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Jak1 has a dominant role over Jak3 in signal transduction through gammaC containing cytokine receptors

Haan, Claude and Rolvering, Catherine and Raulf, Friedrich and Kapp, Manuela and Drueckes, Peter and Thoma, Gebhard and Behrmann, Iris and Zerwes, Hans-Guenter (2011) Jak1 has a dominant role over Jak3 in signal transduction through gammaC containing cytokine receptors. Chemistry and Biology, 18 (3). pp. 214-223. ISSN 1074-5521

Abstract

Genetic deficiency of Jak3 leads to abrogation of signal transduction through the common gamma chain (c) and thus to immunodefiency suggesting that specific inhibition of Jak3 kinase may result in immunosuppression. Jak1 cooperates with Jak3 in signalling through c-containing receptors. Unexpectedly, a Jak3-selective inhibitor is less efficient in abolishing STAT5 phosphorylation than pan-Jak inhibitors. We therefore explored the roles of Jak1 and Jak3 kinase functionality in signalling using a reconstituted system. The presence of kinase-inactive Jak1 but not kinase-inactive Jak3 resulted in complete abolishment of STAT5 phosphorylation. Specific inhibition of the “analogue-sensitive” mutant Jak1AS but not Jak3AS by the ATP-competitive analogue 1NM-PP1 abrogated IL2 signalling, corroborating the data with the selective Jak3 inhibitor. Jak1 thus plays a dominant role over Jak3 and these data challenge the notion that selective Jak3 kinase inhibitors will be effective.

Item Type: Article
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Keywords: Janus kinase, STAT, IL-2
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2904

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