The Orphan GPR50 Receptor Promotes Constitutive TGFβ Receptor Signaling and Protects Against Cancer Development

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Mar 25

PMID 29572483

Citations 14

Authors

Stefanie Wojciech

Raise Ahmad

Zakia Belaid-Choucair

Anne-Sophie Journe

Sarah Gallet

Julie Dam

Avais Daulat

Delphine Ndiaye-Lobry

Olivier Lahuna

Angeliki Karamitri

Jean-Luc Guillaume

Marcio Do Cruzeiro

Francois Guillonneau

Anastasia Saade

Nathalie Clement

Thomas Courivaud

Nawel Kaabi

Kenjiro Tadagaki

Philippe Delagrange

Vincent Prevot

Olivier Hermine

Celine Prunier

Ralf Jockers

Affiliations

Soon will be listed here.

Abstract

Transforming growth factor-β (TGFβ) signaling is initiated by the type I, II TGFβ receptor (TβRI/TβRII) complex. Here we report the formation of an alternative complex between TβRI and the orphan GPR50, belonging to the G protein-coupled receptor super-family. The interaction of GPR50 with TβRI induces spontaneous TβRI-dependent Smad and non-Smad signaling by stabilizing the active TβRI conformation and competing for the binding of the negative regulator FKBP12 to TβRI. GPR50 overexpression in MDA-MB-231 cells mimics the anti-proliferative effect of TβRI and decreases tumor growth in a xenograft mouse model. Inversely, targeted deletion of GPR50 in the MMTV/Neu spontaneous mammary cancer model shows decreased survival after tumor onset and increased tumor growth. Low GPR50 expression is associated with poor survival prognosis in human breast cancer irrespective of the breast cancer subtype. This describes a previously unappreciated spontaneous TGFβ-independent activation mode of TβRI and identifies GPR50 as a TβRI co-receptor with potential impact on cancer development.

Citing Articles

High expression of GPR50 promotes the proliferation, migration and autophagy of hepatocellular carcinoma cells in vitro.

Zhao W, Xi L, Yu G, Wang G, Chang C J Cell Commun Signal. 2023; 17(4):1435-1447.

PMID: 37378811 PMC: 10713896. DOI: 10.1007/s12079-023-00772-9.

Therapeutic potency of compound RMY-205 for pulmonary fibrosis induced by SARS-CoV-2 nucleocapsid protein.

Zhang Z, Ju C, Wu L, Yan H, Hong W, Chen H Cell Chem Biol. 2023; 30(3):261-277.e8.

PMID: 36889311 PMC: 9990178. DOI: 10.1016/j.chembiol.2023.02.004.

The Orphan GPR50 Receptor Regulates the Aggressiveness of Breast Cancer Stem-like Cells via Targeting the NF-kB Signaling Pathway.

Biswas P, Park S, An J, Lim K, Abdal Dayem A, Song K Int J Mol Sci. 2023; 24(3).

PMID: 36769125 PMC: 9917945. DOI: 10.3390/ijms24032804.

Advanced 3D dynamic culture system with transforming growth factor-β3 enhances production of potent extracellular vesicles with modified protein cargoes via upregulation of TGF-β signaling.

Lim K, Kim S, Yeom J, Choi Y, Lee Y, An J J Adv Res. 2022; 47:57-74.

PMID: 36130685 PMC: 10173176. DOI: 10.1016/j.jare.2022.09.005.

Thromboxane-Prostanoid Receptor Signaling Drives Persistent Fibroblast Activation in Pulmonary Fibrosis.

Suzuki T, Kropski J, Chen J, Carrier E, Chen X, Sherrill T Am J Respir Crit Care Med. 2022; 206(5):596-607.

PMID: 35728047 PMC: 9716913. DOI: 10.1164/rccm.202106-1503OC.

References

Sidibe A, Mullier A, Chen P, Baroncini M, Boutin J, Delagrange P . Expression of the orphan GPR50 protein in rodent and human dorsomedial hypothalamus, tanycytes and median eminence. J Pineal Res. 2010; 48(3):263-269. DOI: 10.1111/j.1600-079X.2010.00750.x. View

Chen Y, Liu F, Massague J . Mechanism of TGFbeta receptor inhibition by FKBP12. EMBO J. 1997; 16(13):3866-76. PMC: 1170011. DOI: 10.1093/emboj/16.13.3866. View

Mitra D, Luo X, Morgan A, Wang J, Hoang M, Lo J . An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background. Nature. 2012; 491(7424):449-53. PMC: 3521494. DOI: 10.1038/nature11624. View

