The FGFR D3 Domain Determines Receptor Selectivity For Fibroblast Growth Factor 21

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• 作者：Jamila Gupte¹ ; ^† ; ; Li Yang¹ ; ^† ; ; Xinle Wu¹ ; ^† ; ; Jennifer Weiszmann¹ ; Randy Hecht² ; Bryan Lemon¹ ; Richard Lindberg¹ ; Zhulun Wang¹ ; Yang Li¹ ; ^{yangl@amgen.com}
• 关键词：fibroblast growth factor ; FGF19 ; FGF21 ; FGFR1c ; FGFR4
• 刊名：Journal of Molecular Biology
• 出版年：2011
• 出版时间：6 May 2011
• 年：2011
• 卷：408
• 期：3
• 页码：491-502
• 全文大小：1590 K

文摘

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 βKlotho as a co-receptor to activate FGFR signaling. In the presence of βKlotho, 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 βC’-βE 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.