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Related Experiment Video

Updated: Mar 29, 2026

Analysis of Transforming Growth Factor &#223; Family Cleavage Products Secreted Into the Blastocoele of Xenopus laevis Embryos
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Circulating FGF21 proteolytic processing mediated by fibroblast activation protein.

Eugene Y Zhen1, Zhaoyan Jin2, Bradley L Ackermann2

  • 1Tailored Therapeutics, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, U.S.A. zhen@lilly.com.

The Biochemical Journal
|December 5, 2015
PubMed
Summary

Fibroblast growth factor 21 (FGF21) is proteolysed in circulation, with fibroblast activation protein (FAP) identified as the key enzyme inactivating FGF21. This discovery offers new therapeutic strategies for metabolic disorders.

Keywords:
dipeptidyl peptidase IVfibroblast activation proteinfibroblast growth factor 21post-transcriptional processingprolyl peptidase

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Area of Science:

  • Biochemistry
  • Endocrinology
  • Proteomics

Background:

  • Fibroblast growth factor 21 (FGF21) regulates glucose homeostasis, insulin sensitivity, lipid metabolism, and body weight.
  • FGF21 is a potential therapeutic target for metabolic disorders, but its circulating levels are poorly understood due to rapid proteolysis.

Purpose of the Study:

  • To systematically investigate the mechanisms of human FGF21 protein processing and identify the proteases involved.
  • To understand how FGF21 protein levels are regulated in circulation.

Main Methods:

  • Mass spectrometry was used to analyze human FGF21 protein processing.
  • In vitro digestion, immunodepletion, FAP-specific inhibitor administration, and FAP knockout mouse plasma were employed to confirm protease activity.

Main Results:

  • Human FGF21 undergoes cleavage at Pro-2, Pro-4, and Pro-171.
  • Dipeptidyl peptidase IV (DPP-IV) mediates N-terminal cleavages at Pro-2 and Pro-4.
  • Fibroblast activation protein (FAP) is the primary protease responsible for C-terminal cleavage at Pro-171, leading to FGF21 inactivation.

Conclusions:

  • Fibroblast activation protein (FAP) is identified as the key protease that inactivates FGF21 by cleaving its C-terminus.
  • Understanding FAP's role in FGF21 processing opens novel therapeutic avenues for metabolic diseases.