Jak2 Is Essential for Signaling through a Variety of Cytokine Receptors

Parganas, Evan; Wang, Demin; Stravopodis, Dimitrios J.; Topham, David J.; Marine, Jean–Christophe; Teglund, Stephan; Vanin, Elio F.; Bodner, Sara M.; Colamonici, Oscar R.; Deursen, Jan M. van; Grosveld, Gerard; Ihle, James N.

doi:10.1016/s0092-8674(00)81167-8

Cited by 997 publications

(694 citation statements)

References 53 publications

Supporting

Mentioning

665

Contrasting

Unclassified

Order By: Relevance

“…There is also good evidence suggesting essential role for Jak2-STAT5 pathway in erythropoiesis in vitro and in vivo (Wakao et al, 1997;Iwatsuki et al, 1997;Parganas et al 1998;Neubauer et al, 1998). Our preliminary experiments, however, indicated that none of the transgenes used in this study (ras12V, ras17N, and MAPKKm) induced signi®cant alterations in the basal or EPO-induced phosphorylation of endogenous Jak2 protein nor did the ras17N gene a ect the DNAbinding activity of endogenous STAT5 protein (our unpublished observation).…”

Section: Discussionmentioning

confidence: 58%

See 1 more Smart Citation

Induction of erythroid differentiation by inhibition of Ras/ERK pathway in a Friend murine leukemia cell line

et al. 2000

View full text Add to dashboard Cite

The role of Ras and MAP kinases (MAPKs) in the regulation of erythroid di erentiation was studied using a cell line (SKT6) derived from Friend virus (Anemic strain)-induced murine erythroleukemia. This cell line undergoes di erentiation in vitro in response to erythropoietin (EPO) or other chemical inducers such as dimethylsulfoxide (DMSO). When a constitutively active ras mutant (ras12V) was expressed in SKT6 cells, EPO-induced di erentiation was inhibited. Conversely, a dominant negative ras mutant (ras17N) induced di erentiation even in the absence of EPO, suggesting that the basal Ras activity is essential for the maintenance of the undi erentiated phenotype and proliferative potential in this cell line. Rapid inactivation of ERK was observed after expression of ras17N. Slow but signi®cant inactivation of ERK was also observed during EPOinduced di erentiation. Furthermore, overexpression of a constitutively active mutant of ERK-activating kinase (MAPKK) was found to suppress erythroid di erentiation, while pharmacological inhibition of MAPKK induced di erentiation. These ®ndings suggest that down-regulation of Ras/ERK signaling pathway may be an essential event in EPO-induced erythroid di erentiation in this system. Oncogene (2000) 19, 1500 ± 1508.

show abstract

Section: Discussionmentioning

confidence: 58%

“…Conversely, forced expression of protein tyrosine phosphatase b2 gene was found to induce di erentiation in murine erythroleukemia cells (Kume et al, 1996). In addition, Jak2-de®cient mice were found to have defects in de®nitive erythropoiesis which lead to embryonic death due to anemia (Parganas et al, 1998;Neubauer et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Induction of erythroid differentiation by inhibition of Ras/ERK pathway in a Friend murine leukemia cell line

et al. 2000

View full text Add to dashboard Cite

show abstract

“…JAK-2 mediates signaling via the hematopoietic cytokines EPO, GM-CSF, and thrombopoietin (8,9). Patients receiving the highest dosage of CP-690,550 (30 mg twice daily) had higher incidences of anemia, granulocytopenia, and thrombocytopenia than did the placebo group (12).…”

Section: Discussionmentioning

confidence: 99%

“…Tyk-2 deficiency results in a human primary immunodeficiency similar to the JAK-3 SCID phenotype; however, neither JAK-1-deficient nor JAK-2-deficient humans have been identified, and deficient mice are not viable (8,9). Several of the cytokines that require JAK-1, JAK-2, and/or Tyk-2 activity, including IL-6, IL-12, and IL-23, play a pathogenic role in human rheumatoid arthritis (RA) (10,11), suggesting that inhibiting the JAK family more broadly may be beneficial.…”

mentioning

confidence: 99%

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

Lin

Hegen

Quadros

et al. 2010

Arthritis & Rheumatism

View full text Add to dashboard Cite

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.

show abstract

“…Gene targeting studies in mice have illustrated the importance of the Jak family members in hematopoiesis. Lymphoid development is impaired in mice deficient in Jak1 (Rodig et al, 1998) and Jak3 (Nosaka et al, 1995;Park et al, 1995;Thomis et al, 1995), and erythropoiesis is lost in Jak2-deficient mice (Parganas et al, 1998). Loss of Jak3 has also been implicated in dysregulated myelopoiesis (Grossman et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Granulocyte colony-stimulating factor-induced upregulation of Jak3 transcription during granulocytic differentiation is mediated by the cooperative action of Sp1 and Stat3

et al. 2006

View full text Add to dashboard Cite

We previously demonstrated that Jak3 is a primary response gene for G-CSF and ectopic overexpression of Jak3 can accelerate granulocytic differentiation of normal mouse bone marrow cells induced by G-CSF and GM-CSF. To gain insight into the regulation of G-CSFinduced transcription of Jak3, we constructed deletion and linker scanning mutants of the Jak3 promoter sequences and performed luciferase reporter assays in the murine myeloid cell line 32Dcl3, with and without G-CSF stimulation. These experiments showed that mutation of a À67 to À85 element, which contained a putative Sp1 binding site, or mutation of a À44 to À53 GAS element resulted in a marked reduction of Jak3 promoter activity. Electrophoretic mobility shift assays revealed that Sp1 and Stat3 present in nuclear lysates of 32Dcl3 cells stimulated with G-CSF can bind to the À67 to À85 element and À44 to À53 GAS element, respectively. In addition, cotransfection of a constitutively active mutant of Stat3 along with a Jak3 promoter/luciferase reporter resulted in enhanced Jak3 promoter activity. Together, these results demonstrate that activation of Jak3 transcription during G-CSF-induced granulocytic differentiation is mediated by the combined action of Sp1 and Stat3, a mechanism also shown to be important in IL-6-induced monocytic differentiation.

show abstract

Jak2 Is Essential for Signaling through a Variety of Cytokine Receptors

Cited by 997 publications

References 53 publications

Induction of erythroid differentiation by inhibition of Ras/ERK pathway in a Friend murine leukemia cell line

Induction of erythroid differentiation by inhibition of Ras/ERK pathway in a Friend murine leukemia cell line

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

Granulocyte colony-stimulating factor-induced upregulation of Jak3 transcription during granulocytic differentiation is mediated by the cooperative action of Sp1 and Stat3

Contact Info

Product

Resources

About