TheJanusprotein tyrosine kinases in hematopoietic cytokine signaling

Ihle, James N.

doi:10.1006/smim.1995.0029

Cited by 60 publications

(48 citation statements)

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“…Once bound, ligand-mediated receptor conformational changes occur, resulting in trans-phosphorylation and activation of the JAKs (Ihle, 1995). In turn, activated JAKs phosphorylate particular tyrosine residues in the receptor's cytoplasmic domain.…”

Section: Discussionmentioning

confidence: 99%

Engagement of the B-cell antigen receptor activates STAT through Lyn in a Jak-independent pathway

2006

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Engagement of the B-cell antigen receptor (BCR) initiated by the Src kinase Lyn triggers rapid signaling cascades, leading to proliferation, differentiation or growth arrest of B cells. The Janus kinase (JAK)-STAT (signal transducer and activator of transcription) pathway, activated through cytokine receptors, mediates similar responses. Hypothesizing that Src and JAK pathways engage in crosstalk in B-cell signaling, we studied wild-type and Lyn-null B-cell lines, which express BCR. We found that activated BCR results in tyrosine phosphorylation of JAK-STAT, which required Lyn. To confirm that STAT activation is not due to JAK, we cloned the chicken homologs of JAK1 and JAK2 and made their antisense constructs. In cells expressing antisense JAK1 and JAK2, tyrosine phosphorylation of STAT was not inhibited following BCR stimulation. Using activation loop-specific phosphotyrosine antibodies, we did not detect phospho-JAK1 and phospho-JAK2 after BCR stimulation. The JAK inhibitor AG490 did not inhibit the tyrosine phosphorylation of Lyn or STAT after BCR simulation. An in vitro phosphorylation assay showed that Lyn directly phosphorylates STAT3. In an electrophoretic mobility shift assay, BCR stimulation led to enhanced DNA binding of the STAT3 in DT40, but not in the Lynnull cells. We conclude that BCR engagement activates the STAT pathway via Lyn, independent of JAK.

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Section: Discussionmentioning

confidence: 99%

Engagement of the B-cell antigen receptor activates STAT through Lyn in a Jak-independent pathway

2006

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“…The JAK/STAT cascade was originally discovered as a cytokineinduced signalling pathway required by myeloid and lymphoid cell lineages (reviewed by Ihle, 1995). It has subsequently been shown to play a central role in orchestrating mammalian immune responses (reviewed by Boehm et al, 1997;Hanlon et al, 2002;Trinchieri, 2003;Watford et al, 2003).…”

Section: Immune Responsesmentioning

confidence: 99%

JAK/STAT signalling inDrosophila: insights into conserved regulatory and cellular functions

2006

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DEVELOPMENT 2605High levels of interspecies conservation characterise all signal transduction cascades and demonstrate the significance of these pathways over evolutionary time. Here, we review advances in the field of JAK/STAT signalling, focusing on recent developments in Drosophila. In particular, recent results from genetic and genome-wide RNAi screens, as well as studies into the developmental roles played by this pathway, highlight striking levels of physical and functional conservation in processes such as cellular proliferation, immune responses and stem cell maintenance. These insights underscore the value of model organisms for improving our understanding of this human disease-relevant pathway.

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“…JAK3, a member of the Janus family of tyrosine kinases (JAK1, JAK2, JAK3, and Tyk2), is constitutively associated with the common ␥ chain of the receptors of numerous cytokines, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 (1). Upon cytokine binding to the receptor, the Janus kinases become activated, autophosphorylate, and transphosphorylate the receptor, leading to association of Stat proteins with the receptor (2)(3)(4)(5)(6)(7)(8). Tyrosine phosphorylation of the Stat proteins by JAK lead to dimerization and translocation of the complexes to the cell nucleus where they induce DNA transcription of specific target genes.…”

Section: Jak3 Inhibition Significantly Attenuates Psoriasiform Skin Imentioning

confidence: 99%

JAK3 Inhibition Significantly Attenuates Psoriasiform Skin Inflammation in CD18 Mutant PL/J Mice

Chang

Zhao

et al. 2009

The Journal of Immunology

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JAK3, a member of the Janus kinase family, is predominantly expressed in hemopoietic cells and binds specifically to the common γ chain of a subfamily of cytokine receptors that includes IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Previous studies suggest that this tyrosine kinase plays key roles in mediating T cell functions, and inhibition of JAK3 has been shown to prevent graft rejection and decrease the severity of arthritis in rodent models. However, the functions of JAK3 in the development of skin immune responses and diseases such as psoriasis have not been determined. CD18 mutant PL/J mice develop spontaneous T cell-dependent psoriasiform skin disease with several similarities to human psoriasis. In this study, we treated mice with established skin disease with R348, a small molecule inhibitor of JAK3, and observed a marked attenuation of skin lesions following 6 wk of treatment. Histological analyses revealed major reductions of both epidermal and dermal lesion severity scores in R348-treated CD18-deficient PL/J mice compared with vehicle controls, which was associated with decreased CD4+ T cell infiltration. In addition, systemic levels of IL-17, IL-22, IL-23, and TNF-α were significantly lower in mice receiving the compound, and T cells isolated from R348-treated mice also showed reduced phosphorylation of Stat5 after stimulation with IL-2. These findings suggest that small-molecule inhibitors of JAK3 may be useful in the treatment of inflammatory skin diseases such as psoriasis and strongly implicate JAK signaling events as important in the pathogenesis of this disease.

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TheJanusprotein tyrosine kinases in hematopoietic cytokine signaling

Cited by 60 publications

References 0 publications

Engagement of the B-cell antigen receptor activates STAT through Lyn in a Jak-independent pathway

Engagement of the B-cell antigen receptor activates STAT through Lyn in a Jak-independent pathway

JAK/STAT signalling inDrosophila: insights into conserved regulatory and cellular functions

JAK3 Inhibition Significantly Attenuates Psoriasiform Skin Inflammation in CD18 Mutant PL/J Mice

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