The cancer-associated FGFR4-G388R polymorphism enhances pancreatic insulin secretion and modifies the risk of diabetes.

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.

• Authors: Shereen Ezzat, Lei Zheng, Jose C Florez, Norbert Stefan, Thomas Mayr, Maw Maw Hliang, Kathleen Jablonski, Maegan Harden, Alena Stančáková, Markku Laakso, Hans-Ulrich Haring, Axel Ullrich, Sylvia L Asa
• Journal: Cell metabolism (Cell Metab) Vol. 17 Issue 6 Pg. 929-940 (Jun 04 2013) ISSN: 1932-7420 [Electronic] United States
• PMID: 23747250 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Retracted Publication)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Grb14 protein, mouse
• Insulin
• Proteins
• RNA, Small Interfering
• STAT3 Transcription Factor
• STAT5 Transcription Factor
• Stat3 protein, mouse
• Fgfr4 protein, mouse
• Receptor, Fibroblast Growth Factor, Type 4
• Receptor, Insulin

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• Cells, Cultured
• Diabetes Mellitus, Type 2 (genetics, metabolism, prevention & control)
• Gene Expression Profiling
• Gene Knock-In Techniques
• Humans
• Hyperinsulinism
• Insulin (biosynthesis, metabolism)
• Insulin Secretion
• Mice
• Mice, Knockout
• Neoplasms (genetics, metabolism)
• Pancreas (metabolism)
• Polymorphism, Single Nucleotide
• Proteins (genetics, metabolism)
• RNA Interference
• RNA, Small Interfering
• Rats
• Receptor, Fibroblast Growth Factor, Type 4 (genetics, metabolism)
• Receptor, Insulin (metabolism)
• STAT3 Transcription Factor (metabolism)
• STAT5 Transcription Factor (metabolism)
• Signal Transduction (genetics)