Functional Activation of Jak1 and Jak3 by Selective Association with IL-2 Receptor Subunits

Miyazaki, Tatsuya; Kawahara, Atsuo; Fujii, Hodaka; Nakagawa, Yoko; Minami, Yasuhiro; Liu, Zhao Jun; Oishi, Isao; Silvennoinen, Olli; Witthuhn, Bruce A.; Ihle, James N.; Taniguchi, Tadatsugu

doi:10.1126/science.7973659

Cited by 536 publications

(402 citation statements)

References 33 publications

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“…Two members of the Jak kinase family protein tyrosine kinases, Jak1 and Jak3, are associated with IL-2Rβ and γc, respectively, and activated upon IL-2 stimulation [6][7][8]. Activation of Jak1 and Jak3 induces activation of Stat5/Stat3 and other signaling pathways to initiate cell proliferation [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Cell type-specific roles of Jak3 in IL-2-induced proliferative signal transduction

Fujii

2007

Biochemical and Biophysical Research Communications

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Binding of IL-2 to its specific receptor induces activation of two members of Jak family protein tyrosine kinases, Jak1 and Jak3. An IL-2R-reconstituted NIH 3T3 fibroblast cell line proliferates in response to IL-2 only when hematopoietic lineage-specific Jak3 is ectopically expressed. However, the mechanism of Jak3-dependent proliferation in the fibroblast cell line is not known. Here, I showed that Jak3 expression is dispensable for IL-2-induced activation of Jak1 and Stat proteins and expression of nuclear proto-oncogenes in the IL-2R-reconstituted fibroblast cell line. However, Jak3 expression markedly enhanced these IL-2-induced signaling events. In contrast, Jak3 expression was essential for induction of cyclin genes involved in the G1-S transition. These data suggest a critical role of Jak3 in IL-2 signaling in the fibroblast cell line and may provide further insight into the cell type-specific mechanism of cytokine signaling.

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Section: Introductionmentioning

confidence: 99%

Cell type-specific roles of Jak3 in IL-2-induced proliferative signal transduction

Fujii

2007

Biochemical and Biophysical Research Communications

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“…In comparison, CP-690,550 was similarly selective in our assays for JAK-2 and Tyk-2 but less selective versus JAK-1. Since JAK-1 pairs with JAK-3 in all ␥-chain receptor-mediated signaling pathways (24), inhibitors of JAK-3 that also inhibit JAK-1 may exhibit increased cellular potency. However, JAK-1 inhibition will also interfere with signaling pathways mediated by other cytokines, such as the gp130 receptor cytokines (IL-6 family) and the cytokine type II receptors such as the IFNs and the IL-10 family (38).…”

Section: Discussionmentioning

confidence: 99%

“…IL-2 signals via a heterotrimeric receptor complex consisting of IL-2 receptor ␤ (IL-2R␤), IL-2R␣, and ␥-chain. Following IL-2R engagement, the receptorassociated JAK-1 and JAK-3 kinases phosphorylate STAT-5 protein (23,24). In human PBMC blasts, WYE-151650 inhibited both a functional readout of IL-2-induced proliferation with an IC 50 of 50 nM ( Figure 1B) and also inhibited IL-2-induced STAT-5 phosphorylation, a more proximal event ( Figure 1C).…”

Section: Il-2-induced Interferon-␥ (Ifn␥) Production In Micementioning

confidence: 98%

Selective functional inhibition of JAK‐3 is sufficient for efficacy in collagen‐induced arthritis in mice

Lin

Hegen

Quadros

et al. 2010

Arthritis & Rheumatism

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Objective. All ␥-chain cytokines signal through JAK-3 and JAK-1 acting in tandem. We undertook this study to determine whether the JAK-3 selective inhibitor WYE-151650 would be sufficient to disrupt cytokine signaling and to ameliorate autoimmune disease pathology without inhibiting other pathways mediated by JAK-1, JAK-2, and Tyk-2.Methods. JAK-3 kinase selective compounds were characterized by kinase assay and JAK-3-dependent (interleukin-2 [IL-2]) and -independent (IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF]) cell-based assays measuring proliferation or STAT phosphorylation. In vivo, off-target signaling was measured by IL-22-and erythropoietin (EPO)-mediated models, while on-target signaling was measured by IL-2-mediated signaling. Efficacy of JAK-3 inhibitors was determined using delayed-type hypersensitivity (DTH) and collagen-induced arthritis (CIA) models in mice.Results. In vitro, WYE-151650 potently suppressed IL-2-induced STAT-5 phosphorylation and cell proliferation, while exhibiting 10-29-fold less activity against JAK-3-independent IL-6-or GM-CSF-induced STAT phosphorylation. Ex vivo, WYE-151650 suppressed IL-2-induced STAT phosphorylation, but not IL-6-induced STAT phosphorylation, as measured in whole blood. In vivo, WYE-151650 inhibited JAK-3-mediated IL-2-induced interferon-␥ production and decreased the natural killer cell population in mice, while not affecting IL-22-induced serum amyloid A production or EPO-induced reticulocytosis. WYE-151650 was efficacious in mouse DTH and CIA models.Conclusion. In vitro, ex vivo, and in vivo assays demonstrate that WYE-151650 is efficacious in mouse CIA despite JAK-3 selectivity. These data question the need to broadly inhibit JAK-1-, JAK-2-, or Tyk-2-dependent cytokine pathways for efficacy.

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“…The membrane proximal, the serine-rich region of IL-2Rfl is essential for activation of JAK-family PTKs [21] and Src-family Syk [22] as well as for c-myc gene induction. On the other hand, the membrane distal, the acidic region of IL-2R,fl is crucial for activation of Src-family PTKs and for c-fos and c-jun gene induction [23].…”

Section: Discussionmentioning

confidence: 99%

IL‐2‐induced gene expression of protein‐tyrosine phosphatase LC‐PTP requires acidic and serine‐rich regions within IL‐2 receptor β chain

et al. 1995

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Functional Activation of Jak1 and Jak3 by Selective Association with IL-2 Receptor Subunits

Cited by 536 publications

References 33 publications

Cell type-specific roles of Jak3 in IL-2-induced proliferative signal transduction

Cell type-specific roles of Jak3 in IL-2-induced proliferative signal transduction

Selective functional inhibition of JAK‐3 is sufficient for efficacy in collagen‐induced arthritis in mice

IL‐2‐induced gene expression of protein‐tyrosine phosphatase LC‐PTP requires acidic and serine‐rich regions within IL‐2 receptor β chain

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