Ligand stimulation of CD95 induces activation of Plk3 followed by phosphorylation of caspase-8

  • 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.

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Author:Christina Helmke, Monika Raab, Franz RödelORCiDGND, Yves Matthess, Thomas OellerichORCiD, Ranadip MandalORCiDGND, Mourad Sanhaji, Henning Urlaub, Claus RödelORCiDGND, Sven Becker, Klaus Strebhardt
URN:urn:nbn:de:hebis:30:3-452265
DOI:https://doi.org/10.1038/cr.2016.78
ISSN:1748-7838
ISSN:1001-0602
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/27325299
Parent Title (English):Cell research
Publisher:Institute of Biochemistry and Cell Biology
Place of publication:Shanghai
Document Type:Article
Language:English
Year of Completion:2016
Date of first Publication:2016/06/21
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2017/12/14
Tag:Apoptosis; CD95/Fas receptor; Cancer; Cell signalling; Phosphorylation; caspase-8; kinase regulation; polo-like kinase
Volume:26
Issue:8
Page Number:21
First Page:914
Last Page:934
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/
HeBIS-PPN:427891906
Institutes:Biowissenschaften / Biowissenschaften
Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0