Non-canonical STAT1 signaling in natural killer cells
Non-canonical STAT1 signaling in natural killer cells
Disciplines
Biology (50%); Clinical Medicine (10%); Medical-Theoretical Sciences, Pharmacy (40%)
Keywords
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Serine/Threonine Kinase 38,
Natural Killer Cells,
Non-Canonical Stat1 Signaling,
Immunological Synapse,
Tumor Surveillance,
Mouse And Human
Natural killer (NK) cells are large granular lymphocytes and part of the innate immune system. Individuals as well as mice lacking functional NK cells have an increased risk of developing tumors, thereby highlighting the importance of NK cells in the elimination of cancer cells. The rapid and powerful activity of NK cells against cancer cells, while efficiently sparing healthy tissue, makes them an invaluable tool in cancer therapy. Accordingly, ways to enhance NK cell numbers and functionality are manifold and a fast expanding area of current research. The JAK/STAT signaling pathway harbors several hubs that may serve as starting points to boost NK cells anti-tumor potential. In the last decade, we and others found that NK cell functionality can be increased by targeting distinct family members of the JAK/STAT pathway, such as STAT3, CIS, CDK8, or by disabling STAT1-S727 phosphorylation. As part of the JAK/STAT signaling pathway, STAT1 transports extracellular signals from the cell membrane to the nucleus mediating responses to interferons, interleukins and growth factors. Thereby, STAT1 regulates a variety of cellular processes, such as host defense to infection, cell growth and cell death. In the canonical JAK/STAT1 pathway, cytokine binding to the cell surface receptor activates Janus kinases to phosphorylate STAT1 on the amino acid tyrosine 701. Thereby activated, STAT1 proteins form complexes and migrate to the nucleus, where they bind to DNA and modulate target gene transcription. In the nucleus, STAT1 is phosphorylated on serine 727 (S727) by the cyclin-dependent kinase 8 (CDK8). In recent years, a paradigm shift took place when we found deviations from the canonical JAK/STAT pathway depending on the type of stimulation and most importantly depending on the cell origin. In this project, we hypothesize that STAT1 participates in non-canonical signaling pathways that are activated independently of cytokine signaling in the immunological synapse of natural killer cells. We hypothesize that STAT1 is phosphorylated on S727 by a serinehreonine kinase upon target cell contact, and ultimately restrains NK cell cytotoxicity. We aim to (i) define the signals and upstream regulators responsible for non-canonical STAT1 activation and to (ii) study the general role of this serinehreonine kinase in mouse and human NK cells. In the course of this project, we aim to find a novel target to improve NK cell functionality for the potential use in immunotherapy.
- Andre Müller, CeMM – Forschungszentrum für Molekulare Medizin GmbH , national collaboration partner
- Veronika Sexl, Universität Innsbruck , national collaboration partner
- Fengyuan Tang, Universität Basel - Switzerland
Research Output
- 8 Citations
- 7 Publications
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2024
Title STAT3 in acute myeloid leukemia facilitates natural killer cell-mediated surveillance DOI 10.3389/fimmu.2024.1374068 Type Journal Article Author Witalisz-Siepracka A Journal Frontiers in Immunology Pages 1374068 Link Publication -
2024
Title Cell size induced bias of current density in hypertrophic cardiomyocytes DOI 10.1080/19336950.2024.2361416 Type Journal Article Author Lilliu E Journal Channels Pages 2361416 Link Publication -
2024
Title A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations DOI 10.1038/s41467-024-47945-7 Type Journal Article Author Saldana-Guerrero I Journal Nature Communications Pages 3745 Link Publication -
2023
Title NK cells shape the clonal evolution of B cell leukaemia by IFN-? production DOI 10.1101/2023.11.16.567430 Type Preprint Author Buri M Pages 2023.11.16.567430 Link Publication -
2022
Title High-content drug screening in zebrafish xenografts reveals high efficacy of dual MCL-1/BCL-XL inhibition against Ewing sarcoma DOI 10.1016/j.canlet.2022.216028 Type Journal Article Author Grissenberger S Journal Cancer Letters Pages 216028 Link Publication -
2022
Title A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations DOI 10.1101/2022.11.21.515753 Type Preprint Author Saldana-Guerrero I Pages 2022.11.21.515753 Link Publication -
2022
Title High-content drug screening in zebrafish xenografts reveals high efficacy of dual MCL-1/BCL-XL inhibition against Ewing sarcoma DOI 10.5167/uzh-226851 Type Other Author Grissenberger