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Circulating FGF21 proteolytic processing mediated by fibroblast activation protein
Open accessAbstract
Fibroblast growth factor 21 (FGF21), a hormone implicated in the regulation of glucose homoeostasis, insulin sensitivity, lipid metabolism and body weight, is considered to be a promising therapeutic target for the treatment of metabolic disorders. Despite observations that FGF21 is rapidly proteolysed in circulation rending it potentially inactive, little is known regarding mechanisms by which FGF21 protein levels are regulated. We systematically investigated human FGF21 protein processing using mass spectrometry. In agreement with previous reports, circulating human FGF21 was found to be cleaved primarily after three proline residues at positions 2, 4 and 171. The extent of FGF21 processing was quantified in a small cohort of healthy human volunteers. Relative abundance of FGF21 proteins cleaved after Pro-2, Pro-4 and Pro-171 ranged from 16 to 30%, 10 to 25% and 10 to 34%, respectively. Dipeptidyl peptidase IV (DPP-IV) was found to be the primary protease responsible for N-terminal cleavages after residues Pro-2 and Pro-4. Importantly, fibroblast activation protein (FAP) was implicated as the protease responsible for C-terminal cleavage after Pro-171, rendering the protein inactive. The requirement of FAP for FGF21 proteolysis at the C-terminus was independently demonstrated by in vitro digestion, immunodepletion of FAP in human plasma, administration of an FAP-specific inhibitor and by human FGF21 protein processing patterns in FAP knockout mouse plasma. The discovery that FAP is responsible for FGF21 inactivation extends the FGF21 signalling pathway and may enable novel approaches to augment FGF21 actions for therapeutic applications.
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“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 [43]
In the citing paper
“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 [43]
In the citing paper
“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 [150]
In the citing paper
“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 [150]
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Cites
IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040
Ogurtsova, K., Fernandes, J. D. D. R., Huang, Y., Linnenkamp, U., Guariguata, L., Cho, N. H., Cavan, D. A., Shaw, J. E., & Makaroff, L. (2017) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2017.03.024 · Cited by 7,138
IDF Diabetes Atlas: Global estimates of the prevalence of diabetes for 2011 and 2030
Whiting, D. R., Guariguata, L., Weil, C., & Shaw, J. E. (2011) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2011.10.029 · Cited by 4,018
The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes
Gaich, G., Chien, J. Y., Fu, H., Glass, L. C., Deeg, M. A., Holland, W. L., Kharitonenkov, A., Bumol, T., Schilske, H. K., & Moller, D. E. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.08.005 · Cited by 885
The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21
Kharitonenkov, A., Wroblewski, V. J., Koester, A., Chen, Y.-F., Clutinger, C. K., Tigno, X. T., Hansen, B. C., Shanafelt, A. B., & Etgen, G. J. (2007) · Endocrinology · doi:10.1210/en.2006-1168 · Cited by 738
Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease
Itoh, N., & Ornitz, D. M. (2010) · The Journal of Biochemistry · doi:10.1093/jb/mvq121 · Cited by 726
Scanlan, M. J., Raj, B. K. M., Calvo, B. F., Garin‐Chesa, P., Sanz-Moncasi, M. P., Healey, J. H., Old, L. J., & Rettig, W. J. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.12.5657 · Cited by 577
Gälman, C., Lundåsen, T., Kharitonenkov, A., Bina, H. A., Eriksson, M., Hafström, I., Dahlin, M., Åmark, P., Angelin, B., & Rudling, M. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.06.014 · Cited by 512
