CDK8-Mediated STAT1-S727 Phosphorylation Restrains NK Cell Cytotoxicity and Tumor Surveillance

Putz, Eva Maria; Gotthardt, Dagmar; Hoermann, Gregor; Csiszar, Agnes; Wirth, Silvia; Berger, Angelika; Straka, Elisabeth; Rigler, Doris; Wallner, Barbara; Jamieson, Amanda M.; Pickl, Winfried F.; Zebedin-Brandl, Eva; Müller, Mathias; Decker, Thomas; Sexl, Veronika

doi:10.1016/j.celrep.2013.07.012

Cited by 107 publications

(104 citation statements)

References 49 publications

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“…It seems likely that the role of TYK2 is linked to its role in IFNa/b signaling, as NK cells from both Ifnar1 ¡/¡ and Stat1 ¡/¡ mice have impaired killing activity. [40][41][42]44 Effects on the expression of the lytic proteins GzmB and Prf1 and on degranulation could be excluded as the underlying mechanisms for IFNAR1 40 and TYK2. Furthermore, we show that TYK2 is not required for conjugate formation of NK cells with their target cells.…”

Section: Discussionmentioning

confidence: 99%

In vivotumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity

et al. 2015

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Abbreviations: CCL3, chemokine (C-C motif) ligand 3; CFSE, carboxyfluorescein diacetate succinimidyl ester; GzmB, granzyme B; IFN, interferon; IFNAR, interferon a and b receptor; IL, interleukin; IL-12Rb1, interleukin-12 receptor subunit b-1; iNK, immature natural killer; JAK, xJanus kinase; MACS, magnetic-activated cell sorting; MFI, mean fluorescence intensity; MHC, major histocompatibility complex; miR, microRNA; mNK, mature natural killer; NK, natural killer; NKP, natural killer precursor; Prf1, perforin; SEM, standard error of the mean; STAT, signal transducer and activator of transcription; T-ALL, T cell acute lymphoblastic leukemia; TYK2, tyrosine kinase 2; TYK2 K923E , kinase-inactive tyrosine kinase 2; WT, wild-typeTyrosine kinase 2 (TYK2) is a Janus kinase (JAK) that is crucially involved in inflammation, carcinogenesis and defense against infection. The cytotoxic activity of natural killer (NK) cells in TYK2-deficient (Tyk2 ¡/¡ ) mice is severely reduced, although the underlying mechanisms are largely unknown. Using Tyk2 ¡/¡ mice and mice expressing a kinase-inactive version of TYK2 (Tyk2 K923E ), we show that NK cell function is partly independent of the enzymatic activity of TYK2. Tyk2 ¡/¡ and Tyk2 K923E NK cells develop normally in the bone marrow, but the maturation of splenic Tyk2 ¡/¡ NK cells (and to a lesser extent of Tyk2 K923E NK cells) is impaired. In contrast, the production of interferon g (IFNg) in response to interleukin 12 (IL-12) or to stimulation through NK cell-activating receptors strictly depends on the presence of enzymatically active TYK2. The cytotoxic activity of Tyk2 K923E NK cells against a range of target cells in vitro is higher than that of Tyk2 ¡/¡ NK cells. Consistently, Tyk2 K923E mice control the growth of NK cell-targeted tumors significantly better than TYK2-deficient mice, showing the physiological relevance of the finding. Inhibitors of TYK2's kinase activity are being developed for the treatment of inflammatory diseases and cancers, but their effects on tumor immune surveillance have not been investigated. Our finding that TYK2 has kinase-independent functions in vivo suggests that such inhibitors will leave NK cell mediated tumor surveillance largely intact and that they will be suitable for use in cancer therapy.

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Section: Discussionmentioning

confidence: 99%

In vivotumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity

et al. 2015

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“…No changes in PAK1 and PAK2 levels were detectable (Fig S3). Stable knockdown of PAK1 , PAK2 , or both genes was achieved using an established, miR30‐shRNA‐based system (Zuber et al , 2011; Fellmann et al , 2013; Putz et al , 2013, 2014; Berger et al , 2014; Scheicher et al , 2015). Knockdown efficiencies were verified by qPCR and immunoblotting (Fig 2A and B).…”

Section: Resultsmentioning

confidence: 99%

Expansion of BCR/ABL1⁺ cells requires PAK2 but not PAK1

et al. 2017

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SummaryThe p21‐activated kinases (PAKs) are key nodes in oncogenic signalling pathways controlling growth, survival, and motility of cancer cells. Their activity is increased in many human cancers and is associated with poor prognosis. To date, PAK deregulation has mainly been studied in solid tumours, where PAK1 and PAK4 are the main isoforms deregulated. We show that PAK1 and PAK2 are the critical isoforms in a BCR/ABL1 + haematopoietic malignancy. In suspension, leukaemic cells deficient for PAK1 and PAK2 undergo apoptosis, while the loss of either protein is well tolerated. Transfer of medium conditioned by shPAK2‐ but not shPAK1‐expressing leukaemic cells interferes with endothelial cell growth. We found that leukaemic cells produce exosomes containing PAK2. Transfer of isolated exosomes supports endothelial cell proliferation. In parallel, we found that leukaemic cells explicitly require PAK2 to grow towards an extracellular matrix. PAK2‐deficient cells fail to form colonies in methylcellulose and to induce lymphomas in vivo. PAK2 might therefore be the critical isoform in leukaemic cells by controlling tumour growth in a dual manner: vascularization via exosome‐mediated transfer to endothelial cells and remodelling of the extracellular matrix. This finding suggests that the PAK2 isoform represents a promising target for the treatment of haematological diseases.

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“…53 CDK8 has been implicated as a STAT1 Ser727 phosphorylating enzyme in NK cells as well, 54 although in this case the enzymatic activity seems rather related with the presence of a basal level of Ser727 STAT1 phosphorylation. With these observations in mind, the basal phosphorylation status of STAT1 in freshly isolated NK cells from both wt and PKC-u ¡/¡ mice reported here is likely attributable to CDK8.…”

Section: Discussionmentioning

confidence: 99%

“…NK cells from mice expressing a mutant STAT1 recalcitrant to phosphorylation in Ser727 have been previously shown to exhibit higher cytotoxicity and granzyme B expression. 54 Considering that granzyme B expression has been shown to be regulated by a post-transcriptional mechanism in NK cells, 47 this effect of mutant STAT1 may relate to an unknown, non-transcriptional role of STAT1. In MEFs expressing mutant STAT1 and stimulated with IFNg the transcription of CXCL10 is augmented rather than diminished.…”

Section: Discussionmentioning

confidence: 99%

IFNα signaling through PKC-θ is essential for antitumor NK cell function

et al. 2014

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CDK8-Mediated STAT1-S727 Phosphorylation Restrains NK Cell Cytotoxicity and Tumor Surveillance

Cited by 107 publications

References 49 publications

In vivotumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity

In vivotumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity

Expansion of BCR/ABL1⁺ cells requires PAK2 but not PAK1

IFNα signaling through PKC-θ is essential for antitumor NK cell function

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CDK8-Mediated STAT1-S727 Phosphorylation Restrains NK Cell Cytotoxicity and Tumor Surveillance

Cited by 107 publications

References 49 publications

In vivotumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity

In vivotumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity

Expansion of BCR/ABL1+ cells requires PAK2 but not PAK1

IFNα signaling through PKC-θ is essential for antitumor NK cell function

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Expansion of BCR/ABL1⁺ cells requires PAK2 but not PAK1