JAK activation

Stable Identifier
Reaction [omitted]
Homo sapiens
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The molecular mechanism of Jak activation upon cytokine stimulation is not understood in detail (Haan et al. 2008). Cytokine-induced receptor aggregation and the resulting close proximity of Jaks bound to the beta receptor subunit is believed to trigger trans-phosphorylation of Jak tyrosines in their kinase activation loop, confering kinase activity. This active state is believed to be maintained by further autocatalytic tyrosine phosphorylations. For JAK1 the activation loop tyrosine residues are predicted by homology with models of JAK2 (Lindauer et al. 2001) to be Tyr-1034/1035. Mutation of Tyr-1034 abolishes JAK1 kinase activity (Liu et al. 1997). Evidence supporting JAK1 transphosphorylation includes JAK1 mutant cell lines, which cannot activate Tyk2 after stimulation with interferon alpha/beta (Velazquez et al. 1995) and the observation that IL-2 cannot activate JAK1 in the absence of JAK3 (Oakes et al. 1996). The receptor is not merely a docking site for JAKs as certain gp130 residues are required for JAK1 activation, but not essential for JAK1 binding (Haan et al. 2002).
Literature References
PubMed ID Title Journal Year
8272873 Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components

Witthuhn, BA, Barbieri, G, Pellegrini, S, Quelle, FW, Ip, NY, Silvennoinen, O, Davis, S, Boulton, TG, Stahl, N, Farruggella, T

Science 1994
8134389 Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gp130

Witthuhn, BA, Kishimoto, T, Taga, T, Yoshida, K, Narazaki, M, Yasukawa, K, Silvennoinen, O, Ihle, JN

Proc Natl Acad Sci U S A 1994
9382798 Janus kinases in interleukin-2-mediated signaling: JAK1 and JAK3 are differentially regulated by tyrosine phosphorylation

Goldsmith, MA, Liu, KD, Gaffen, SL, Greene, WC

Curr Biol 1997
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