Tyrosine kinases compete for growth hormone receptor binding and regulate receptor mobility and degradation.

Autor:	Chhabra Y; Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia; The University of Queensland, Institute for Molecular Bioscience, St. Lucia, QLD 4072, Australia; Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21204, USA. Electronic address: ychhabr1@jhmi.edu., Seiffert P; Structural Biology and NMR Laboratory (SBiNLab) and REPIN, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark., Gormal RS; The Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia., Vullings M; The University of Queensland, Institute for Molecular Bioscience, St. Lucia, QLD 4072, Australia., Lee CMM; Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia., Wallis TP; The Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia., Dehkhoda F; Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia., Indrakumar S; Structural Biology and NMR Laboratory (SBiNLab) and REPIN, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark; Structural Biology and NMR Laboratory & Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen, Denmark., Jacobsen NL; Structural Biology and NMR Laboratory (SBiNLab) and REPIN, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark., Lindorff-Larsen K; Structural Biology and NMR Laboratory & Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen, Denmark., Durisic N; The Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia., Waters MJ; The University of Queensland, Institute for Molecular Bioscience, St. Lucia, QLD 4072, Australia., Meunier FA; The Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: f.meunier@uq.edu.au., Kragelund BB; Structural Biology and NMR Laboratory (SBiNLab) and REPIN, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark. Electronic address: bbk@bio.ku.dk., Brooks AJ; Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia; The University of Queensland, Institute for Molecular Bioscience, St. Lucia, QLD 4072, Australia. Electronic address: a.brooks@uq.edu.au.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 May 30; Vol. 42 (5), pp. 112490. Date of Electronic Publication: 2023 May 09.
DOI:	10.1016/j.celrep.2023.112490
Abstrakt:	Growth hormone (GH) acts via JAK2 and LYN to regulate growth, metabolism, and neural function. However, the relationship between these tyrosine kinases remains enigmatic. Through an interdisciplinary approach combining cell biology, structural biology, computation, and single-particle tracking on live cells, we find overlapping LYN and JAK2 Box1-Box2-binding regions in GH receptor (GHR). Our data implicate direct competition between JAK2 and LYN for GHR binding and imply divergent signaling profiles. We show that GHR exhibits distinct mobility states within the cell membrane and that activation of LYN by GH mediates GHR immobilization, thereby initiating its nanoclustering in the membrane. Importantly, we observe that LYN mediates cytokine receptor degradation, thereby controlling receptor turnover and activity, and this applies to related cytokine receptors. Our study offers insight into the molecular interactions of LYN with GHR and highlights important functions for LYN in regulating GHR nanoclustering, signaling, and degradation, traits broadly relevant to many cytokine receptors. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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