Dispensability of Jak1 tyrosine kinase for interleukin‐2‐induced cell growth signaling in a human T cell line

Higuchi, Masakazu; Asao, Hironobu; Tanaka, Nobuyuki; Oda, Kazuaki; Takeshita, Toru; Nakamura, Masataka; Snick, Jacques Van; Sugamura, Kazuo

doi:10.1002/eji.1830260622

Cited by 42 publications

(29 citation statements)

References 39 publications

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“…Analysis of IL-2 signaling in B cell lines lacking JAK3 has demonstrated that IL-2-induced phosphorylation of IL-2␤, JAK1, and STAT5 all require the presence of JAK3 (19). In contrast, it has been suggested that JAK1 activation is not required for activation of JAK3 and STAT5 in the human T cell line (40). These findings strongly suggest that phosphorylation of JAK3 is important in IL-2 signaling, and the importance of JAK1 remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Distinct tyrosine phosphorylation sites in JAK3 kinase domain positively and negatively regulate its enzymatic activity

Zhou

Hanson

Chen

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

110

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Cytokines are critically important for the growth and development of a variety of cells. Janus kinases (JAKs) associate with cytokine receptors and are essential for transmitting downstream cytokine signals. However, the regulation of the enzymatic activity of the JAKs is not well understood. Here, we investigated the role of tyrosine phosphorylation of JAK3 in regulating its kinase activity by analyzing mutations of tyrosine residues within the putative activation loop of the kinase domain. Specifically, tyrosine residues 980 and 981 of JAK3 were mutated to phenylalanine individually or doubly. We found that JAK3 is autophosphorylated on multiple sites including Y980 and Y981. Compared with the activity of wild-type (WT) JAK3, mutant Y980F demonstrated markedly decreased kinase activity, and optimal phosphorylation of JAK3 on other sites was dependent on Y980 phosphorylation. The mutant Y980F also exhibited reduced phosphorylation of its substrates, ␥c and STAT5A. In contrast, mutant Y981F had greatly increased kinase activity, whereas the double mutant, YY980͞981FF, had intermediate activity. These results indicate that Y980 positively regulates JAK3 kinase activity whereas Y981 negatively regulates JAK3 kinase activity. These observations in JAK3 are similar to the findings in the kinase that is closely related to the JAK family, ZAP-70; mutations of tyrosine residues within the putative activation loop of ZAP-70 also have opposing actions. Thus, it will be important to determine whether this feature of regulation is unique to JAK3 or if it is also a feature of other JAKs. Given the importance of JAKs and particularly JAK3, it will be critical to fully dissect the positive and negative regulatory function of these and other tyrosine residues in the control of kinase activity and hence cytokine signaling.

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Section: Discussionmentioning

confidence: 99%

Distinct tyrosine phosphorylation sites in JAK3 kinase domain positively and negatively regulate its enzymatic activity

Zhou

Hanson

Chen

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

110

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“…Catalytically active Jak3 is required for IL-2-driven tyrosine phosphorylation of Jak1 and Stat5a/b (12,23,24,40,41). Moreover, since Stat5a/b gene-deficient mice are unable to proliferate in response to IL-2, we examined whether AG-490 inhibits IL-2-induced activation of Stat5a/b via Jak3.…”

Section: Ag-490 Inhibits Jak3 Activation and Stat5a/b Tyrosine And Sementioning

confidence: 99%

Concomitant Inhibition of Janus Kinase 3 and Calcineurin-Dependent Signaling Pathways Synergistically Prolongs the Survival of Rat Heart Allografts

