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

Research output: Contribution to journalArticlepeer-review


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 languageEnglish (US)
Article number112490
JournalCell Reports
Issue number5
StatePublished - May 30 2023


  • 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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