Biological actions and therapeutic potential of the glucagon-like peptides
Drucker, D. J. (2002) · Gastroenterology · doi:10.1053/gast.2002.31068 · Cited by 509
Hamson, E., Keane, F. M., Tholen, S., Schilling, O., & Gorrell, M. D. (2014) · PROTEOMICS - CLINICAL APPLICATIONS · doi:10.1002/prca.201300095 · Cited by 501
Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice
Santos, A., Jung, J. J., Aziz, N., Kissil, J. L., & Puré, E. (2009) · Journal of Clinical Investigation · doi:10.1172/jci38988 · Cited by 436
Cunningham, D. F., & O’Connor, B. F. (1997) · Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology · doi:10.1016/s0167-4838(97)00134-9 · Cited by 348
Suzuki, M., Uehara, Y., Motomura-Matsuzaka, K., Oki, J., Koyama, Y., Kimura, M., Asada, M., Komi-Kuramochi, A., Oka, S., & Toru, T. (2008) · Molecular Endocrinology · doi:10.1210/me.2007-0313 · Cited by 345
Xu, J., Stanislaus, S., Chinookoswong, N., Lau, Y. Y., Hager, T., Patel, J., Ge, H., Weiszmann, J., Lu, S.-C., Graham, M., et al. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00348.2009 · Cited by 340
Levy, M. T., McCaughan, G. W., Abbott, C. A., Park, J. E., Cunningham, A. M., Müller, E., Rettig, W. J., & Gorrell, M. D. (1999) · Hepatology · doi:10.1002/hep.510290631 · Cited by 338
FGF‐21/FGF‐21 receptor interaction and activation is determined by βKlotho
Kharitonenkov, A., Dunbar, J. D., Bina, H. A., Bright, S. W., Moyers, J. S., Zhang, C., Ding, L., Micanovic, R., Mehrbod, S. F., Knierman, M. D., et al. (2007) · Journal of Cellular Physiology · doi:10.1002/jcp.21357 · Cited by 333
[Proline specific peptidases].
Yoshimoto, T., Kabashima, T., & Ito, K. (1997) · PubMed · Cited by 285
Prolyl peptidases: a serine protease subfamily with high potential for drug discovery
Rosenblum, J. S., & Kozarich, J. W. (2003) · Current Opinion in Chemical Biology · doi:10.1016/s1367-5931(03)00084-x · Cited by 284
Abbott, C. A., Yu, D. M. T., Woollatt, E., Sutherland, G. R., McCaughan, G. W., & Gorrell, M. D. (2000) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2000.01617.x · Cited by 272
Molecular characterization of dipeptidyl peptidase activity in serum
Durinx, C., Lambeir, A., Bosmans, E., Falmagne, J., Berghmans, R., Haemers, A., Scharpé, S., & Meester, I. D. (2000) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2000.01634.x · Cited by 267
The breadth of FGF21's metabolic actions are governed by FGFR1 in adipose tissue
Adams, A. C., Yang, C., Coskun, T., Cheng, C. C., Gimeno, R. E., Luo, Y., & Kharitonenkov, A. (2013) · Molecular Metabolism · doi:10.1016/j.molmet.2012.08.007 · Cited by 266
Circulating fibroblast growth factors as metabolic regulators--a critical appraisal.
Angelin, B., Larsson, T., & Rudling, M. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.11.001 · Cited by 210
A Role for Dipeptidyl Peptidase IV in Suppressing the Malignant Phenotype of Melanocytic Cells
Wesley, U., Albino, A., Tiwari, S., & Houghton, A. (1999) · Journal of Experimental Medicine · doi:10.1084/jem.190.3.311 · Cited by 207
Proline residues in the maturation and degradation of peptide hormones and neuropeptides
Mentlein, R. (1988) · FEBS Letters · doi:10.1016/0014-5793(88)80092-9 · Cited by 203
Antiplasmin-cleaving enzyme is a soluble form of fibroblast activation protein
Lee, K. N., Jackson, K. W., Christiansen, V. J., Lee, C. S., Chun, J.-G., & McKee, P. A. (2005) · Blood · doi:10.1182/blood-2005-08-3452 · Cited by 192
LY2405319, an engineered FGF21 variant, improves the metabolic status of diabetic monkeys
Adams, A. C., Halstead, C. A., Hansen, B. C., Irizarry, A. R., Martin, J. A., Myers, S. R., Reynolds, V. L., Smith, H. W., Wroblewski, V. J., & Kharitonenkov, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065763 · Cited by 169
