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

Helmke, C., Raab, M., Rödel, F., Matthess, Y., Oellerich, T., Mandal, R., et al. (2016). Ligand stimulation of CD95 induces activation of Plk3 followed by phosphorylation of caspase-8. Cell Research, 26(8), 914-934. doi:10.1038/cr.2016.78.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002B-2F12-0 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-C273-B
Genre: Journal Article

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 Creators:
Helmke, C., Author
Raab, M., Author
Rödel, F., Author
Matthess, Y., Author
Oellerich, T., Author
Mandal, R., Author
Sanhaji, M., Author
Urlaub, H.1, Author              
Rödel, C., Author
Becker, S., Author
Strebhardt, K., Author
Affiliations:
1Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society, ou_578613              

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Free keywords: polo-like kinase; caspase-8; CD95/Fas receptor; apoptosis; kinase regulation
 Abstract: 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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Language(s): eng - English
 Dates: 2016-06-212016-08
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1038/cr.2016.78
 Degree: -

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Title: Cell Research
Source Genre: Journal
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Pages: - Volume / Issue: 26 (8) Sequence Number: - Start / End Page: 914 - 934 Identifier: -