Phosphorylation of Human Jak3 at Tyrosines 904 and 939 Positively Regulates Its Activity

Department of Biological Sciences, Biosciences Building, University of Texas at El Paso, 500 W. University Ave., El Paso, TX 79902, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 05/2008; 28(7):2271-82. DOI: 10.1128/MCB.01789-07
Source: PubMed


Janus tyrosine kinase 3 (Jak3) is essential for signaling by interleukin-2 (IL-2) family cytokines and proper immune function.
Dysfunctional regulation of Jak3 may result in certain disease states. However, the molecular mechanisms governing Jak3 activation
are not fully understood. In this study, we used a functional-proteomics approach to identify two novel tyrosine phosphorylation
sites within Jak3, Y904 and Y939, which are conserved among Jak family proteins. By using phosphospecific antibodies, both
residues were observed to be rapidly induced by stimulation of cells with IL-2 or other γc cytokines. Mechanistic studies
indicated that Y904 and Y939 regulate Jak3 activities. A phenylalanine substitution at either site greatly reduced Jak3 kinase
activity in vitro and its ability to phosphorylate signal transducer and activator of transcription 5 (Stat5) in vivo, suggesting
that phosphorylation of these previously unrecognized residues positively regulates Jak3 activity. Y904 and Y939 were required
for optimal ATP usage by Jak3, while phosphorylation of Y939 preferentially promoted Stat5 activity in intact cells. Together,
these findings demonstrate positive functional roles for two novel Jak3 phosphoregulatory sites which may be similarly important
for other Jak family members. Identification of these sites also provides new therapeutic opportunities to modulate Jak3 function.

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Available from: Jeffrey A Frost, Jan 22, 2014
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    • "Although differences in the biochemical steps associated with cytokine receptor-triggered signal transduction have been described, it has been assumed that both Jak kinases are equally important for signal transduction. (Chen et al., 2000; Cheng et al., 2008; Fujii, 2008; Kirken et al., 1995; Liu et al., 1997; Zhou et al., 1997). Several low molecular weight Jak inhibitors have been reported recently which potently inhibit kinase activity in vitro and cellular responses to cytokines (reviewed in Haan et al., 2010; Pesu et al., 2008). "
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