Janus kinases in immune cell signaling

Ghoreschi, Kamran; Laurence, Arian; O’Shea, John J.

doi:10.1111/j.1600-065x.2008.00754.x

Cited by 995 publications

(909 citation statements)

References 146 publications

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“…39 No band shifts were observed in DNA samples extracted from the enriched tumour cell populations of 19 Sézary patients (data not shown). The CTCL cell lines HuT78, SeAx and MyLa, and the leukaemic cell line Jurkat also did not harbour either mutation.…”

Section: Jak1 V658f and Jak2 V617f Mutations Are Not Present In Primamentioning

confidence: 99%

Constitutive activation of STAT3 in Sézary syndrome is independent of SHP-1

et al. 2011

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Constitutive and persistent activation of STAT3 has been implicated in the pathogenesis of many malignancies. Studies of CTCL cell lines have previously suggested that aberrant activation of STAT3 is mediated via silencing of the negative regulator SHP-1 by promoter methylation. In this study of ex vivo tumour cell populations from 18 Sé zary syndrome (SS) patients, constitutive phosphorylation of STAT3, JAK1 and JAK2 was present in all patients, but was absent in comparative CD4 þ T-cells from healthy controls. Furthermore, no loss or significant difference in SHP-1 expression was observed between patients and healthy control samples. Methylationspecific PCR analysis of the SHP-1 CpG island in 47 SS patients and 11 healthy controls did not detect any evidence of methylation. Moreover, small interfering RNA knockdown of SHP-1 had no effect on phosphorylation of STAT3. In contrast, treatment of SS tumour cells with the pan-JAK inhibitor pyridone 6 led to downregulation of phosphorylated STAT3 (pSTAT3), its target genes and induction of apoptosis. No evidence for common JAK1/JAK2-activating mutations was found. These data demonstrate that constitutive activation of STAT3 in SS is not due to the loss of SHP-1, but is mediated by constitutive aberrant activation of JAK family members.

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Section: Jak1 V658f and Jak2 V617f Mutations Are Not Present In Primamentioning

confidence: 99%

Constitutive activation of STAT3 in Sézary syndrome is independent of SHP-1

et al. 2011

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“…SB1578 was administered orally twice daily to the mice only after the onset of disease (starting days [18][19][20][21][22], which was evident by swelling in at least one paw, and the treatment was continued for 10 d postenrollment. In the vehicle group, the clinical arthritic score rapidly increased from 0.52 6 0.2 on disease day 1 to 2.8 6 1.2 on disease day 11 (Fig.…”

Section: Amelioration Of Cia In Mice With Oral Administration Of Sb1578mentioning

confidence: 99%

“…Clinical scores for the mice were determined for each of the four paws on study days [16][17][18][19][20][21][22][23][24][25][26][27][28]. The scores for all the four paws were given using the following criteria: 0, normal joints; 1, swelling in one digit or joint or minimal diffuse erythema; 2, swelling in two digits or joints or mild diffuse erythema; 3, swelling in three digits or joints or moderate diffuse erythema; 4, swelling in four digits or joints or marked diffuse erythema; 5, severe diffuse erythema and severe swelling of the entire paw and rigid joints.…”

Section: Collagen-induced Arthritismentioning

confidence: 99%

“…As JAKs play an essential role in the cellular signaling pathways involved in regulating the immune system and several important physiological processes such as hematopoiesis, targeting of all the JAK family members simultaneously may lead to immunosuppression and adverse consequences. Therefore, identification of small-molecule inhibitors specifically targeting the JAKs involved in the signal transduction of key cytokines and chemokines associated with the pathogenesis of RA would be beneficial (18,19). JAK2 plays an essential role in the signaling of proinflammatory cytokines involved in the pathogenesis of RA (20).…”

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confidence: 99%

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SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

Madan¹,

Goh²,

Hart³

et al. 2012

The Journal of Immunology

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SB1578 is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK family and also potent activity against FLT3 and c-Fms. These three tyrosine kinases play a pivotal role in activation of pathways that underlie the pathogenesis of rheumatoid arthritis. SB1578 blocks the activation of these kinases and their downstream signaling in pertinent cells, leading to inhibition of pathological cellular responses. The biochemical and cellular activities of SB1578 translate into its high efficacy in two rodent models of arthritis. SB1578 not only prevents the onset of arthritis but is also potent in treating established disease in collagen-induced arthritis mice with beneficial effects on histopathological parameters of bone resorption and cartilage damage. SB1578 abrogates the inflammatory response and prevents the infiltration of macrophages and neutrophils into affected joints. It also leads to inhibition of Ag-presenting dendritic cells and inhibits the autoimmune component of the disease. In summary, SB1578 has a unique kinase spectrum, and its pharmacological profile provides a strong rationale for the ongoing clinical development in autoimmune diseases.

