title: JAK2 activation by growth hormone and other cytokines.
abstract: Growth hormone (GH) and structurally related cytokines regulate a great number of physiological and pathological processes. They do this by coupling their single transmembrane domain (TMD) receptors to cytoplasmic tyrosine kinases, either as homodimers or heterodimers. Recent studies have revealed that many of these receptors exist as constitutive dimers rather than being dimerized as a consequence of ligand binding, which has necessitated a new paradigm for describing their activation process. In the present study, we describe a model for activation of the tyrosine kinase Janus kinase 2 (JAK2) by the GH receptor homodimer based on biochemical data and molecular dynamics simulations. Binding of the bivalent ligand reorientates and rotates the receptor subunits, resulting in a transition from a form with parallel TMDs to one where the TMDs separate at the point of entry into the cytoplasm. This movement slides the pseudokinase inhibitory domain of one JAK kinase away from the kinase domain of the other JAK within the receptor dimer-JAK complex, allowing the two kinase domains to interact and trans-activate. This results in phosphorylation and activation of STATs and other signalling pathways linked to this receptor which then regulate postnatal growth, metabolism and stem cell activation. We believe that this model will apply to most if not all members of the class I cytokine receptor family, and will be useful in the design of small antagonists and agonists of therapeutic value.
authors: *Institute for Molecular Bioscience, The University of Queensland Institute, QLD 4072, Australia.
authors: Michael J
authors: MJ
authors: Waters
authors: *Institute for Molecular Bioscience, The University of Queensland Institute, QLD 4072, Australia.
authors: Andrew J
authors: AJ
authors: Brooks
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D013006:Growth Hormone / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D020239:Receptor Cross-Talk; D018121:Receptors, Cytokine / Q000235:genetics* / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D018121:Receptors, Cytokine; D011986:Receptors, Somatotropin; D013006:Growth Hormone; C507924:JAK2 protein, human; D053614:Janus Kinase 2
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