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.
Structural Biology and NMR Laboratory (SBiNLab) and REPIN, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.
Cell Rep. 2023 May 30;42(5):112490. doi: 10.1016/j.celrep.2023.112490. Epub 2023 May 9.
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.
生长激素（GH）通过 JAK2 和 LYN 发挥作用，调节生长、代谢和神经功能。然而，这些酪氨酸激酶之间的关系仍然扑朔迷离。通过结合细胞生物学、结构生物学、计算和活细胞上的单颗粒追踪的跨学科方法，我们在生长激素受体（GHR）中发现了重叠的 LYN 和 JAK2 Box1-Box2 结合区域。我们的数据表明 JAK2 和 LYN 直接竞争与 GHR 的结合，并暗示了不同的信号转导特征。我们表明 GHR 在细胞膜内表现出不同的流动性状态，并且 GH 对 LYN 的激活介导了 GHR 的固定化，从而启动其在膜中的纳米聚类。重要的是，我们观察到 LYN 介导细胞因子受体的降解，从而控制受体周转率和活性，这适用于相关的细胞因子受体。我们的研究提供了 LYN 与 GHR 分子相互作用的见解，并强调了 LYN 在调节 GHR 纳米聚类、信号转导和降解方面的重要功能，这些功能广泛适用于许多细胞因子受体。
