1.
2.
Cell Metab
; 17(6): 929-940, 2013 Jun 04.
Article
in English
| MEDLINE
| ID: mdl-23747250
ABSTRACT
The fibroblast growth factor receptor 4 (FGFR4)-R388 single-nucleotide polymorphism has been associated with cancer risk and prognosis. Here we show that the FGFR4-R388 allele yields a receptor variant that preferentially promotes STAT3/5 signaling. This STAT activation transcriptionally induces Grb14 in pancreatic endocrine cells to promote insulin secretion. Knockin mice with the FGFR4 variant allele develop pancreatic islets that secrete more insulin, a feature that is reversed through Grb14 deletion and enhanced with FGF19 administration. We also show in humans that the FGFR4-R388 allele enhances islet function and may protect against type 2 diabetes. These data support a common genetic link underlying cancer and hyperinsulinemia.
Subject(s)
Insulin/metabolism , Proteins/metabolism , Receptor, Fibroblast Growth Factor, Type 4/metabolism , STAT3 Transcription Factor/metabolism , STAT5 Transcription Factor/metabolism , Adaptor Proteins, Signal Transducing , Animals , Cells, Cultured , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/prevention & control , Gene Expression Profiling , Gene Knock-In Techniques , Humans , Hyperinsulinism , Insulin/biosynthesis , Insulin Secretion , Mice , Mice, Knockout , Neoplasms/genetics , Neoplasms/metabolism , Pancreas/metabolism , Polymorphism, Single Nucleotide , Proteins/genetics , RNA Interference , RNA, Small Interfering , Rats , Receptor, Fibroblast Growth Factor, Type 4/genetics , Receptor, Insulin/metabolism , Signal Transduction/genetics
3.
Adv Exp Med Biol
; 524: 333-8, 2003.
Article
in English
| MEDLINE
| ID: mdl-12675255