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JAK2 activation by growth hormone and other cytokines.

Waters MJ, Brooks AJ - Biochem. J. (2015)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: *Institute for Molecular Bioscience, The University of Queensland Institute, QLD 4072, Australia.

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.

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Related in: MedlinePlus

Growth hormone and the growth hormone receptorCrystal structure of the growth hormone and the growth hormone receptor extracellular domain with illustration representing the extracellular juxtamembrane linker, transmembrane domain, intracellular domain and Box1 motif. The growth hormone high affinity site 1 and lower affinity site 2 which are supplemented by receptor–receptor binding in the lower FNIII dimerization domain (site 3) are indicated.
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Figure 2: Growth hormone and the growth hormone receptorCrystal structure of the growth hormone and the growth hormone receptor extracellular domain with illustration representing the extracellular juxtamembrane linker, transmembrane domain, intracellular domain and Box1 motif. The growth hormone high affinity site 1 and lower affinity site 2 which are supplemented by receptor–receptor binding in the lower FNIII dimerization domain (site 3) are indicated.

Mentions: The ligand-induced receptor association model stemmed from key publications by Genentech researchers who showed that the ECD of the GH receptor could be dimerized by GH both in solution [17,35] and in a crystal complex with GH [14]. Such dimerization was proposed to induce proximity of the associated JAK2s, hence their trans-activation and signal initiation. This model was supported by studies showing that 3 of 3 monoclonal antibodies (MAbs) to the ECD of the GH receptor acted as agonists, but only when bivalent [36], and by the bell-shaped dose–response curve which was explained by an inability of occupied receptors to dimerize if all of the receptors were taken in hormone site 1 interactions. Together with data showing that hindering of binding to the second receptor through substituting a bulky residue at Gly-120 in GH Helix 3 (i.e. in site 2; see Figure 2) resulted in an effective antagonist, the evidence for hormone-induced dimerization for this archetypal cytokine receptor appeared definitive. However, the cell line used for both experiments expressed a hybrid receptor consisting of the ECD of the human GH receptor fused to the N-terminal FNIII domain of the G-CSF receptor, so that the signalling which was observed was that of the G-CSF receptor, with receptor dimer formation likely to be influenced by its additional FNIII domains.


JAK2 activation by growth hormone and other cytokines.

Waters MJ, Brooks AJ - Biochem. J. (2015)

Growth hormone and the growth hormone receptorCrystal structure of the growth hormone and the growth hormone receptor extracellular domain with illustration representing the extracellular juxtamembrane linker, transmembrane domain, intracellular domain and Box1 motif. The growth hormone high affinity site 1 and lower affinity site 2 which are supplemented by receptor–receptor binding in the lower FNIII dimerization domain (site 3) are indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4325515&req=5

Figure 2: Growth hormone and the growth hormone receptorCrystal structure of the growth hormone and the growth hormone receptor extracellular domain with illustration representing the extracellular juxtamembrane linker, transmembrane domain, intracellular domain and Box1 motif. The growth hormone high affinity site 1 and lower affinity site 2 which are supplemented by receptor–receptor binding in the lower FNIII dimerization domain (site 3) are indicated.
Mentions: The ligand-induced receptor association model stemmed from key publications by Genentech researchers who showed that the ECD of the GH receptor could be dimerized by GH both in solution [17,35] and in a crystal complex with GH [14]. Such dimerization was proposed to induce proximity of the associated JAK2s, hence their trans-activation and signal initiation. This model was supported by studies showing that 3 of 3 monoclonal antibodies (MAbs) to the ECD of the GH receptor acted as agonists, but only when bivalent [36], and by the bell-shaped dose–response curve which was explained by an inability of occupied receptors to dimerize if all of the receptors were taken in hormone site 1 interactions. Together with data showing that hindering of binding to the second receptor through substituting a bulky residue at Gly-120 in GH Helix 3 (i.e. in site 2; see Figure 2) resulted in an effective antagonist, the evidence for hormone-induced dimerization for this archetypal cytokine receptor appeared definitive. However, the cell line used for both experiments expressed a hybrid receptor consisting of the ECD of the human GH receptor fused to the N-terminal FNIII domain of the G-CSF receptor, so that the signalling which was observed was that of the G-CSF receptor, with receptor dimer formation likely to be influenced by its additional FNIII domains.

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: *Institute for Molecular Bioscience, The University of Queensland Institute, QLD 4072, Australia.

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.

Show MeSH
Related in: MedlinePlus