JAK2 is phosphorylated, activated

Stable Identifier
R-HSA-879910
Type
Reaction
Species
Homo sapiens
Compartment
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JAK2 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.

Literature References
PubMed ID Title Journal Year
8007942 JAK2 associates with the beta c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region

Witthuhn, BA, Miyajima, A, Sato, N, Quelle, FW, Inhorn, RC, Ihle, JN, Griffin, JD, Eder, M

Mol Cell Biol 1994
9111318 Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop

Matsuda, T, Witthuhn, BA, Kerr, IM, Kohlhuber, F, Feng, J, Ihle, JN

Mol Cell Biol 1997
Participants
Participates
Catalyst Activity

non-membrane spanning protein tyrosine kinase activity of High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2 [plasma membrane]

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