The apelin receptor (APLNR) regulates many biological processes including metabolism, angiogenesis, circulating blood volume and cardiovascular function. Additionally, APLNR is overexpressed in various types of cancer and influences cancer progression. APLNR is reported to regulate tumor recognition during immune surveillance by modulating the IFN-γ response. However, the mechanism of APLNR cross-talk with intratumoral IFN-γ signaling remains unknown. Here, we show that activation of APLNR up-regulates IFN-γ signaling in melanoma cells through APLNR mediated β-arrestin 1 but not β-arrestin 2 recruitment. Our data suggests that β-arrestin 1 directly interacts with STAT1 to inhibit STAT1 phosphorylation to attenuate IFN-γ signaling. The APLNR mutant receptor, I109A, which is deficient in β-arrestins recruitment, is unable to enhance intratumoral IFN-γ signaling. While APLNR N112G, a constitutively active mutant receptor, increases intratumoral sensitivity to IFN-γ signaling by enhancing STAT1 phosphorylation upon IFN-γ exposure. We also demonstrate in a co-culture system that APLNR regulates tumor survival rate. Taken together, our findings reveal that APLNR modulates IFN-γ signaling in melanoma cells and suggest that APLNR may be a potential target to enhance the efficacy of immunotherapy.
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February 2022
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Cover Image
Immunofluorescence staining of WT, IKKα KO, IKKβ KO and IKKα/β DKO HCT116 cells with anti-p65 NF-kB antibody (green); nuclei stained with DAPI (blue) by Jack Prescott. This figure demonstrates a critical role for IKKα in TNFα-induced p65 nuclear translocation with only a minor role for IKKβ.
Research Article|
February 11 2022
APLNR Regulates IFN-γ signaling via β-arrestin 1 mediated JAK-STAT1 pathway in melanoma cells
Yingying Liu;
Yingying Liu
*
Resources, Data curation, Formal analysis, Funding acquisition, Validation, Investigation, Methodology, Writing - original draft, Project administration, Writing - review & editing
1Amgen Research, Amgen Biopharmaceutical R&D (Shanghai) Co., Ltd, Shanghai 201210, China
2Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Cancer Institutes, Fudan University, Shanghai 200032, China
3ReCentrics Biotechnology Co., Ltd, Shanghai 201203, China
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Xiaochuan Ma;
Xiaochuan Ma
*
Conceptualization, Supervision, Methodology
1Amgen Research, Amgen Biopharmaceutical R&D (Shanghai) Co., Ltd, Shanghai 201210, China
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Hui Yang;
Hui Yang
Data curation, Methodology
1Amgen Research, Amgen Biopharmaceutical R&D (Shanghai) Co., Ltd, Shanghai 201210, China
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Xun Li;
Xun Li
Software
1Amgen Research, Amgen Biopharmaceutical R&D (Shanghai) Co., Ltd, Shanghai 201210, China
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Yingli Ma;
Yingli Ma
Project administration
1Amgen Research, Amgen Biopharmaceutical R&D (Shanghai) Co., Ltd, Shanghai 201210, China
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Brandon Ason;
Brandon Ason
Writing - review & editing
4Amgen Research, South San Francisco, CA, U.S.A
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Suling Liu;
2Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Cancer Institutes, Fudan University, Shanghai 200032, China
Correspondence: Liaoyuan A. Hu (liaoyuanhu@recentrics.com) or Suling Liu (suling@fudan.edu.cn)
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Liaoyuan A. Hu
1Amgen Research, Amgen Biopharmaceutical R&D (Shanghai) Co., Ltd, Shanghai 201210, China
3ReCentrics Biotechnology Co., Ltd, Shanghai 201203, China
Correspondence: Liaoyuan A. Hu (liaoyuanhu@recentrics.com) or Suling Liu (suling@fudan.edu.cn)
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Publisher: Portland Press Ltd
Received:
November 30 2021
Revision Received:
January 17 2022
Accepted:
January 27 2022
Accepted Manuscript online:
January 27 2022
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2022
Biochem J (2022) 479 (3): 385–399.
Article history
Received:
November 30 2021
Revision Received:
January 17 2022
Accepted:
January 27 2022
Accepted Manuscript online:
January 27 2022
Citation
Yingying Liu, Xiaochuan Ma, Hui Yang, Xun Li, Yingli Ma, Brandon Ason, Suling Liu, Liaoyuan A. Hu; APLNR Regulates IFN-γ signaling via β-arrestin 1 mediated JAK-STAT1 pathway in melanoma cells. Biochem J 11 February 2022; 479 (3): 385–399. doi: https://doi.org/10.1042/BCJ20210813
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