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Details on Person JAK2 is tyrosine phosphorylated in response to IL-3 (Silvenn...

Class:IdSummation:879955
_displayNameJAK2 is tyrosine phosphorylated in response to IL-3 (Silvenn...
_timestamp2010-12-20 14:22:43
created[InstanceEdit:879892] Jupe, S, 2010-06-25
literatureReference[LiteratureReference:893525] Structure of the murine Jak2 protein-tyrosine kinase and its role in interleukin 3 signal transduction
[LiteratureReference:879936] JAK2 associates with the beta c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region
[LiteratureReference:914070] Characterization of critical residues in the cytoplasmic domain of the human interleukin-5 receptor alpha chain required for growth signal transduction
[LiteratureReference:893552] The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor
[LiteratureReference:208236] The Jak/STAT pathway in model organisms: emerging roles in cell movement
[LiteratureReference:873856] Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop
[LiteratureReference:893535] Tyrosine phosphorylation of Jak2 in the JH2 domain inhibits cytokine signaling
[LiteratureReference:873860] Autophosphorylation of JAK2 on tyrosines 221 and 570 regulates its activity
[LiteratureReference:873836] Tyrosines 868, 966, and 972 in the kinase domain of JAK2 are autophosphorylated and required for maximal JAK2 kinase activity
[LiteratureReference:893540] JAK2 V617F Constitutive Activation Requires JH2 Residue F595: A Pseudokinase Domain Target for Specific Inhibitors
modified[InstanceEdit:893547] Jupe, S, 2010-07-01
[InstanceEdit:909735] Jupe, S, 2010-07-07
[InstanceEdit:914066] Jupe, S, 2010-07-21
[InstanceEdit:914195] Jupe, S, 2010-07-23
[InstanceEdit:1168386] Jupe, S, 2010-12-20
textJAK2 is tyrosine phosphorylated in response to IL-3 (Silvennoinen et al. 1993), GM-CSF (Quelle et al. 1994) and IL-5 (Cornelis et al. 1995) leading to kinase activity. Although structures of JAK kinase domains exist (e.g. Lucet et al. 2006) no complete structures of Janus kinases (JAKs) are available and the activation mechanism is poorly understood. Activation is believed to be a consequence of conformational changes, propagated from conformational changes in the common beta chain (Bc) following alpha-beta dimerization. This is believed to result in a trans-activation event whereby JAKs bound to activated, dimerized receptors phosphorylate and thereby activate each other (Quelle et al. 1994, Hou et al. 2002). This model is similar to IL2R activation of JAK1/3. In addition to the observed activation of JAK2 following stimulation with IL-3, IL-5 or GM-CSF, other supporting observations include: phosphorylation of JAK2 at Y1007 is critical for kinase activation (Feng et al. 1997, Lucet et al. 2006) and autophosphorylation at several other sites appears to regulate activity (e.g. Feener et al. 2004, Argetsinger et al. 2004, 2010). Only the critical Y1007 phosphorylation is represented for this reaction.

Constitutive activation of JAK2 resulting from the V617F mutation is present in over 95% of Polycythemia Vera patients (Dusa et al. 2010). F595 is indispensible for constitutive activation by V617F, but not for JAK2 activation, suggesting that this is not part of the cytokine-induced mechansim of JAK2 activation.
(summation)[Reaction:879910] JAK2 is phosphorylated, activated [Homo sapiens]
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