A growth hormone receptor SNP promotes lung cancer by impairment of SOCS2-mediated degradation

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

A growth hormone receptor SNP promotes lung cancer by impairment of SOCS2-mediated degradation. / Chhabra, Y.; Wong, H. Y.; Nikolajsen, Louise Fletcher; Steinocher, Helena; Papadopulos, A.; Tunny, K. A.; Meunier, F. A.; Smith, A. G.; Kragelund, Birthe Brandt; Brooks, A. J.; Waters, M. J.

In: Oncogene, Vol. 37, 2018, p. 489-501.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Chhabra, Y, Wong, HY, Nikolajsen, LF, Steinocher, H, Papadopulos, A, Tunny, KA, Meunier, FA, Smith, AG, Kragelund, BB, Brooks, AJ & Waters, MJ 2018, 'A growth hormone receptor SNP promotes lung cancer by impairment of SOCS2-mediated degradation', Oncogene, vol. 37, pp. 489-501. https://doi.org/10.1038/onc.2017.352

APA

Chhabra, Y., Wong, H. Y., Nikolajsen, L. F., Steinocher, H., Papadopulos, A., Tunny, K. A., Meunier, F. A., Smith, A. G., Kragelund, B. B., Brooks, A. J., & Waters, M. J. (2018). A growth hormone receptor SNP promotes lung cancer by impairment of SOCS2-mediated degradation. Oncogene, 37, 489-501. https://doi.org/10.1038/onc.2017.352

Vancouver

Chhabra Y, Wong HY, Nikolajsen LF, Steinocher H, Papadopulos A, Tunny KA et al. A growth hormone receptor SNP promotes lung cancer by impairment of SOCS2-mediated degradation. Oncogene. 2018;37:489-501. https://doi.org/10.1038/onc.2017.352

Author

Chhabra, Y. ; Wong, H. Y. ; Nikolajsen, Louise Fletcher ; Steinocher, Helena ; Papadopulos, A. ; Tunny, K. A. ; Meunier, F. A. ; Smith, A. G. ; Kragelund, Birthe Brandt ; Brooks, A. J. ; Waters, M. J. / A growth hormone receptor SNP promotes lung cancer by impairment of SOCS2-mediated degradation. In: Oncogene. 2018 ; Vol. 37. pp. 489-501.

Bibtex

@article{a1fe8416fed849b2a14fe4c083c4494b,
title = "A growth hormone receptor SNP promotes lung cancer by impairment of SOCS2-mediated degradation",
abstract = "Both humans and mice lacking functional growth hormone (GH) receptors are known to be resistant to cancer. Further, autocrine GH has been reported to act as a cancer promoter. Here we present the first example of a variant of the GH receptor (GHR) associated with cancer promotion, in this case lung cancer. We show that the GHRP495T variant located in the receptor intracellular domain is able to prolong the GH signal in vitro using stably expressing mouse pro-B-cell and human lung cell lines. This is relevant because GH secretion is pulsatile, and extending the signal duration makes it resemble autocrine GH action. Signal duration for the activated GHR is primarily controlled by suppressor of cytokine signalling 2 (SOCS2), the substrate recognition component of the E3 protein ligase responsible for ubiquitinylation and degradation of the GHR. SOCS2 is induced by a GH pulse and we show that SOCS2 binding to the GHR is impaired by a threonine substitution at Pro 495. This results in decreased internalisation and degradation of the receptor evident in TIRF microscopy and by measurement of mature (surface) receptor expression. Mutational analysis showed that the residue at position 495 impairs SOCS2 binding only when a threonine is present, consistent with interference with the adjacent Thr494. The latter is key for SOCS2 binding, together with nearby Tyr487, which must be phosphorylated for SOCS2 binding. We also undertook nuclear magnetic resonance spectroscopy approach for structural comparison of the SOCS2 binding scaffold Ile455-Ser588, and concluded that this single substitution has altered the structure of the SOCS2 binding site. Importantly, we find that lung BEAS-2B cells expressing GHRP495T display increased expression of transcripts associated with tumour proliferation, epithelial-mesenchymal transition and metastases (TWIST1, SNAI2, EGFR, MYC and CCND1) at 2 h after a GH pulse. This is consistent with prolonged GH signalling acting to promote cancer progression in lung cancer.Oncogene advance online publication, 2 October 2017; doi:10.1038/onc.2017.352.",
keywords = "Journal Article",
author = "Y. Chhabra and Wong, {H. Y.} and Nikolajsen, {Louise Fletcher} and Helena Steinocher and A. Papadopulos and Tunny, {K. A.} and Meunier, {F. A.} and Smith, {A. G.} and Kragelund, {Birthe Brandt} and Brooks, {A. J.} and Waters, {M. J.}",
year = "2018",
doi = "10.1038/onc.2017.352",
language = "English",
volume = "37",
pages = "489--501",
journal = "Oncogene",
issn = "0950-9232",
publisher = "nature publishing group",

}

RIS

TY - JOUR

T1 - A growth hormone receptor SNP promotes lung cancer by impairment of SOCS2-mediated degradation

AU - Chhabra, Y.

