title: Jak1 has a dominant role over Jak3 in signal transduction through γc-containing cytokine receptors.
abstract: Genetic deficiency of Jak3 leads to abrogation of signal transduction through the common gamma chain (γc) and thus to immunodeficiency suggesting that specific inhibition of Jak3 kinase may result in immunosuppression. Jak1 cooperates with Jak3 in signaling through γc-containing receptors. Unexpectedly, a Jak3-selective inhibitor was less efficient in abolishing STAT5 phosphorylation than pan-Jak inhibitors. We therefore explored the roles of Jak1 and Jak3 kinase functionality in signaling 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 "analog-sensitive" mutant AS-Jak1 but not AS-Jak3 by the ATP-competitive analog 1NM-PP1 abrogated IL-2 signaling, corroborating the data with the selective Jak3 inhibitor. Jak1 thus plays a dominant role over Jak3 and these data challenge the notion that selective ATP-competitive Jak3 kinase inhibitors will be effective.
authors: Life Sciences Research Unit-Signal Transduction Laboratory, University of Luxembourg, Luxembourg, L-1511, Luxembourg. claude.haan@uni.lu
authors: Claude
authors: C
authors: Haan
authors: Catherine
authors: C
authors: Rolvering
authors: Friedrich
authors: F
authors: Raulf
authors: Manuela
authors: M
authors: Kapp
authors: Peter
authors: P
authors: Drückes
authors: Gebhard
authors: G
authors: Thoma
authors: Iris
authors: I
authors: Behrmann
authors: Hans-Günter
authors: HG
authors: Zerwes
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D018121:Receptors, Cytokine / Q000737:chemistry / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007376:Interleukin-2; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D018121:Receptors, Cytokine; D050799:STAT5 Transcription Factor; D053613:Janus Kinase 1; D053616:Janus Kinase 3