Shi Y, Massague J . Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003; 113(6):685-700. DOI: 10.1016/s0092-8674(03)00432-x. View

Levoye A, Dam J, Ayoub M, Guillaume J, Jockers R . Do orphan G-protein-coupled receptors have ligand-independent functions? New insights from receptor heterodimers. EMBO Rep. 2006; 7(11):1094-8. PMC: 1679777. DOI: 10.1038/sj.embor.7400838. View

Wieser R, Wrana J, Massague J . GS domain mutations that constitutively activate T beta R-I, the downstream signaling component in the TGF-beta receptor complex. EMBO J. 1995; 14(10):2199-208. PMC: 398326. DOI: 10.1002/j.1460-2075.1995.tb07214.x. View

Bhattacharyya S, Luan J, Challis B, Keogh J, Montague C, Brennand J . Sequence variants in the melatonin-related receptor gene (GPR50) associate with circulating triglyceride and HDL levels. J Lipid Res. 2006; 47(4):761-6. DOI: 10.1194/jlr.M500338-JLR200. View

Massague J . TGFbeta in Cancer. Cell. 2008; 134(2):215-30. PMC: 3512574. DOI: 10.1016/j.cell.2008.07.001. View

Maurice P, Guillaume J, Benleulmi-Chaachoua A, Daulat A, Kamal M, Jockers R . GPCR-interacting proteins, major players of GPCR function. Adv Pharmacol. 2011; 62:349-80. DOI: 10.1016/B978-0-12-385952-5.00001-4. View

10.

Jockers R, Delagrange P, Dubocovich M, Markus R, Renault N, Tosini G . Update on melatonin receptors: IUPHAR Review 20. Br J Pharmacol. 2016; 173(18):2702-25. PMC: 4995287. DOI: 10.1111/bph.13536. View

11.

Prevot V, Cornea A, Mungenast A, Smiley G, Ojeda S . Activation of erbB-1 signaling in tanycytes of the median eminence stimulates transforming growth factor beta1 release via prostaglandin E2 production and induces cell plasticity. J Neurosci. 2003; 23(33):10622-32. PMC: 6740908. View

12.

Massague J . TGFβ signalling in context. Nat Rev Mol Cell Biol. 2012; 13(10):616-30. PMC: 4027049. DOI: 10.1038/nrm3434. View

13.

Watanabe Y, Itoh S, Goto T, Ohnishi E, Inamitsu M, Itoh F . TMEPAI, a transmembrane TGF-beta-inducible protein, sequesters Smad proteins from active participation in TGF-beta signaling. Mol Cell. 2010; 37(1):123-34. DOI: 10.1016/j.molcel.2009.10.028. View

14.

Wang T, Donahoe P, Zervos A . Specific interaction of type I receptors of the TGF-beta family with the immunophilin FKBP-12. Science. 1994; 265(5172):674-6. DOI: 10.1126/science.7518616. View

15.

Andre W, Nondier I, Valensi M, Guillonneau F, Federici C, Hoffner G . Identification of brain substrates of transglutaminase by functional proteomics supports its role in neurodegenerative diseases. Neurobiol Dis. 2017; 101:40-58. DOI: 10.1016/j.nbd.2017.01.007. View

16.

Larsson J, Goumans M, Sjostrand L, van Rooijen M, Ward D, Leveen P . Abnormal angiogenesis but intact hematopoietic potential in TGF-beta type I receptor-deficient mice. EMBO J. 2001; 20(7):1663-73. PMC: 145465. DOI: 10.1093/emboj/20.7.1663. View

17.

Ikushima H, Miyazono K . TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer. 2010; 10(6):415-24. DOI: 10.1038/nrc2853. View

18.

Zhang Y, Feng X, We R, Derynck R . Receptor-associated Mad homologues synergize as effectors of the TGF-beta response. Nature. 1996; 383(6596):168-72. DOI: 10.1038/383168a0. View

19.

Dufourny L, Levasseur A, Migaud M, Callebaut I, Pontarotti P, Malpaux B . GPR50 is the mammalian ortholog of Mel1c: evidence of rapid evolution in mammals. BMC Evol Biol. 2008; 8:105. PMC: 2323367. DOI: 10.1186/1471-2148-8-105. View

20.

Batailler M, Mullier A, Sidibe A, Delagrange P, Prevot V, Jockers R . Neuroanatomical distribution of the orphan GPR50 receptor in adult sheep and rodent brains. J Neuroendocrinol. 2012; 24(5):798-808. DOI: 10.1111/j.1365-2826.2012.02274.x. View