Haan, Claude, Rolvering, Catherine, Raulf, Friedrich, Kapp, Manuela, Drueckes, Peter, Thoma, Gebhard, 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
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed?term=...
Keywords:	Janus kinase, STAT, IL-2
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed?term=...
Date Deposited:	13 Oct 2015 13:16
Last Modified:	13 Oct 2015 13:16
URI:	https://oak.novartis.com/id/eprint/2904