title: 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.affiliation: Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada. Electronic address: shereen.ezzat@utoronto.ca.
authors.forename: Shereen
authors.initials: S
authors.lastname: Ezzat
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Center for Human Genetic Research and Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02142, USA.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.affiliation: University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Stefan
authors.affiliation: Department of Molecular Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mayr
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: Maw Maw
authors.initials: MM
authors.lastname: Hliang
authors.affiliation: The Biostatistics Center, George Washington University, Rockville, MD 20852, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Jablonski
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Maegan
authors.initials: M
authors.lastname: Harden
authors.affiliation: Department of Medicine, University of Eastern Finland, 70210 Kuopio, Finland.
authors.forename: Alena
authors.initials: A
authors.lastname: Stančáková
authors.affiliation: Department of Medicine, University of Eastern Finland, 70210 Kuopio, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.affiliation: University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Haring
authors.affiliation: Department of Molecular Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Ullrich
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Asa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D020869:Gene Expression Profiling; D055879:Gene Knock-In Techniques; D006801:Humans; D006946:Hyperinsulinism; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism*; D000078790:Insulin Secretion; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490977:Grb14 protein, mouse; D007328:Insulin; D011506:Proteins; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; C496372:Fgfr4 protein, mouse; D051499:Receptor, Fibroblast Growth Factor, Type 4; D011972:Receptor, Insulin