Limits...
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.

Show MeSH

Related in: MedlinePlus

Domain structure of Class I cytokine receptorsDomain structures depicted for the homomeric signalling receptors, and examples of heteromeric receptors that interact with the shared γc, gp130, βc and LIF-R (LIFR).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4325515&req=5

Figure 1: Domain structure of Class I cytokine receptorsDomain structures depicted for the homomeric signalling receptors, and examples of heteromeric receptors that interact with the shared γc, gp130, βc and LIF-R (LIFR).

Mentions: Before reviewing the receptor activation mechanism, a summary of class I cytokine receptor structure is necessary (Figure 1). As first shown for the GH receptor, these receptors are single pass transmembrane receptors with an extracellular domain (ECD) structure containing at least one cytokine receptor homology (CRH) domain which possesses two fibronectin III-like (FNIII) domains, each with an immunoglobulin-like β sandwich domain with seven strands in two layers [11]. The membrane proximal domain contains a WSxWS motif (YGeFS in the GH receptor) creating an aromatic stack which appears to be necessary for expression and stability [12]. Additional immunoglobulin or FNIII domains are present in many of these receptors [13], but the GH [14], prolactin [15] and EPO receptor [16] set of homomeric receptors, with just one CRH domain, is the simplest of these, and therefore most tractable for understanding the activation mechanism. In this case, the ligand/hormone has two asymmetrically placed binding sites, a high affinity site 1 and a lower affinity site 2 surface which are supplemented by receptor–receptor binding in the lower FNIII domain (site 3) upon binding of the ligand [17–20]. This is particularly evident in the GH receptor, and studies have shown that site 3 interaction is essential for signal transmission [21,22]. A second major feature of this receptor class is the proline rich Box1 motif, which together with the less-conserved distal Box2 sequence of aromatic and acidic residues serves to bind the JAK2 close to the inner cell membrane [23–27]. Recent NMR studies show that below this the cytoplasmic domains of the GH and prolactin receptors at least are essentially unstructured, with some transient alpha helix formation (unpublished data). This is concordant with the role of this domain in recruiting SH2 domain signalling proteins and the need for the relevant tyrosine residues to reach up to the JAK2 for phosphorylation.


JAK2 activation by growth hormone and other cytokines.

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

Domain structure of Class I cytokine receptorsDomain structures depicted for the homomeric signalling receptors, and examples of heteromeric receptors that interact with the shared γc, gp130, βc and LIF-R (LIFR).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Domain structure of Class I cytokine receptorsDomain structures depicted for the homomeric signalling receptors, and examples of heteromeric receptors that interact with the shared γc, gp130, βc and LIF-R (LIFR).
Mentions: Before reviewing the receptor activation mechanism, a summary of class I cytokine receptor structure is necessary (Figure 1). As first shown for the GH receptor, these receptors are single pass transmembrane receptors with an extracellular domain (ECD) structure containing at least one cytokine receptor homology (CRH) domain which possesses two fibronectin III-like (FNIII) domains, each with an immunoglobulin-like β sandwich domain with seven strands in two layers [11]. The membrane proximal domain contains a WSxWS motif (YGeFS in the GH receptor) creating an aromatic stack which appears to be necessary for expression and stability [12]. Additional immunoglobulin or FNIII domains are present in many of these receptors [13], but the GH [14], prolactin [15] and EPO receptor [16] set of homomeric receptors, with just one CRH domain, is the simplest of these, and therefore most tractable for understanding the activation mechanism. In this case, the ligand/hormone has two asymmetrically placed binding sites, a high affinity site 1 and a lower affinity site 2 surface which are supplemented by receptor–receptor binding in the lower FNIII domain (site 3) upon binding of the ligand [17–20]. This is particularly evident in the GH receptor, and studies have shown that site 3 interaction is essential for signal transmission [21,22]. A second major feature of this receptor class is the proline rich Box1 motif, which together with the less-conserved distal Box2 sequence of aromatic and acidic residues serves to bind the JAK2 close to the inner cell membrane [23–27]. Recent NMR studies show that below this the cytoplasmic domains of the GH and prolactin receptors at least are essentially unstructured, with some transient alpha helix formation (unpublished data). This is concordant with the role of this domain in recruiting SH2 domain signalling proteins and the need for the relevant tyrosine residues to reach up to the JAK2 for phosphorylation.

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