Rewriting the mechanism of JAK2 activation

Class I cytokine receptors regulate a wide range of clinically relevant cellular processes. This family of receptors contains around 30 members including receptors for erythropoietin (EPO), prolactin (PRL), growth hormone (GH), thrombopoietin (TPO), granulocyte-macrophage colony-stimulating factor (GM-CSF), leukemia inhibitory factor (LIF), interleukin-3 (IL-3), IL-5, and IL-6.¹ The growth hormone receptor has been the archetype for the class I cytokine receptor family, as it was the first to be both cloned and have its extracellular domain crystal structure solved. The original paradigm for the mechanism of activation was based on biophysical and structural studies over 20 y ago showing that growth hormone binding to the extracellular domain of the receptor occurred in a sequential fashion, first binding to a high affinity site on a single receptor (site 1) and then binding to a lower affinity site (site 2) on a second receptor.² The subsequent publication of the crystal structure showed a single hormone bound to 2 receptor domains at the site 1 and site 2 positions, and also revealed the lower fibronectin III domain of the receptor locked together (site 3 or dimerization domain).³ The conclusion from these studies was that hormone binding induced dimerization of the receptor and that this would bring the intracellular signaling domains together to allow association and activation of the associated janus kinases (JAKs). However, despite great progress in elucidating the structural details of ligand binding to the extracellular domain of receptors for several members of this family, the means by which these receptors activate their associated JAKs to initiate signaling had remained elusive. The original ligand-mediated activation model was undermined by several lines of evidence, particularly by studies showing that the GH receptor and other related receptors such as the PRL, EPO, and TPO receptors exist predominantly as dimers prior to ligand binding.⁴ The question remained as to how ligand binding was able to transmit its signal through the transmembrane domain and to the intracellular domain of the pre-dimerized receptors to activate the associated kinases. Our group embarked on studies to unravel this mechanism, and recently were able to present the first complete mechanistic model of JAK2 activation by an archetypal class I cytokine receptor, the growth hormone receptor.⁵