Christina Helmke, Monika Raab, Franz Rödel, Yves Matthess, Thomas Oellerich, Ranadip Mandal, Mourad Sanhaji, Henning Urlaub, Claus Rödel, Sven Becker, Klaus Strebhardt
- Upon interaction of the CD95 receptor with its ligand, sequential association of the adaptor molecule FADD (MORT1), pro-forms of caspases-8/10, and the caspase-8/10 regulator c-FLIP leads to the formation of a death-inducing signaling complex. Here, we identify polo-like kinase (Plk) 3 as a new interaction partner of the death receptor CD95. The enzymatic activity of Plk3 increases following interaction of the CD95 receptor with its ligand. Knockout (KO) or knockdown of caspase-8, CD95 or FADD prevents activation of Plk3 upon CD95 stimulation, suggesting a requirement of a functional DISC for Plk3 activation. Furthermore, we identify caspase-8 as a new substrate for Plk3. Phosphorylation occurs on T273 and results in stimulation of caspase-8 proapoptotic function. Stimulation of CD95 in cells expressing a non-phosphorylatable caspase-8-T273A mutant in a rescue experiment or in Plk3-KO cells generated by CRISPR/Cas9 reduces the processing of caspase-8 prominently. Low T273 phosphorylation correlates significantly with low Plk3 expression in a cohort of 95 anal tumor patients. Our data suggest a novel mechanism of kinase activation within the Plk family and propose a new model for the stimulation of the extrinsic death pathway in tumors with high Plk3 expression.
MetadatenAuthor: | Christina Helmke, Monika RaabORCiD, Franz RödelORCiDGND, Yves MatthessORCiDGND, Thomas OellerichORCiD, Ranadip MandalORCiDGND, Mourad SanhajiORCiDGND, Henning UrlaubORCiD, Claus RödelORCiDGND, Sven BeckerORCiDGND, Klaus StrebhardtORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-452265 |
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DOI: | https://doi.org/10.1038/cr.2016.78 |
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ISSN: | 1748-7838 |
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ISSN: | 1001-0602 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/27325299 |
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Parent Title (English): | Cell research |
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Publisher: | Institute of Biochemistry and Cell Biology |
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Place of publication: | Shanghai |
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Document Type: | Article |
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Language: | English |
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Year of Completion: | 2016 |
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Date of first Publication: | 2016/06/21 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2017/12/14 |
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Tag: | Apoptosis; CD95/Fas receptor; Cancer; Cell signalling; Phosphorylation; caspase-8; kinase regulation; polo-like kinase |
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Volume: | 26 |
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Issue: | 8 |
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Page Number: | 21 |
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First Page: | 914 |
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Last Page: | 934 |
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Note: | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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HeBIS-PPN: | 427891906 |
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Institutes: | Biowissenschaften / Biowissenschaften |
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| Medizin / Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0 |
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