Inborn Errors of Human JAKs and STATs

Casanova, Jean‐Laurent; Holland, Steven M.; Notarangelo, Luigi D.

doi:10.1016/j.immuni.2012.03.016

Cited by 294 publications

(272 citation statements)

References 148 publications

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“…The basis for the small increased transcriptional activity and, presumably, the partial oncogenic capacity of STAT3C (as the mutant was named) was a more avid DNA binding of the STAT3C mutant leading to a slower off time from DNA than wild type and a concomitant slower dephosphorylation rate. Most recently human mutations, both positive-and negative-acting in STATs 1 and 3 (21,(27)(28)(29)(30)(31), have been reported especially in the SH2 domain, some of which have constitutive activity (31).…”

Section: Stat3 | Linker Domain | Mutantsmentioning

confidence: 99%

Mutations in the linker domain affect phospho-STAT3 function and suggest targets for interrupting STAT3 activity

Mertens

Haripal

Klinge

et al. 2015

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

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Crystallography of the cores of phosphotyrosine-activated dimers of STAT1 (132–713) and STAT3 (127–722) bound to a similar double-stranded deoxyoligonucleotide established the domain structure of the STATs and the structural basis for activation through tyrosine phosphorylation and dimerization. We reported earlier that mutants in the linker domain of STAT1 that connect the DNA-binding domain and SH2 domain can prevent transcriptional activation. Because of the pervasive importance of persistently activated STAT3 in many human cancers and the difficulty of finding useful drug candidates aimed at disrupting the pY interchange in active STAT3 dimers, we have examined effects of an array of mutants in the STAT3 linker domain. We have found several STAT3 linker domain mutants to have profound effects of inhibiting STAT3 transcriptional activation. From these results, we propose (i) there is definite functional interaction of the linker both with the DNA binding domain and with the SH2 domain, and (ii) these putative contacts provide potential new targets for small molecule-induced pSTAT3 inhibition.

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Section: Stat3 | Linker Domain | Mutantsmentioning

confidence: 99%

Mutations in the linker domain affect phospho-STAT3 function and suggest targets for interrupting STAT3 activity

Mertens

Haripal

Klinge

et al. 2015

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

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“…This suggested that the wild-type residues would contribute to formation and stabilization of the antiparallel dimer and help to facilitate the subsequent Tyr-701 dephosphorylation process. In fact, in addition to the GOF residues of the CCD, the DBD residues facing the ␣3 helix of the dimeric counterpart, such as Gly-384, Thr-385, and Lys-388, were also frequently identified as CMC pathogenic mutations (3,4). Hence, missense mutations substituting Gln-275 or Glu-282, which were newly identified in this report as GOF residues and that surrounded the interface of the anti-parallel dimer, could give a high risk for onset and development of CMC disease.…”

Section: Discussionmentioning

confidence: 99%

“…Recent progress in the methodologies of genome sequencing has revealed a wide variety of single nucleotide polymorphisms in the STAT1 gene locus (3,4). These mutations frequently change the resultant STAT1 amino acid sequence but rarely generate critical damage to its immunoregulatory functions.…”

mentioning

confidence: 99%

Molecular mechanism and structural basis of gain-of-function of STAT1 caused by pathogenic R274Q mutation

Fujiki

Hijikata

Shirai

et al. 2017

Journal of Biological Chemistry

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Edited by Eric R. FearonGain-of-function (GOF) mutations in the STAT1 gene are critical for the onset of chronic mucocutaneous candidiasis (CMC) disease. However, the molecular basis for the gain of STAT1 function remains largely unclear. Here, we investigated the structural features of STAT1 GOF residues to better understand the impact of these pathogenic mutations. We constructed STAT1 alanine mutants of the ␣3 helix residues of the coiled-coil domain, which are frequently found in CMC pathogenic mutations, and measured their transcriptional activities. Most of the identified GOF residues were located inside the coiled-coil domain stem structure or at the protein surface of the anti-parallel dimer interface. Unlike those, Arg-274 was adjacent to the DNA-binding domain. In addition, Arg-274 was found to functionally interact with Gln-441 in the DNA-binding domain. Because Gln-441 is located at the anti-parallel dimer contact site, Gln-441 reorientation by Arg-274 mutation probably impedes formation of the dimer. Further, the statistical analysis of RNA-seq data with STAT1-deficient epithelial cells and primary T cells from a CMC patient revealed that the R274Q mutation affected gene expression levels of 66 and 76 non-overlapping RefSeq genes, respectively. Because their transcription levels were only slightly modulated by wild-type STAT1, we concluded that the R274Q mutation increased transcriptional activity but did not change dramatically the repertoire of STAT1 targets. Hence, we provide a novel mechanism of STAT1 GOF triggered by a CMC pathogenic mutation.

