TY - JOUR
T1 - Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor
AU - Goetz, Regina
AU - Ohnishi, Mutsuko
AU - Kir, Serkan
AU - Kurosu, Hiroshi
AU - Wang, Lei
AU - Pastor, Johanne
AU - Ma, Jinghong
AU - Gai, Weiming
AU - Kuro-o, Makoto
AU - Razzaque, Mohammed S.
AU - Mohammadi, Moosa
PY - 2012/8/17
Y1 - 2012/8/17
N2 - FGFs 19, 21, and 23 are hormones that regulate in a Klothoco-receptor- dependent fashion major metabolic processes suchas glucose and lipid metabolism (FGF21) and phosphate andvitamin D homeostasis (FGF23). The role of heparan sulfate glycosaminoglycanin the formation of the cell surface signalingcomplex of endocrine FGFs has remained unclear. Here we showthat heparan sulfate is not a component of the signal transductionunit of FGF19 and FGF23. In support of our model, weconvert a paracrine FGF into an endocrine ligand by diminishingheparan sulfate-binding affinity of the paracrine FGF andsubstituting its C-terminal tail for that of an endocrine FGF containingthe Klotho co-receptor-binding site to home the ligandinto the target tissue. In addition to serving as a proof of concept,the ligand conversion provides a novel strategy for engineeringendocrine FGF-like molecules for the treatment of metabolicdisorders, including global epidemics such as type 2 diabetesand obesity.
AB - FGFs 19, 21, and 23 are hormones that regulate in a Klothoco-receptor- dependent fashion major metabolic processes suchas glucose and lipid metabolism (FGF21) and phosphate andvitamin D homeostasis (FGF23). The role of heparan sulfate glycosaminoglycanin the formation of the cell surface signalingcomplex of endocrine FGFs has remained unclear. Here we showthat heparan sulfate is not a component of the signal transductionunit of FGF19 and FGF23. In support of our model, weconvert a paracrine FGF into an endocrine ligand by diminishingheparan sulfate-binding affinity of the paracrine FGF andsubstituting its C-terminal tail for that of an endocrine FGF containingthe Klotho co-receptor-binding site to home the ligandinto the target tissue. In addition to serving as a proof of concept,the ligand conversion provides a novel strategy for engineeringendocrine FGF-like molecules for the treatment of metabolicdisorders, including global epidemics such as type 2 diabetesand obesity.
UR - http://www.scopus.com/inward/record.url?scp=84865258676&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84865258676&partnerID=8YFLogxK
U2 - 10.1074/jbc.M112.342980
DO - 10.1074/jbc.M112.342980
M3 - Article
C2 - 22733815
AN - SCOPUS:84865258676
SN - 0021-9258
VL - 287
SP - 29134
EP - 29146
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 34
ER -