Current biology, 2013-11, Vol.23 (22), p.2245-2254
2013
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Details
- Autor(en) / Beteiligte
- Titel
- Regulation of Autophosphorylation Controls PLK4 Self-Destruction and Centriole Number
- Ist Teil von
- Current biology, 2013-11, Vol.23 (22), p.2245-2254
- Ort / Verlag
- England: Elsevier Ltd
- Erscheinungsjahr
- 2013
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Polo-like kinase 4 (PLK4) is a major player in centriole biogenesis: in its absence centrioles fail to form, while in excess leads to centriole amplification [1–5]. The SCF-Slimb/βTrCP-E3 ubiquitin ligase controls PLK4 levels through recognition of a conserved phosphodegron [6–13]. SCF-Slimb/βTrCP substrate binding and targeting for degradation is normally regulated by phosphorylation cascades, controlling complex processes, such as circadian clocks and morphogenesis [14]. Here, we show that PLK4 is a suicide kinase, autophosphorylating in residues that are critical for SCF-Slimb/βTrCP binding. We demonstrate a multisite trans-autophosphorylation mechanism, likely to ensure that both a threshold of PLK4 concentration is attained and a sequence of events is observed before PLK4 can autodestruct. First, we show that PLK4 trans-autophosphorylates other PLK4 molecules on both Ser293 and Thr297 within the degron and that these residues contribute differently for PLK4 degradation, the first being critical and the second maximizing auto-destruction. Second, PLK4 trans-autophosphorylates a phospho-cluster outside the degron, which regulates Thr297 phosphorylation, PLK4 degradation, and centriole number. Finally, we show the importance of PLK4-Slimb/βTrCP regulation as it operates in both soma and germline. As βTrCP, PLK4, and centriole number are deregulated in several cancers [14–17], our work provides novel links between centriole number control and tumorigenesis. [Display omitted] •PLK4 trans-autophosphorylates degron residues Ser293/Thr297 and a phospho-cluster•Ser293 is critical whereas Thr297 maximizes PLK4 degradation•Thr297 phosphorylation is regulated by a phospho-cluster•PLK4 protein levels are controlled by Slimb in vivo
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0960-9822eISSN: 1879-0445DOI: 10.1016/j.cub.2013.09.037Titel-ID: cdi_proquest_miscellaneous_1492618728
- Format
- –
- Schlagworte
- Amino Acid Sequence, Animals, Animals, Genetically Modified, biogenesis, carcinogenesis, Cell Cycle Proteins - genetics, Cell Cycle Proteins - metabolism, centrioles, Centrioles - metabolism, circadian rhythm, Drosophila - genetics, Drosophila - metabolism, Drosophila Proteins - genetics, Drosophila Proteins - metabolism, Female, Gene Expression Regulation, germ cells, Male, Molecular Sequence Data, morphogenesis, neoplasms, Phosphorylation, Protein-Serine-Threonine Kinases - genetics, Protein-Serine-Threonine Kinases - metabolism, Serine - metabolism, Threonine - metabolism, ubiquitin-protein ligase, Ubiquitin-Protein Ligases - genetics, Ubiquitin-Protein Ligases - metabolism