Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 408, Issue 3, Pages 491-502Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2011.03.003
Keywords
fibroblast growth factor; FGF19; FGF21; FGFR1c; FGFR4
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FGF21 is a member of a unique subfamily of fibroblast growth factors that function as endocrine hormones and regulate a variety of metabolic activities. Unlike paracrine FGFs, FGF21 does not bind heparin and requires beta Klotho as a co-receptor to activate FGFR signaling. In the presence of beta Klotho, FGF21 is able to activate FGFRs 1c, 2c and 3c but not FGFR4. Chimeric FGFR1c/FGFR4 receptors were constructed to identify domains that confer this specificity and to understand regions important for FGF21-induced receptor activation. With these chimeras, we showed that domain 3 of the FGFR1c extracellular domain plays a critical role in specificity determination and receptor activation by FGF21. Furthermore, we were able to narrow down the sequences important for this function to a six amino acid region within domain 3 of FGFR1c. It is interesting to note that this region falls into the beta C'-beta E loop, which has been shown to be important for receptor specificity determination in paracrine FGFs, suggesting a common principle in both endocrine and paracrine FGF receptor interaction and activation. (c) 2011 Elsevier Ltd. All rights reserved.
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