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“…JAKs contain a TK domain, a pseudokinase domain, an SH2 domain, and a FERM domain that mediates receptor binding (11). Activation is initiated when a cytokine binds to and induces the clustering of its cognate cell surface receptor.…”

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confidence: 99%

Identification of the kinase that activates a nonmetazoan STAT gives insights into the evolution of phosphotyrosine-SH2 domain signaling

Araki

Kawata

Williams

2012

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

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SH2 domains are integral to many animal signaling pathways. By interacting with specific phosphotyrosine residues, they provide regulatable protein-protein interaction domains. Dictyostelium is the only nonmetazoan with functionally characterized SH2 domains, but the cognate tyrosine kinases are unknown. There are no orthologs of the animal tyrosine kinases, but there are very many tyrosine kinase-like kinases (TKLs), a group of kinases which, despite their family name, are classified mainly as serine-threonine kinases. STATs are transcription factors that dimerize via phosphotyrosine-SH2 domain interactions. STATc is activated by phosphorylation on Tyr922 when cells are exposed to the prestalk inducer differentiation inducing factor (DIF-1), a chlorinated hexaphenone. We show that in a null mutant for Pyk2, a tyrosine-specific TKL, exposure to DIF-1 does not activate STATc. Conversely, overexpression of Pyk2 causes constitutive STATc activation. Pyk2 phosphorylates STATc on Tyr922 in vitro and complexes with STATc both in vitro and in vivo. This demonstration that a TKL directly activates a STAT has significant implications for understanding the evolutionary origins of SH2 domain-phosphotyrosine signaling. It also has mechanistic implications. Our previous work suggested that a predicted constitutive STATc tyrosine kinase activity is counterbalanced in vivo by the DIF-1-regulated activity of PTP3, a Tyr922 phosphatase. Here we show that the STATc-Pyk2 complex is formed constitutively by an interaction between the STATc SH2 domain and phosphotyrosine residues on Pyk2 that are generated by autophosphorylation. Also, as predicted, Pyk2 is constitutively active as a STATc kinase. This observation provides further evidence for this highly atypical, possibly ancestral, STAT regulation mechanism. S H2 domains form part of a paradigmatic "writer/reader/ eraser" control module (1, 2) in which the writers are tyrosine kinases (TKs), the readers are SH2 domains, and the erasers are protein tyrosine phosphatases (PTPs). In principle no one element of such a three-component system can function usefully independently of the other two. So how could such a three-component system have evolved? Here the fungi and the amoebozoan Dictyostelium have been informative.Metazoa possess large numbers of TKs, but the only unicellular organisms known to possess them are choanoflagellates, unicellular close relatives of the Metazoa (3, 4). Although neither Dictyostelium nor fungi possess TKs, they do have PTPs, thus suggesting that tyrosine phosphorylation arose in a common ancestor of fungi and Amoebozoa, mediated perhaps by dualspecificity kinases and regulated by dephosphorylation via PTPs (2). There are no phosphotyrosine-binding SH2 domains in fungi, but there is a sequence-related domain within the SPT6 protein that binds phospho-serine and that may have been ancestral to modern SH2 domains (5). In the fungi, therefore, phosphorylation of tyrosine appears to be used solely as a direct modulator of enzymatic function, but in Dictyoste...

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Janus kinases in immune cell signaling

Cited by 995 publications

References 146 publications

Constitutive activation of STAT3 in Sézary syndrome is independent of SHP-1

Constitutive activation of STAT3 in Sézary syndrome is independent of SHP-1

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

Identification of the kinase that activates a nonmetazoan STAT gives insights into the evolution of phosphotyrosine-SH2 domain signaling

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