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

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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.
OriginalsprogEngelsk
Artikelnummer112490
TidsskriftCell Reports
Vol/bind42
Udgave nummer5
Antal sider26
ISSN2211-1247
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
The work was supported by NHMRC Australia APP1157348 to A.J.B. and APP1084797 to A.J.B. and M.J.W. The Novo Nordisk Foundation Challenge program Rethinking Protein Interactions ( REPIN ; grant #NNF18OC0033926 to B.B.K.) and the Lundbeck Foundation BRAINSTRUC initiative (to K.L.L. and B.B.K.). We thank Signe A. Sjørup for skilled technical assistance, and Yong Wang for assistance with molecular simulations. F.A.M. is supported by an NHMRC Fellowship ( GNT1155794 ) and an Australian Research Council Discovery Project ( DP190100674 ). This work involved research that was carried out at the Translational Research Institute, Woolloongabba , QLD 4102 , Australia. The Translational Research Institute (TRI) is supported by a grant from the Australian Government. We thank that assistance of the TRI Flow Cytometry Suite.

Funding Information:
The work was supported by NHMRC Australia APP1157348 to A.J.B. and APP1084797 to A.J.B. and M.J.W. The Novo Nordisk Foundation Challenge program Rethinking Protein Interactions (REPIN; grant #NNF18OC0033926 to B.B.K.) and the Lundbeck Foundation BRAINSTRUC initiative (to K.L.L. and B.B.K.). We thank Signe A. Sjørup for skilled technical assistance, and Yong Wang for assistance with molecular simulations. F.A.M. is supported by an NHMRC Fellowship (GNT1155794) and an Australian Research Council Discovery Project (DP190100674). This work involved research that was carried out at the Translational Research Institute, Woolloongabba, QLD 4102, Australia. The Translational Research Institute (TRI) is supported by a grant from the Australian Government. We thank that assistance of the TRI Flow Cytometry Suite. Y.C. A.J.B. B.B.K. and M.J.W. conceived the study. Y.C. P.S. F.A.M. B.B.K. M.J.W. and A.J.B. designed the project and experiments. Y.C. P.S. M.V. and F.D. generated constructs. Y.C. established cell lines. Y.C. P.S. R.S.G. C.M.M.L. S.I. and N.L.J. acquired the data. Y.C. P.S. R.S.G. S.I. K.L.L. T.P.W. F.A.S. N.D. B.B.K. and A.J.B. analyzed and interpreted the data. Y.C. P.S. R.S.G. F.A.M. M.J.W. B.B.K. and A.J.B. contributed to writing and review of the manuscript. The authors declare no competing interests.

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© 2023

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