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

doi:10.1016/j.celrep.2023.112490

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

Bloomberg School of Public Health

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Article number	112490
Journal	Cell Reports
Volume	42
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2023.112490
State	Published - May 30 2023

Keywords

CP: Molecular biology
ERK1/2
IDPs
JAK2
LYN
NMR
box1-box2
cytokine receptor
integrative structural biology
intrinsically disordered proteins
nanoclusters
nuclear magnetic resonance
super-resolution microscopy

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2023.112490

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Chhabra, Y., Seiffert, P., Gormal, R. S., Vullings, M., Lee, C. M. M., Wallis, T. P., Dehkhoda, F., Indrakumar, S., Jacobsen, N. L., Lindorff-Larsen, K., Durisic, N., Waters, M. J., Meunier, F. A., Kragelund, B. B., & Brooks, A. J. (2023). Tyrosine kinases compete for growth hormone receptor binding and regulate receptor mobility and degradation. Cell Reports, 42(5), Article 112490. https://doi.org/10.1016/j.celrep.2023.112490

Chhabra, Y, Seiffert, P, Gormal, RS, Vullings, M, Lee, CMM, Wallis, TP, Dehkhoda, F, Indrakumar, S, Jacobsen, NL, Lindorff-Larsen, K, Durisic, N, Waters, MJ, Meunier, FA, Kragelund, BB & Brooks, AJ 2023, 'Tyrosine kinases compete for growth hormone receptor binding and regulate receptor mobility and degradation', Cell Reports, vol. 42, no. 5, 112490. https://doi.org/10.1016/j.celrep.2023.112490

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title = "Tyrosine kinases compete for growth hormone receptor binding and regulate receptor mobility and degradation",

abstract = "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.",

keywords = "CP: Molecular biology, ERK1/2, IDPs, JAK2, LYN, NMR, box1-box2, cytokine receptor, integrative structural biology, intrinsically disordered proteins, nanoclusters, nuclear magnetic resonance, super-resolution microscopy",

author = "Yash Chhabra and Pernille Seiffert and Gormal, {Rachel S.} and Manon Vullings and Lee, {Christine Mei Mei} and Wallis, {Tristan P.} and Farhad Dehkhoda and Sowmya Indrakumar and Jacobsen, {Nina L.} and Kresten Lindorff-Larsen and Nela Durisic and Waters, {Michael J.} and Meunier, {Fr{\'e}d{\'e}ric A.} and Kragelund, {Birthe B.} and Brooks, {Andrew J.}",

note = "Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = may,

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doi = "10.1016/j.celrep.2023.112490",

language = "English (US)",

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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.

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.

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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

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JO - Cell Reports

JF - Cell Reports

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

Abstract

Keywords

ASJC Scopus subject areas

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