Mechanism of Activation of Protein Kinase JAK2 by the Growth Hormone Receptor

  title={Mechanism of Activation of Protein Kinase JAK2 by the Growth Hormone Receptor},
  author={Andrew J. Brooks and Wei Dai and Megan L. O’Mara and Daniel Abankwa and Yash Chhabra and Rebecca A. Pelekanos and Olivier Gardon and Kathryn A. Tunny and Kristopher M. Blucher and Craig J. Morton and Michael W. Parker and Emma Sierecki and Yann Gambin and Guillermo A. Gomez and Kirill Alexandrov and Ian A. Wilson and Manolis Doxastakis and Alan E. Mark and Michael J. Waters},
Introduction Class I cytokines regulate key processes such as growth, lactation, hematopoiesis, and immune function and contribute to oncogenesis. Although the extracellular domain structures of their receptors are well characterized, little is known about how the receptors activate their associated JAK (Janus kinase) protein kinases. We provide a mechanistic description for this process, focusing on the growth hormone (GH) receptor and its associated JAK2. Receptor-JAK2 activation process… 

JAK2 activation by growth hormone and other cytokines

This study describes 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 and believes 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.

Rewriting the mechanism of JAK2 activation

The first complete mechanistic model of JAK2 activation by an archetypal class I cytokine receptor, the growth hormone receptor, is presented and it is confirmed that the GH receptor exists as a preformed dimer in vivo by using confocal microscopy anisotropy analysis at the surface of live mammalian cells.

A new mechanism for growth hormone receptor activation of JAK2, and implications for related cytokine receptors

Progress in understanding the activation mechanism of the growth hormone receptor is reviewed, in particular the molecular movements made by this constitutively dimerized receptor in response to ligand binding, and how these lead to a separation of JAK-binding Box1 motifs.

Mechanistic Insights into Regulation of JAK2 Tyrosine Kinase

The molecular mechanisms that maintain the basal, low-activity state of JAKs and that, via mutation, lead to constitutive activity and disease are examined to potentially inform drug development efforts aimed at obtaining a mutant (V617F)-selective inhibitor of J AK2.

The molecular regulation of Janus kinase (JAK) activation.

The JAK (Janus kinase) family members serve essential roles as the intracellular signalling effectors of cytokine receptors, and the current knowledge of their physiological functions and the causative role of activating and inactivating JAK mutations in human diseases is reviewed.

The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects

This review covers the molecular mechanisms of GHR activation and signal transduction as well as the physiological consequences of growth hormone signaling, which plays a significant role in cancer development and aging.

Receptor-mediated dimerization of JAK2 FERM domains is required for JAK2 activation

Two crystal structures of the human JAK2 FERM and SH2 domains bound to Leptin receptor and Erythropoietin receptor are presented, which identify a novel dimeric conformation for Jak2.

The growth hormone receptor.

  • M. Waters
  • Biology
    Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society
  • 2016

Fos-Zippered GH Receptor Cytosolic Tails Act as Jak2 Substrates and Signal Transducers.

Analysis by blue-native gel electrophoresis revealed high molecular-weight complexes containing both Jak2 and nonphosphorylated GHR tails, whereas Jak2-dissociated tails were highly phosphorylated and monomeric, implying that Jak2 detaches from its substrate upon phosphorylation.



Janus kinase 2 determinants for growth hormone receptor association, surface assembly, and signaling.

Evidence is reported for the existence of a novel GH-inducible functional interaction between JAK2 molecules that may be important in the mechanism of GH-triggered JAK1 signaling and the results suggest that FERM motifs play an important role in the interaction of GHR andJAK2.

Model for growth hormone receptor activation based on subunit rotation within a receptor dimer

It is shown that there is no substantial change in the crystal structure of the liganded and unliganded human GHR extracellular domain, and an activation mechanism involving a relative rotation of subunits within a dimeric receptor as a result of asymmetric placement of the receptor-binding sites on the ligand is proposed.

The Role of Receptor Dimerization Domain Residues in Growth Hormone Signaling*

It is concluded that serine 145, histidine 150, aspartate 152, tyrosine 200, and serine 201, but not leucine 146 or threonine 147 are required for effective signal transduction through the dimerization domain.

The growth hormone receptor: mechanism of activation and clinical implications

A model in which the growth hormone receptor exists as a constitutive dimer is discussed in the light of salient information from closely related class 1 cytokine receptors, such as the erythropoietin, prolactin and thrombopOietin receptors.

Ligand-independent growth hormone receptor dimerization occurs in the endoplasmic reticulum and is required for ubiquitin system-dependent endocytosis

It is postulate that dimerization of GHR molecules is required for ubiquitin system-dependent endocytosis, and evidence is provided that the extracellular domain of the GHR is not required to maintain this interaction.

Jak2 FERM Domain Interaction with the Erythropoietin Receptor Regulates Jak2 Kinase Activity

The properties of the Jak2-Y613E mutant suggest that under normal conditions, Jak2 that is not associated with a receptor is locked into an inactive state and receptor binding through the FERM domain relieves steric constraints, allowing the potential to be activated with receptor engagement.

The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor.

A structural basis of high-affinity JAK-specific inhibition that will undoubtedly provide an invaluable tool for the further design of novel, potent, and specific therapeutics against the JAK family is presented.

Spatio-temporal kinetics of growth hormone receptor signaling in single cells using FRET microscopy.

Dimerization of Receptor Protein-Tyrosine Phosphatase alpha in living cells

It is demonstrated here that RPTPα dimerized constitutively in living cells, which may be mediated by the transmembrane domain, providing strong support for the model that dimerization is involved in regulation of RPTPs.