Rational Design of a Fibroblast Growth Factor 21-Based Clinical Candidate, LY2405319
Kharitonenkov, A., Beals, J. M., Micanovic, R., Strifler, B. A., Rathnachalam, R., Wroblewski, V. J., Li, S., Köester, A., Ford, A. M., Coşkun, T., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0058575 · Cited by 168
Hecht, R. I., Li, Y., Sun, J., Belouski, E., Hall, M. P., Hager, T., Yie, J., Wang, W., Winters, D., Smith, S. H., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049345 · Cited by 166
FGF21-based pharmacotherapy – potential utility for metabolic disorders
Gimeno, R. E., & Moller, D. E. (2014) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2014.03.001 · Cited by 163
Mu, J., Pinkstaff, J. K., Li, Z., Skidmore, L. K., Li, N., Myler, H. A., Dallas-Yang, Q., Hays, A. A., Yao, J., Bussell, S., et al. (2011) · Diabetes · doi:10.2337/db11-0838 · Cited by 162
FGF21 N‐ and C‐termini play different roles in receptor interaction and activation
Yie, J., Hecht, R., Patel, J., Stevens, J., Wang, W., Hawkins, N., Steavenson, S., Smith, S., Winters, D., Fisher, S., et al. (2009) · FEBS Letters · doi:10.1016/j.febslet.2008.11.023 · Cited by 149
Long-Acting FGF21 Has Enhanced Efficacy in Diet-Induced Obese Mice and in Obese Rhesus Monkeys
Véniant, M. M., Komorowski, R., Chen, P., Stanislaus, S., Winters, K., Hager, T., Zhou, L., Wada, R., Hecht, R. I., & Xu, J. (2012) · Endocrinology · doi:10.1210/en.2012-1211 · Cited by 148
Different roles of N‐ and C‐ termini in the functional activity of FGF21
Micanovic, R., Raches, D. W., Dunbar, J. D., Driver, D. A., Bina, H. A., Dickinson, C. D., & Kharitonenkov, A. (2009) · Journal of Cellular Physiology · doi:10.1002/jcp.21675 · Cited by 146
Identification and characterization of human DPP9 , a novel homologue of dipeptidyl peptidase IV
Olsen, C., & Wagtmann, N. R. (2002) · Gene · doi:10.1016/s0378-1119(02)01059-4 · Cited by 140
Keane, F. M., Nadvi, N. A., Yao, T., & Gorrell, M. D. (2011) · FEBS Journal · doi:10.1111/j.1742-4658.2011.08051.x · Cited by 129
Christiansen, V. J., Jackson, K. W., Lee, K. N., & McKee, P. A. (2006) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2006.11.006 · Cited by 129
A novel plasma proteinase potentiates α2-antiplasmin inhibition of fibrin digestion
Lee, K. N., Jackson, K. W., Christiansen, V. J., Chung, K. H., & McKee, P. A. (2004) · Blood · doi:10.1182/blood-2003-12-4240 · Cited by 126
Catalysis of serine oligopeptidases is controlled by a gating filter mechanism
Fülöp, V., Szeltner, Z., & Polgár, L. (2000) · EMBO Reports · doi:10.1093/embo-reports/kvd048 · Cited by 112
Edosada, C. Y., Quan, C. L., Tran, T., Pham, V. C., Wiesmann, C., Fairbrother, W. J., & Wolf, B. B. (2006) · FEBS Letters · doi:10.1016/j.febslet.2006.01.087 · Cited by 106
An alternate pathway of cAMP-stimulated Cl− secretion across the NKCC1-null murine duodenum
Walker, N. M., Flagella, M., Gawenis, L. R., Shull, G. E., & Clarke, L. L. (2002) · Gastroenterology · doi:10.1053/gast.2002.34757 · Cited by 100
Underwood, R., Chiravuri, M., Lee, H., Schmitz, T. L., Kabcenell, A. K., Yardley, K., & Huber, B. T. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.48.34053 · Cited by 97
Expression of the fibroblast activation protein during mouse embryo development
Niedermeyer, J., Garin‐Chesa, P., Kriz, M., Hilberg, F., Mueller, E., Bamberger, U., Rettig, W. J., & Schnapp, A. (2001) · The International Journal of Developmental Biology · doi:10.1387/ijdb.11330865 · Cited by 92
A new and highly sensitive fluorescence assay for collagenase-like peptidase activity
Kojima, K., Kinoshita, H., Kato, T., Nagatsu, T., Takada, K., & Sakakibara, S. (1979) · Analytical Biochemistry · doi:10.1016/0003-2697(79)90106-4 · Cited by 71
