TY  - JOUR
A1  - Helmke, Christina
A1  - Raab, Monika
A1  - Rödel, Franz
A1  - Matthess, Yves
A1  - Oellerich, Thomas
A1  - Mandal, Ranadip
A1  - Sanhaji, Mourad
A1  - Urlaub, Henning
A1  - Rödel, Claus
A1  - Becker, Sven
A1  - Strebhardt, Klaus
T1  - Ligand stimulation of CD95 induces activation of Plk3 followed by phosphorylation of caspase-8
T2  - Cell research
N2  - 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.
KW  - Apoptosis
KW  - Cancer
KW  - Cell signalling
KW  - Phosphorylation
KW  - polo-like kinase
KW  - caspase-8
KW  - CD95/Fas receptor
KW  - kinase regulation
Y1  - 2016
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/45226
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-452265
SN  - 1748-7838
SN  - 1001-0602
N1  - 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/
VL  - 26
IS  - 8
SP  - 914
EP  - 934
PB  - Institute of Biochemistry and Cell Biology
CY  - Shanghai
ER  -