Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes.

Kawamura, Masaru; McVicar, Daniel W.; Johnston, James A.; Blake, Trevor; Chen, Y Q; Lal, Binesh; Lloyd, Andrew R.; Kelvin, David J.; Staples, J. Erin; Ortaldo, John R.

doi:10.1073/pnas.91.14.6374

Cited by 264 publications

(196 citation statements)

References 46 publications

(45 reference statements)

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“…As shown in Fig. 1A, 3T3αβγ cells did not express Jak3 [6], whose expression is detected only in the hematopoietic cell lineages [20,21]. In contrast, this cell line expressed Jak1 (Fig.…”

Section: Resultsmentioning

confidence: 75%

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: Resultsmentioning

confidence: 75%

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 contrast, JAK-3 is restricted in expression to immune cells (4)(5)(6). Interestingly, the expression of JAK-3 and STATs in synovial tissue decreases in response to successful DMARD treatment (36).…”

Section: Discussionmentioning

confidence: 99%

“…Of the JAK family kinases, JAK-3 expression is restricted to cells primarily of hematopoietic origin (4)(5)(6). In contrast, JAK-1, JAK-2, and Tyk-2 are more ubiquitously expressed.…”

Section: In Vitro Activity Wye-151650 (mentioning

confidence: 99%

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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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“…Both IL-2 and IL-4 activate in lymphocytes a newly described member of the tyk2/Jak family, Jak3 (92,93). This kinase, unlike the other tyk2/Jak kinases that have a broad tissue distribution, is restricted to lymphocytes, but its expression can be induced in monocytes by endotoxin or IFN y treatment (94). In addition to Jak3, Jakl is also activated by IL-2 and IL-4.…”

Section: Egf Was One Of the First Non-ifn Cytokines Demonstrated To Amentioning

confidence: 99%

Induction of early response genes by interferons, interleukins, and growth factors by the tyrosine phosphorylation of latent transcription factors

Finbloom

Larner

1995

Arthritis & Rheumatism

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Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes.

Cited by 264 publications

References 46 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

Induction of early response genes by interferons, interleukins, and growth factors by the tyrosine phosphorylation of latent transcription factors

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