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“…JAK activation leads to phosphorylation of the receptor and recruitment of STAT family transcription factors, which are then phosphorylated by the JAK and translocated to the nucleus where they induce gene transcription. The JAK family consists of four members (JAK1, JAK2, JAK3, and tyrosine kinase 2 or TYK2), each of which binds a distinct set of cytokine receptor subtypes and hence has a unique gene knockout phenotype, ranging from embryonic lethality due to neuronal and erythropoietic defects (JAK1 and JAK2, respectively) (3)(4)(5), to profound immune system deficiencies (JAK3 and TYK2) (6).…”

Section: Jak1 | Jak3mentioning

confidence: 99%

Structure of the pseudokinase–kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition

Lupardus¹,

Ultsch²,

Wallweber³

et al. 2014

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

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241

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Janus kinases (JAKs) are receptor-associated multidomain tyrosine kinases that act downstream of many cytokines and interferons. JAK kinase activity is regulated by the adjacent pseudokinase domain via an unknown mechanism. Here, we report the 2.8-Å structure of the two-domain pseudokinase-kinase module from the JAK family member TYK2 in its autoinhibited form. We find that the pseudokinase and kinase interact near the kinase active site and that most reported mutations in cancer-associated JAK alleles cluster in or near this interface. Mutation of residues near the TYK2 interface that are analogous to those in cancer-associated JAK alleles, including the V617F and "exon 12" JAK2 mutations, results in increased kinase activity in vitro. These data indicate that JAK pseudokinases are autoinhibitory domains that hold the kinase domain inactive until receptor dimerization stimulates transition to an active state. JAK1 | JAK3H elical bundle cytokines of the interleukin and IFN families regulate a wide variety of immune and cellular growth responses (1). These signaling pathways are initiated by cytokinemediated receptor dimerization and subsequent activation of nonreceptor tyrosine kinases called Janus kinases (JAKs) that are associated with the receptor intracellular domains (2). JAK activation leads to phosphorylation of the receptor and recruitment of STAT family transcription factors, which are then phosphorylated by the JAK and translocated to the nucleus where they induce gene transcription. The JAK family consists of four members (JAK1, JAK2, JAK3, and tyrosine kinase 2 or TYK2), each of which binds a distinct set of cytokine receptor subtypes and hence has a unique gene knockout phenotype, ranging from embryonic lethality due to neuronal and erythropoietic defects (JAK1 and JAK2, respectively) (3-5), to profound immune system deficiencies (JAK3 and TYK2) (6).The JAK kinases are large (∼1,150-aa) multidomain proteins whose primary sequences were initially organized into seven JAK-homology (JH) domains that reflected distinct regions of high sequence homology (7). Subsequent structure predictions indicated that JAKs contain four distinct domains: N-terminal 4.1, Ezrin, Radixin, Moesin (FERM) and Src homology 2 (SH2) domains, followed by C-terminal pseudokinase and kinase domains (7,8) (Fig. 1A). The FERM and SH2 domains constitute the receptor-binding module (2), whereas the pseudokinase, which has a canonical kinase fold but lacks key catalytic residues, is thought to regulate kinase activity. Deletion of the pseudokinase in JAK2 and JAK3 increases basal kinase activity and deregulates signaling through cognate receptors (9, 10). Additionally, the JAK2 pseudokinase and kinase domains have been reported to coimmunoprecipitate, and coexpression of the JAK2 pseudokinase domain inhibits activity of the isolated kinase domain (10). Recent work on the JAK2 pseudokinase domain indicates that it has weak catalytic activity and autophosphorylates two inhibitory sites within the SH2-pseudokinase linker and pseudokinase...

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Inborn Errors of Human JAKs and STATs

Cited by 294 publications

References 148 publications

Mutations in the linker domain affect phospho-STAT3 function and suggest targets for interrupting STAT3 activity

Mutations in the linker domain affect phospho-STAT3 function and suggest targets for interrupting STAT3 activity

Molecular mechanism and structural basis of gain-of-function of STAT1 caused by pathogenic R274Q mutation

Structure of the pseudokinase–kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition

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