Behbod

Erwin-Cohen

Wang

et al. 2001

The Journal of Immunology

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The cytoplasmic localized Janus tyrosine kinase 3 (Jak3) is activated by multiple cytokines, including IL-2, IL-4, and IL-7, through engagement of the IL-2R common γ-chain. Genetic inactivation of Jak3 is manifested as SCID in humans and mice. These findings have suggested that Jak3 represents a pharmacological target to control certain lymphoid-derived diseases. Using the rat T cell line Nb2-11c, we document that tyrphostin AG-490 blocked in vitro IL-2-induced cell proliferation (IC50 ∼20 μM), Jak3 autophosphorylation, and activation of its key substrates, Stat5a and Stat5b, as measured by tyrosine/serine phosphorylation analysis and DNA-binding experiments. To test the notion that inhibition of Jak3 provides immunosuppressive potential, a 7-day course of i.v. therapy with 5–20 mg/kg AG-490 was used to inhibit rejection of heterotopically transplanted Lewis (RT1l) heart allografts in ACI (RT1a) recipients. In this study, we report that AG-490 significantly prolonged allograft survival, but also acted synergistically when used in combination with the signal 1 inhibitor cyclosporin A, but not the signal 3 inhibitor, rapamycin. Finally, AG-490 treatment reduced graft infiltration of mononuclear cells and Stat5a/b DNA binding of ex vivo IL-2-stimulated graft infiltrating of mononuclear cells, but failed to affect IL2Rα expression, as judged by RNase protection assays. Thus, inhibition of Jak3 prolongs allograft survival and also potentiates the immunosuppressive effects of cyclosporin A, but not rapamycin.

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“…To evaluate whether the parallel decline in proliferation and decreased phosphorylation of STAT5 reflected a change in binding to specific promoter regions, we performed gel-shift analysis using a bovine ␤-casein promoter sequence encoding a STAT-binding consensus motif (38). Upon phosphorylation, STAT proteins are FIGURE 7.…”

Section: Dna-binding Activity Of Stat5 Is Reduced In Anergized T Cellmentioning

confidence: 99%

IL-2 Unresponsiveness in Anergic CD4+ T Cells Is Due to Defective Signaling Through the Common γ-Chain of the IL-2 Receptor

Grundström

Dohlsten

Sundstedt

2000

The Journal of Immunology

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Repeated administration of the superantigen staphylococcal enterotoxin A to mice transduces a state of anergy in the CD4+ T cell compartment, characterized by inhibition of IL-2 production and clonal expansion in vivo. In contrast to what has been reported on anergic T cell clones in vitro, culture of in vivo anergized CD4+ T cells in the presence of exogenous IL-2 did not overcome the block in responsiveness. In this study, we demonstrate that CD4+ T cells from mice anergized with staphylococcal enterotoxin A also exhibit a reduced proliferative capacity in response to IL-7 and IL-15, cytokines that share a common γ-chain with the IL-2R. Flow-cytometric analysis revealed only modest changes in the expression of the different IL-2R chains. In a number of experiments, our results also provide evidence that excludes a major role of the IL-2R α-chain in this system. According to these results, the inability of anergic cells to respond to IL-2 is not mainly due to a down-regulation of the high affinity IL-2R, but to a perturbation in intracellular signaling. Our study confirmed that the activation and tyrosine phosphorylation of Janus-associated kinase 3 and STAT5 were considerably weaker after anergy induction. Moreover, anergic CD4+ T cells showed significantly reduced DNA-binding ability to STAT5-specific elements. Taken together, we suggest that the observed IL-2 unresponsiveness in anergic CD4+ T cells could be due to a defect in signaling through the common γ-chain of the IL-2R.

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Dispensability of Jak1 tyrosine kinase for interleukin‐2‐induced cell growth signaling in a human T cell line

Cited by 42 publications

References 39 publications

Distinct tyrosine phosphorylation sites in JAK3 kinase domain positively and negatively regulate its enzymatic activity

Distinct tyrosine phosphorylation sites in JAK3 kinase domain positively and negatively regulate its enzymatic activity

Concomitant Inhibition of Janus Kinase 3 and Calcineurin-Dependent Signaling Pathways Synergistically Prolongs the Survival of Rat Heart Allografts

IL-2 Unresponsiveness in Anergic CD4+ T Cells Is Due to Defective Signaling Through the Common γ-Chain of the IL-2 Receptor

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