TY - JOUR
T1 - Tyrosine kinases compete for growth hormone receptor binding and regulate receptor mobility and degradation
AU - Chhabra, Yash
AU - Seiffert, Pernille
AU - Gormal, Rachel S.
AU - Vullings, Manon
AU - Lee, Christine Mei Mei
AU - Wallis, Tristan P.
AU - Dehkhoda, Farhad
AU - Indrakumar, Sowmya
AU - Jacobsen, Nina L.
AU - Lindorff-Larsen, Kresten
AU - Durisic, Nela
AU - Waters, Michael J.
AU - Meunier, Frédéric A.
AU - Kragelund, Birthe B.
AU - Brooks, Andrew J.
N1 - 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.
Publisher Copyright:
© 2023
PY - 2023/5/30
Y1 - 2023/5/30
N2 - 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.
AB - 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.
KW - CP: Molecular biology
KW - ERK1/2
KW - IDPs
KW - JAK2
KW - LYN
KW - NMR
KW - box1-box2
KW - cytokine receptor
KW - integrative structural biology
KW - intrinsically disordered proteins
KW - nanoclusters
KW - nuclear magnetic resonance
KW - super-resolution microscopy
UR - http://www.scopus.com/inward/record.url?scp=85158001066&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85158001066&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2023.112490
DO - 10.1016/j.celrep.2023.112490
M3 - Article
C2 - 37163374
AN - SCOPUS:85158001066
SN - 2211-1247
VL - 42
JO - Cell Reports
JF - Cell Reports
IS - 5
M1 - 112490
ER -