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Curr Biol. 2013 Nov 18;23(22):2245-2254. doi: 10.1016/j.cub.2013.09.037. Epub 2013 Oct 31.

Regulation of autophosphorylation controls PLK4 self-destruction and centriole number.

Author information

1
Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal. Electronic address: ananasferreira@gmail.com.
2
Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal.
3
Institute of Biochemistry and Biophysics, PAS, Pawinskiego 5a, 02-106, Warszawa, Poland.
4
Cancer Research UK Cell Cycle Genetics Group, Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
5
Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal. Electronic address: mdias@igc.gulbenkian.pt.

Abstract

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. The SCF-Slimb/βTrCP-E3 ubiquitin ligase controls PLK4 levels through recognition of a conserved phosphodegron. SCF-Slimb/βTrCP substrate binding and targeting for degradation is normally regulated by phosphorylation cascades, controlling complex processes, such as circadian clocks and morphogenesis. 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, our work provides novel links between centriole number control and tumorigenesis.

PMID:
24184099
DOI:
10.1016/j.cub.2013.09.037
[Indexed for MEDLINE]
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