The FGFR4-G388R Polymorphism Signals Through Distinct STAT3 Modifications to Regulate Pituitary Corticotroph Tumors

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 88-111-Cushing's Disease & Non-Functioning Hypothalamus-Pituitary Tumors
Clinical
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-96
Tae Tateno*1, Toru Tateno1, Lei Zheng2, Maw Maw Hliang1, Katsuhiko Yoshimoto3, Shozo Yamada4, Sylvia L. Asa2 and Shereen Z Ezzat1
1Ontario Cancer Institute, Toronto, ON, Canada, 2University Health Network, Toronto, ON, Canada, 3Univ of Tokushima, Tokushima, Japan, 4Toranomon Hosp, Tokyo, Japan
Backgrounds: Fibroblast growth factor receptor 4 (FGFR4) is a member of a family of four transmembrane receptors with ligand-induced tyrosine kinase activity.  We have previously reported that a single nucleotide polymorphism (SNP) substituting an arginine (R) for glycine (G) in the FGFR4 transmembrane domain alters cell signaling, resulting in increased cell proliferation and growth hormone production in mammosomatotroph cells (PloS Genetics). Here we examined the differential properties of the two FGFR4 isotypes on cell signaling, negative feedback, and cellular proliferation in corticotroph cells.

Methods and Results: Mouse AtT20 corticotroph cells were stably transfected with constructs encoding full length human FGFR4 Gly388 (G388) or Arg388 (R388) cDNA. Levels of POMC, glucocorticoid receptor (GR) expression, and phosphorylation of STAT3 (pS-STAT3 and pY-STAT3) were examined after dexamethasone treatment. Compared to controls and FGFR4-R388 cells, FGFR4-WT cells showed enhanced pY-STAT3 responses but significantly decreased GR expression. Fractionation studies revealed diminished nuclear translocation, but not degradation, of the phosphorylated (Ser211) GR. These effects were recapitulated by introducing constitutively active STAT3 mutants. In contrast, FGFR4-R388 cells supported pS-STAT3 which translocates into the mitochondria to enhance basal respiration, drive ATP turnover, increase proton leak, and augment maximal respiration. Using a knock-in mouse model of the FGFR4 SNP we validate altered sensitivity to dexamethasone feedback on corticosterone secretion. Finally, clinical data from 66 patients with ACTH-producing pituitary tumors revealed that those homozygous for the R388 allele showed a higher frequency of silent corticotroph macroadenomas compared to G388 carriers who were more likely to have small microadenomas causing Cushing disease.

Conclusion: Our data demonstrate that the FGFR4 trans-membrane SNP can yield receptor isoforms with differential signaling properties that influence sensitivity to dexamethasone feedback through GR phosphorylation and translocation.  Moreover, enhanced pS-STAT3 serves to drive mitochondrial respiratory rate to support the neoplastic growth of corticotroph macroadenomas.

Tateno T, et al. PloS Genetics 2011.

Nothing to Disclose: TT, TT, LZ, MMH, KY, SY, SLA, SZE

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Supported by the Canadian Institutes of Health Research (CIHR).