is composed of 181 amino acids and is proteolytically cleaved, and inactivated, between Pro-171 and Ser-172 by the endopeptidase fibroblast activation protein (FAP) (29, 150).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [29]
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- Authors
- Dunshee, D. R., Bainbridge, T. W., Kljavin, N. M., Zavala-Solorio, J., Schroeder, A. C., Chan, R., Corpuz, R., Wong, M., Zhou, W., Deshmukh, G., Ly, J., Sutherlin, D. P., Ernst, J. A., & Sonoda, J.
- Affiliations
- Molecular Oncology (United States) (US)
- Genentech (US)
- Corresponding author
- Sonoda, Junichiro
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 291
- Issue
- 11
- Pages
- 5986-5996
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4786731
- OpenAlex
- W2282926206
- Cited by
- 158
- References
- 54
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 20 · 2023: 17 · 2022: 12 · 2021: 21 · 2020: 16 · 2019: 7 · 2018: 20 · 2017: 14 · 2016: 7
- FWCI
- 8.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Genentech
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Oncology › Peptidase Inhibition and Analysis
- Health Sciences › Medicine › Pharmacology › Apelin-related biomedical research
- Keywords
- FGF21, fibroblast activation protein, proteolytic cleavage, FAP inhibitors, obesity, type 2 diabetes, nonalcoholic steatohepatitis, metabolic disorders, Macaca fascicularis
- MeSH terms
- Fibroblast Activation Protein Alpha, Amino Acid Sequence, Animals, Fibroblast Growth Factors, Humans, Macaca fascicularis, Male, Membrane Proteins, Mice, Inbred C57BL, Molecular Sequence Data, Endopeptidases, Recombinant Proteins, Serine Endopeptidases, Gene Deletion, Gelatinases, Mice, Knockout, Mice, HEK293 Cells, Proteolysis
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