Nitric oxide and thiol redox regulation of Janus kinase activity.
The activation of Janus kinases (JAKs) is crucial for propagation of the proliferative response initiated by many cytokines. The proliferation of various cell lines, particularly those of hematopoietic origin, is also modulated by mediators of oxidative stress such as nitric oxide and thiol redox reagents. Herein we demonstrate that nitric oxide and other thiol oxidants can inhibit the autokinase activity of rat JAK2 in vitro, presumably through oxidation of crucial dithiols to disulfides within JAK2. The reduced form of JAK2 is the most active form, and the oxidized JAK2 form is inactive. Nitric oxide pretreatment of quiescent Ba/F3 cells also inhibits the interleukin 3-triggered in vivo activation of JAK2, a phenomenon that correlates with inhibited proliferation. Furthermore, we observed that the autokinase activity of JAK3 responds in a similar fashion to thiol redox reagents in vitro and to nitric oxide donors in vivo. We suggest that the thiol redox regulation of JAKs may partially explain the generally immunosuppressive effects of nitric oxide and of other thiol oxidants.
Duhé
R J
RJ
Intramural Research Support Program, Science Applications International Corporation-Frederick, Frederick, MD 21702-1201, USA. DUHE@ncifcrf.gov
Evans
G A
GA
Erwin
R A
RA
Kirken
R A
RA
Cox
G W
GW
Farrar
W L
WL
D000818:Animals; D016367:Baculoviridae; D002478:Cells, Cultured; D004229:Dithiothreitol / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007463:Iodobenzoates / Q000494:pharmacology; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D051379:Mice; D009569:Nitric Oxide / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051381:Rats; D018411:Spodoptera; D013439:Sulfhydryl Reagents / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D007463:Iodobenzoates; C507936:Jak3 protein, rat; D011518:Proto-Oncogene Proteins; D013439:Sulfhydryl Reagents; C008154:2-iodosobenzoic acid; D009569:Nitric Oxide; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507933:JAK3 protein, human; C507905:Jak1 protein, mouse; C507906:Jak1 protein, rat; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat; C507935:Jak3 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D004229:Dithiothreitol