Ligand stimulation of CD95 induces activation of Plk3 followed by phosphorylation of caspase-8
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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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Phosphorylation of CASP8 at T273 by PLK3 at DISC promotes CASP8 apoptotic functions.
“(2) phosphorylation at T273, which is catalyzed by polo like kinase 3 (PLK3) at the DISC and promotes CASP8 apoptotic functions [307]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [307]
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- Authors
- Helmke, C., Raab, M., Rödel, F., Matthess, Y., Oellerich, T., Mandal, R., Sanhaji, M., Urlaub, H., Rödel, C., Becker, S., & Strebhardt, K.
- Affiliations
- Goethe University Frankfurt (DE)
- Universitätsmedizin Göttingen (DE)
- Corresponding author
- Strebhardt, Klaus
- ORCID
- Venue
- Cell Research
- Published
- 2016-06-21
- Volume
- 26
- Issue
- 8
- Pages
- 914-934
- ISSN
- 1001-0602 (ISSN-L)
- 1748-7838
- PMC
- PMC4973331
- OpenAlex
- W2462979737
- Cited by
- 44
- References
- 70
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 4 · 2022: 4 · 2021: 2 · 2020: 5 · 2019: 5 · 2018: 5 · 2017: 7 · 2016: 2
- FWCI
- 3.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Research (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (acceptedVersion, other-oa)
- GRO (submittedVersion, cc-by-nc-nd)
- Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by-nc-nd)
- MPG.PuRe (Max Planck Society) (submittedVersion, cc-by-nc-nd)
- Funders
- Wilhelm Sander-Stiftung
- Deutsche Krebshilfe
- Deutschen Konsortium für Translationale Krebsforschung
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- Fas, FADD, PLK3, caspase-8, death-inducing signaling complex, extrinsic apoptotic pathway, death receptor signaling, anal cancer, cancer therapy targets
- MeSH terms
- Polo-like Kinases, Enzyme Activation, HeLa Cells, Humans, Isotope Labeling, Ligands, Phosphorylation, Phosphothreonine, Protein Binding, Protein Serine-Threonine Kinases, fas Receptor, Jurkat Cells, Tumor Suppressor Proteins, Protein Interaction Mapping, Immunoprecipitation, Caspase 8, Fas-Associated Death Domain Protein, Death Domain Receptor Signaling Adaptor Proteins
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