JAK2 is phosphorylated, activated Authored: Ray, KP, 2010-05-17 EC Number: 2.7.10.2 Edited: Jupe, S, 2010-08-06 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.<br><br>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. Pubmed12479803 Pubmed15143187 Pubmed15143188 Pubmed16174768 Pubmed20304997 Pubmed20585391 Pubmed7542592 Pubmed8007942 Pubmed8378315 Pubmed9111318 Reactome Database ID Release 43879910 Reactome, http://www.reactome.org ReactomeREACT_23935 Reviewed: Hercus, TR, 2010-09-06 Reviewed: Lopez, AF, 2010-09-06 has a Stoichiometric coefficient of 6 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2 High affinity binding complex dimers of cytokine receptors using Bc, activated JAK2