TY - JOUR
T1 - GPR101 drives growth hormone hypersecretion and gigantism in mice via constitutive activation of Gs and Gq/11
AU - Abboud, Dayana
AU - Daly, Adrian F.
AU - Dupuis, Nadine
AU - Bahri, Mohamed Ali
AU - Inoue, Asuka
AU - Chevigné, Andy
AU - Ectors, Fabien
AU - Plenevaux, Alain
AU - Pirotte, Bernard
AU - Beckers, Albert
AU - Hanson, Julien
N1 - Funding Information:
This work was supported by the Fonds pour la Recherche Scientifique (F.R.S.-FNRS) Incentive Grant for Scientific Research (F.4510.14) and Research Project (PDR T.0111.19), Télévie (7461117 F, 7454719 F), University of Liège (Action de Recherche Concertée ARC 17/21-01), and Léon Fredericq Foundation. D.A. was supported by a postdoctoral In WBI fellowship and is a Télévie fellow. J.H. and A.P. are F.R.S.-FNRS Research Associate and Research Director, respectively. N.D. was supported by a FRIA PhD fellowship. A.I. was funded by the PRIME (JP18gm5910013) and the LEAP (JP18gm0010004) from the Japan Agency for Medical Research and Development (AMED); JSPS KAKENHI grant (17K08264) from Japan Society for the Promotion of Science. A.F.D. and A.B. were supported by grants (to AB) from the Fonds d’Inves-tissement Pour la Recherche Scientifique (FIRS) of the Centre Hospitalier Universitaire de Liège and from the JABBS Foundation, UK. A.C. was supported by the Luxembourg Institute of Health (LIH) and Luxembourg National Research Fund (PRIDE-11012546 "NextImmune). J.H. and A.C. are members of the “European Research Network on Signal Transduction” (ERNEST, COST action CA18133). We thank the GIGA imaging platform for the technical support in confocal image acquisition and FACS analysis, the Histology platform for tissue preparation, the animal facility, the GIGA Transgenics platform as well as the GIGA-CRC in vivo Imaging platform.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Growth hormone (GH) is a key modulator of growth and GH over-secretion can lead to gigantism. One form is X-linked acrogigantism (X-LAG), in which infants develop GH-secreting pituitary tumors over-expressing the orphan G-protein coupled receptor, GPR101. The role of GPR101 in GH secretion remains obscure. We studied GPR101 signaling pathways and their effects in HEK293 and rat pituitary GH3 cell lines, human tumors and in transgenic mice with elevated somatotrope Gpr101 expression driven by the rat Ghrhr promoter (GhrhrGpr101). Here, we report that Gpr101 causes elevated GH/prolactin secretion in transgenic GhrhrGpr101 mice but without hyperplasia/tumorigenesis. We show that GPR101 constitutively activates not only Gs, but also Gq/11 and G12/13, which leads to GH secretion but not proliferation. These signatures of GPR101 signaling, notably PKC activation, are also present in human pituitary tumors with high GPR101 expression. These results underline a role for GPR101 in the regulation of somatotrope axis function.
AB - Growth hormone (GH) is a key modulator of growth and GH over-secretion can lead to gigantism. One form is X-linked acrogigantism (X-LAG), in which infants develop GH-secreting pituitary tumors over-expressing the orphan G-protein coupled receptor, GPR101. The role of GPR101 in GH secretion remains obscure. We studied GPR101 signaling pathways and their effects in HEK293 and rat pituitary GH3 cell lines, human tumors and in transgenic mice with elevated somatotrope Gpr101 expression driven by the rat Ghrhr promoter (GhrhrGpr101). Here, we report that Gpr101 causes elevated GH/prolactin secretion in transgenic GhrhrGpr101 mice but without hyperplasia/tumorigenesis. We show that GPR101 constitutively activates not only Gs, but also Gq/11 and G12/13, which leads to GH secretion but not proliferation. These signatures of GPR101 signaling, notably PKC activation, are also present in human pituitary tumors with high GPR101 expression. These results underline a role for GPR101 in the regulation of somatotrope axis function.
UR - http://www.scopus.com/inward/record.url?scp=85091306229&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-18500-x
DO - 10.1038/s41467-020-18500-x
M3 - Article
C2 - 32958754
AN - SCOPUS:85091306229
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4752
ER -