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Although this constitutive activation of\u00a0cytokine receptors is strongly associated with malignant disorders, ligand-independent receptor activation is also a useful tool in synthetic biology e.g. to improve adoptive cellular therapies with genetically modified T-cells. Balanced Interleukin (IL-)7 signaling via a heterodimer of IL-7 receptor (IL-7R\u03b1) and the common \u03b3-chain (\u03b3c) controls T- and B-cell development and expansion, whereas uncontrolled IL-7 signaling can drive acute lymphoid leukemia (ALL) development. The ALL-driver mutation PPCL in the transmembrane domain of IL-7R\u03b1 is a mutational insertion of the four amino acids proline-proline-cysteine-leucine and leads to ligand-independent receptor dimerization and constitutive activation. We showed here in the cytokine-dependent pre-B-cell line Ba\/F3 that the PPCL-insertion in a synthetic version of the IL-7R\u03b1 induced \u03b3c-independent STAT5 and ERK\u00a0phosphorylation and also proliferation of the cells and that booster-stimulation by arteficial ligands additionally generated non-canonical STAT3 phosphorylation via the synthetic IL-7R\u03b1-PPCL-receptors. Transfer of the\u00a0IL-7R\u03b1 transmembrane domain with the PPCL insertion into\u00a0natural and synthetic cytokine receptor chains of the IL-6, IL-12 and Interferon families also resulted in constitutive receptor signaling. In conclusion, our data suggested that the insertion of the mutated PPCL IL-7R\u03b1 transmembrane domain is an universal approach to generate ligand-independent, constitutively active cytokine receptors.<\/jats:p>","DOI":"10.1515\/hsz-2023-0344","type":"journal-article","created":{"date-parts":[[2024,5,2]],"date-time":"2024-05-02T11:55:31Z","timestamp":1714650931000},"page":"531-544","source":"Crossref","is-referenced-by-count":3,"title":["Unpaired cysteine insertions favor transmembrane dimerization and induce ligand-independent constitutive cytokine receptor signaling"],"prefix":"10.1515","volume":"405","author":[{"given":"Lynn Affrica Felicitas","family":"Baumg\u00e4rtner","sequence":"first","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital D\u00fcsseldorf , Heinrich-Heine-University D\u00fcsseldorf , D-40225 D\u00fcsseldorf , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Ettich","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital D\u00fcsseldorf , Heinrich-Heine-University D\u00fcsseldorf , D-40225 D\u00fcsseldorf , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helene","family":"Balles","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital D\u00fcsseldorf , Heinrich-Heine-University D\u00fcsseldorf , D-40225 D\u00fcsseldorf , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2387-8935","authenticated-orcid":false,"given":"Dorothee Johanna","family":"Lapp","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital D\u00fcsseldorf , Heinrich-Heine-University D\u00fcsseldorf , D-40225 D\u00fcsseldorf , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sofie","family":"Mossner","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital D\u00fcsseldorf , Heinrich-Heine-University D\u00fcsseldorf , D-40225 D\u00fcsseldorf , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christin","family":"Bassenge","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital D\u00fcsseldorf , Heinrich-Heine-University D\u00fcsseldorf , D-40225 D\u00fcsseldorf , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9609-1642","authenticated-orcid":false,"given":"Meryem","family":"Ouzin","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital D\u00fcsseldorf , Heinrich-Heine-University D\u00fcsseldorf , D-40225 D\u00fcsseldorf , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0451-2735","authenticated-orcid":false,"given":"Helmut","family":"Hanenberg","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology and Head\/Neck Surgery, Medical Faculty and University Hospital D\u00fcsseldorf , Heinrich-Heine-University D\u00fcsseldorf , D-40225 D\u00fcsseldorf , Germany"},{"name":"Department of Pediatrics III , University Children\u2019s Hospital Essen, University of Duisburg-Essen , D-45122 Essen , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9932-1055","authenticated-orcid":false,"given":"J\u00fcrgen","family":"Scheller","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital D\u00fcsseldorf , Heinrich-Heine-University D\u00fcsseldorf , D-40225 D\u00fcsseldorf , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6675-5313","authenticated-orcid":false,"given":"Doreen Manuela","family":"Floss","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital D\u00fcsseldorf , Heinrich-Heine-University D\u00fcsseldorf , D-40225 D\u00fcsseldorf , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"374","published-online":{"date-parts":[[2024,5,3]]},"reference":[{"key":"2024071211463067941_j_hsz-2023-0344_ref_001","doi-asserted-by":"crossref","unstructured":"Almeida, A.R.M., Neto, J.L., Cachucho, A., Euzebio, M., Meng, X., Kim, R., Fernandes, M.B., Raposo, B., Oliveira, M.L., Ribeiro, D., et al.. 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