Tyrosine kinases compete for growth hormone receptor binding and regulate receptor mobility and degradation
Yash Chhabra,
Pernille Seiffert,
Rachel S. Gormal,
Manon Vullings,
Christine Mei Mei Lee,
Tristan P. Wallis,
Farhad Dehkhoda,
Sowmya Indrakumar,
Nina L. Jacobsen,
Kresten Lindorff-Larsen,
Nela Durisic,
Michael J. Waters,
Frédéric A. Meunier,
Birthe B. Kragelund,
Andrew J. Brooks
Affiliations
Yash Chhabra
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; Corresponding author
Pernille Seiffert
Structural Biology and NMR Laboratory (SBiNLab) and REPIN, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark
Rachel S. Gormal
The Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
Manon Vullings
The University of Queensland, Institute for Molecular Bioscience, St. Lucia, QLD 4072, Australia
Christine Mei Mei Lee
Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia
Tristan P. Wallis
The Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
Farhad Dehkhoda
Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia
Sowmya Indrakumar
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
Nina L. Jacobsen
Structural Biology and NMR Laboratory (SBiNLab) and REPIN, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark
Kresten Lindorff-Larsen
Structural Biology and NMR Laboratory & Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen, Denmark
Nela Durisic
The Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
Michael J. Waters
The University of Queensland, Institute for Molecular Bioscience, St. Lucia, QLD 4072, Australia
Frédéric A. Meunier
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; Corresponding author
Birthe B. Kragelund
Structural Biology and NMR Laboratory (SBiNLab) and REPIN, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark; Corresponding author
Andrew J. Brooks
Frazer Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia; The University of Queensland, Institute for Molecular Bioscience, St. Lucia, QLD 4072, Australia; Corresponding author
Summary: 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.