AU - Wong, H. Y.

AU - Nikolajsen, Louise Fletcher

AU - Steinocher, Helena

AU - Papadopulos, A.

AU - Tunny, K. A.

AU - Meunier, F. A.

AU - Smith, A. G.

AU - Kragelund, Birthe Brandt

AU - Brooks, A. J.

AU - Waters, M. J.

PY - 2018

Y1 - 2018

N2 - Both humans and mice lacking functional growth hormone (GH) receptors are known to be resistant to cancer. Further, autocrine GH has been reported to act as a cancer promoter. Here we present the first example of a variant of the GH receptor (GHR) associated with cancer promotion, in this case lung cancer. We show that the GHRP495T variant located in the receptor intracellular domain is able to prolong the GH signal in vitro using stably expressing mouse pro-B-cell and human lung cell lines. This is relevant because GH secretion is pulsatile, and extending the signal duration makes it resemble autocrine GH action. Signal duration for the activated GHR is primarily controlled by suppressor of cytokine signalling 2 (SOCS2), the substrate recognition component of the E3 protein ligase responsible for ubiquitinylation and degradation of the GHR. SOCS2 is induced by a GH pulse and we show that SOCS2 binding to the GHR is impaired by a threonine substitution at Pro 495. This results in decreased internalisation and degradation of the receptor evident in TIRF microscopy and by measurement of mature (surface) receptor expression. Mutational analysis showed that the residue at position 495 impairs SOCS2 binding only when a threonine is present, consistent with interference with the adjacent Thr494. The latter is key for SOCS2 binding, together with nearby Tyr487, which must be phosphorylated for SOCS2 binding. We also undertook nuclear magnetic resonance spectroscopy approach for structural comparison of the SOCS2 binding scaffold Ile455-Ser588, and concluded that this single substitution has altered the structure of the SOCS2 binding site. Importantly, we find that lung BEAS-2B cells expressing GHRP495T display increased expression of transcripts associated with tumour proliferation, epithelial-mesenchymal transition and metastases (TWIST1, SNAI2, EGFR, MYC and CCND1) at 2 h after a GH pulse. This is consistent with prolonged GH signalling acting to promote cancer progression in lung cancer.Oncogene advance online publication, 2 October 2017; doi:10.1038/onc.2017.352.

AB - Both humans and mice lacking functional growth hormone (GH) receptors are known to be resistant to cancer. Further, autocrine GH has been reported to act as a cancer promoter. Here we present the first example of a variant of the GH receptor (GHR) associated with cancer promotion, in this case lung cancer. We show that the GHRP495T variant located in the receptor intracellular domain is able to prolong the GH signal in vitro using stably expressing mouse pro-B-cell and human lung cell lines. This is relevant because GH secretion is pulsatile, and extending the signal duration makes it resemble autocrine GH action. Signal duration for the activated GHR is primarily controlled by suppressor of cytokine signalling 2 (SOCS2), the substrate recognition component of the E3 protein ligase responsible for ubiquitinylation and degradation of the GHR. SOCS2 is induced by a GH pulse and we show that SOCS2 binding to the GHR is impaired by a threonine substitution at Pro 495. This results in decreased internalisation and degradation of the receptor evident in TIRF microscopy and by measurement of mature (surface) receptor expression. Mutational analysis showed that the residue at position 495 impairs SOCS2 binding only when a threonine is present, consistent with interference with the adjacent Thr494. The latter is key for SOCS2 binding, together with nearby Tyr487, which must be phosphorylated for SOCS2 binding. We also undertook nuclear magnetic resonance spectroscopy approach for structural comparison of the SOCS2 binding scaffold Ile455-Ser588, and concluded that this single substitution has altered the structure of the SOCS2 binding site. Importantly, we find that lung BEAS-2B cells expressing GHRP495T display increased expression of transcripts associated with tumour proliferation, epithelial-mesenchymal transition and metastases (TWIST1, SNAI2, EGFR, MYC and CCND1) at 2 h after a GH pulse. This is consistent with prolonged GH signalling acting to promote cancer progression in lung cancer.Oncogene advance online publication, 2 October 2017; doi:10.1038/onc.2017.352.

KW - Journal Article

U2 - 10.1038/onc.2017.352

DO - 10.1038/onc.2017.352

M3 - Journal article

C2 - 28967904

VL - 37

SP - 489

EP - 501

JO - Oncogene

JF - Oncogene

SN - 0950-9232

ER -

ID: 188260827