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Regulation of Autophosphorylation Controls PLK4 Self-Destruction and Centriole Number

2013; Elsevier BV; Volume: 23; Issue: 22 Linguagem: Inglês

10.1016/j.cub.2013.09.037

1879-0445

Inês Cunha‐Ferreira, Inês Bento, Ana Pimenta-Marques, Swadhin Chandra Jana, Mariana Lince‐Faria, Paulo Duarte, Joana Borrego-Pinto, Samuel Gilberto, Tiago Amado, Daniela A. Brito, Ana Rodrigues-Martins, Janusz Dębski, Nikola S. Dzhindzhev, Mónica Bettencourt‐Dias,

Nuclear Structure and Function

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 [1Bettencourt-Dias M. Rodrigues-Martins A. Carpenter L. Riparbelli M. Lehmann L. Gatt M.K. Carmo N. Balloux F. Callaini G. Glover D.M. SAK/PLK4 is required for centriole duplication and flagella development.Curr. Biol. 2005; 15: 2199-2207Abstract Full Text Full Text PDF PubMed Scopus (444) Google Scholar, 2Habedanck R. Stierhof Y.-D. Wilkinson C.J. Nigg E.A. The Polo kinase Plk4 functions in centriole duplication.Nat. Cell Biol. 2005; 7: 1140-1146Crossref PubMed Scopus (612) Google Scholar, 3Kleylein-Sohn J. Westendorf J. Le Clech M. Habedanck R. Stierhof Y.-D. Nigg E.A. Plk4-induced centriole biogenesis in human cells.Dev. Cell. 2007; 13: 190-202Abstract Full Text Full Text PDF PubMed Scopus (497) Google Scholar, 4Peel N. Stevens N.R. Basto R. Raff J.W. Overexpressing centriole-replication proteins in vivo induces centriole overduplication and de novo formation.Curr. Biol. 2007; 17: 834-843Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 5Rodrigues-Martins A. Riparbelli M. Callaini G. Glover D.M. Bettencourt-Dias M. Revisiting the role of the mother centriole in centriole biogenesis.Science. 2007; 316: 1046-1050Crossref PubMed Scopus (196) Google Scholar]. The SCF-Slimb/βTrCP-E3 ubiquitin ligase controls PLK4 levels through recognition of a conserved phosphodegron [6Brownlee C.W. Klebba J.E. Buster D.W. Rogers G.C. The Protein Phosphatase 2A regulatory subunit Twins stabilizes Plk4 to induce centriole amplification.J. Cell Biol. 2011; 195: 231-243Crossref PubMed Scopus (74) Google Scholar, 7Cunha-Ferreira I. Rodrigues-Martins A. Bento I. Riparbelli M. Zhang W. Laue E. Callaini G. Glover D.M. Bettencourt-Dias M. The SCF/Slimb ubiquitin ligase limits centrosome amplification through degradation of SAK/PLK4.Curr. 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Cancer. 2008; 8: 438-449Crossref PubMed Scopus (724) Google Scholar]. 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 [14Frescas D. 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