Tyrosine kinase 2 – Surveillant of tumours and bona fide oncogene

Leitner, Nicole R.; Witalisz-Siepracka, Agnieszka; Strobl, Birgit; Müller, Mathias

doi:10.1016/j.cyto.2015.10.015

Cited by 49 publications

(50 citation statements)

References 192 publications

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“…This conceptual dualistic view could advance diagnostic predictions in the future. (6)(7)(8)(9)(10)(11)(12). The JAK-STAT pathway is highly conserved and diseases caused by germ-line or somatic mutations in JAKs or STATs are almost equivalent when studied in transgenic mice or found in patients and explored molecularly in human/patient-derived cell systems (13-15).…”

Section: Discussionmentioning

confidence: 99%

Steering of carcinoma progression by the YIN/YANG interaction of STAT1/STAT3

Friedrich¹,

Dolznig

Han

et al. 2017

BST

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Section: Discussionmentioning

confidence: 99%

Steering of carcinoma progression by the YIN/YANG interaction of STAT1/STAT3

Friedrich¹,

Dolznig

Han

et al. 2017

BST

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“…JAK/ STAT signaling components are frequently altered in cancers, and considerable effort is directed toward the development of specific inhibitors for tumor therapy (21)(22)(23)(24). TYK2 inhibitors are considered for the treatment of inflammatory diseases and tumor therapy (25)(26)(27)(28)(29)(30)(31)(32). However, to realize their full potential and to identify harmful side effects, a better understanding of how TYK2 regulates NK cell function and antitumor activity is required.…”

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confidence: 99%

NK Cells Require Cell-Extrinsic and -Intrinsic TYK2 for Full Functionality in Tumor Surveillance and Antibacterial Immunity

Simonović

Witalisz-Siepracka

Meissl

et al. 2019

The Journal of Immunology

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Tyrosine kinase 2 (TYK2) is a widely expressed receptor-associated kinase that is involved in signaling by a variety of cytokines with important immune regulatory activities. Absence of TYK2 in mice results in impaired NK cell maturation and antitumor activity, although underlying mechanisms are largely unknown. Using conditional ablation of TYK2 in NK cells we show that TYK2 is required for IFN-g production by NK cells in response to IL-12 and for an efficient immune defense against Listeria monocytogenes. Deletion of TYK2 in NK cells did not impact NK cell maturation and IFN-g production upon NK cell activating receptor (actR) stimulation. Similarly, NK cell-mediated tumor surveillance was unimpaired upon deletion of TYK2 in NK cells only. In line with the previously reported maturation-associated Ifng promoter demethylation, the less mature phenotype of Tyk2 2/2 NK cells correlated with an increased CpG methylation at the Ifng locus. Treatment with the DNA hypomethylating agent 5-aza-2-deoxycytidine restored the ability of Tyk2 2/2 NK cells to produce IFN-g upon actR but not upon IL-12 stimulation. NK cell maturation was dependent on the presence of TYK2 in dendritic cells and could be rescued in Tyk2-deficient mice by treatment with exogenous IL-15/IL-15Ra complexes. IL-15 treatment also rescued the in vitro cytotoxicity defect and the impaired actR-induced IFN-g production of Tyk2 2/2 NK cells. Collectively, our findings provide the first evidence, to our knowledge, for a key role of TYK2 in the host environment in promoting NK cell maturation and antitumor activity.

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“…Some STATs also exhibit transcriptional activity when non-phosphorylated; these have been covered in recent reviews [49,50]. TYK2 activity is negatively regulated by intrinsic mechanisms, such as post-translational modifications and conformational inhibition [33,37], and by extrinsic effectors, such as protein tyrosine phosphatases (PTPs, e.g., PTB1B, SHP1 [51,52]) and suppressor of cytokine signaling (SOCS) proteins (e.g., SOCS1, SOCS3 [53]). In addition, chaperones, in particular heat shock protein (HSP) 90 [54], and noncoding RNAs [55,56] influence the stability and production of TYK2.…”

Section: Identification and Structure-function Relations Of Tyk2mentioning

confidence: 99%

TYK2 in Tumor Immunosurveillance

Karjalainen¹,

Shoebridge²,

Krunic³

et al. 2020

Cancers

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We review the history of the tyrosine kinase 2 (TYK2) as the founding member of the Janus kinase (JAK) family and outline its structure-function relation. Gene-targeted mice and hereditary defects of TYK2 in men have established the biological and pathological functions of TYK2 in innate and adaptive immune responses to infection and cancer and in (auto-)inflammation. We describe the architecture of the main cytokine receptor families associated with TYK2, which activate signal transducers and activators of transcription (STATs). We summarize the cytokine receptor activities with well characterized dependency on TYK2, the types of cells that respond to cytokines and TYK2 signaling-induced cytokine production. TYK2 may drive beneficial or detrimental activities, which we explain based on the concepts of tumor immunoediting and the cancer-immunity cycle in the tumor microenvironment. Finally, we summarize current knowledge of TYK2 functions in mouse models of tumor surveillance. The biology and biochemistry of JAKs, TYK2-dependent cytokines and cytokine signaling in tumor surveillance are well covered in recent reviews and the oncogenic properties of TYK2 are reviewed in the recent Special Issue ‘Targeting STAT3 and STAT5 in Cancer’ of Cancers.

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Tyrosine kinase 2 – Surveillant of tumours and bona fide oncogene

Cited by 49 publications

References 192 publications

Steering of carcinoma progression by the YIN/YANG interaction of STAT1/STAT3

Steering of carcinoma progression by the YIN/YANG interaction of STAT1/STAT3

NK Cells Require Cell-Extrinsic and -Intrinsic TYK2 for Full Functionality in Tumor Surveillance and Antibacterial Immunity

TYK2 in Tumor Immunosurveillance

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