Tsai, T., Yeh, T., Chen, X., Hsu, T., Jao, Y., Huang, C., Song, J., Huang, Y., Chien, C., Chiu, J.-H., et al. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm1002556 · Cited by 71
Purification, identification and characterisation of seprase from bovine serum
Collins, P. J., McMahon, G. P., O’Brien, P., & O’Connor, B. F. (2004) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2004.05.006 · Cited by 71
Hager, T., Spahr, C. S., Xu, J., Salimi-Moosavi, H., & Hall, M. P. (2013) · Analytical Chemistry · doi:10.1021/ac303203y · Cited by 62
Polyethylene Glycol Modified FGF21 Engineered to Maximize Potency and Minimize Vacuole Formation
Xu, J., Bussiere, J. L., Yie, J., Sickmier, E. A., An, P., Belouski, E., Stanislaus, S., & Walker, K. W. (2013) · Bioconjugate Chemistry · doi:10.1021/bc300603k · Cited by 61
Chung, K., Cheng, J., Suen, C., Huang, C., Tsai, C., Huang, L., Chen, Y., Wang, A. H. ‐., Jiaang, W., Hwang, M., et al. (2010) · Protein Science · doi:10.1002/pro.443 · Cited by 38
Camacho, R. C., Zafian, P., Achanfuo-Yeboah, J., Manibusan, A., & Berger, J. P. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.06.023 · Cited by 38
Lee, K. N., Jackson, K. W., Terzyan, S. S., Christiansen, V. J., & McKee, P. A. (2009) · Biochemistry · doi:10.1021/bi900257m · Cited by 33
Huang, C., Suen, C., Lin, C., Chien, C., Lee, H.-Y., Chung, K., Tsai, T., Jiaang, W.-T., Hwang, M., & Chen, X. (2011) · The Journal of Biochemistry · doi:10.1093/jb/mvr017 · Cited by 30
Membrane orientation of rat gp110 as studied by in vitro translation.
Hong, W., & Doyle, D. J. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)37475-1 · Cited by 26
Osborne, B., Yao, T., Wang, X. M., Chen, Y., Kotan, L. D., Nadvi, N. A., Herdem, M., McCaughan, G. W., Allen, J. D., Yu, D. M. T., et al. (2014) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2014.03.015 · Cited by 20
Novel Sandwich Immunoassays for The Measurement of Total and Active Fgf21
Umberger, T. S., Sloan, J. H., Chen, J., Cheng, C., Siegel, R. W., Qian, Y., Troutt, J. S., & Konrad, R. J. (2014) · Bioanalysis · doi:10.4155/bio.14.241 · Cited by 16
Fibroblast activation protein, a potential diagnostic and therapeutic target for cancer—reply
Tchou, J. C., & Conejo-Garcia, J. R. (2014) · Human Pathology · doi:10.1016/j.humpath.2013.11.022 · Cited by 4
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Metadata
- Authors
- Zhen, E. Y., Jin, Z., Ackermann, B. L., Thomas, M. K., & Gutierrez, J. A.
- Affiliations
- Tailored Therapeutics, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, U.S.A.
- Eli Lilly (United States) (US)
- ORCID
- Thomas, Melissa K.
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2016-02-24
- Volume
- 473
- Issue
- 5
- Pages
- 605-614
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC4764976
- OpenAlex
- W2292257555
- Cited by
- 123
- References
- 54
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 11 · 2023: 16 · 2022: 9 · 2021: 17 · 2020: 16 · 2019: 7 · 2018: 15 · 2017: 12 · 2016: 7
- FWCI
- 4.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Biochemical Journal (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- University of Pennsylvania
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Peptidase Inhibition and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Keywords
- FGF21, fibroblast activation protein, proteolytic processing, proteolytic cleavage, dipeptidyl peptidase IV, FAP inhibitors, metabolic disorders, glucose homeostasis, insulin sensitivity, lipid metabolism
- MeSH terms
- Animals, Fibroblasts, Humans, Insulin Resistance, Protein Processing, Post-Translational, Lipid Metabolism, Proteolysis
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