Abstract
Centrioles are the main constituents of the mammalian centrosome and act as basal bodies for ciliogenesis. Centrosomes organize the cytoplasmic microtubule network during interphase and the mitotic spindle during mitosis, and aberrations in centrosome number have been implicated in chromosomal instability and tumor formation. The centriolar protein Polo-like kinase 4 (Plk4) is a key regulator of centriole biogenesis and is crucial for maintaining constant centriole number, but the mechanisms regulating its activity and expression are only beginning to emerge. Here, we show that human Plk4 is subject to betaTrCP-dependent proteasomal degradation, indicating that this pathway is conserved from Drosophila to human. Unexpectedly, we found that stable overexpression of kinase-dead Plk4 leads to centriole overduplication. This phenotype depends on the presence of endogenous wild-type Plk4. Our data indicate that centriole overduplication results from disruption of Plk4 trans-autophosphorylation by kinase-dead Plk4, which then shields endogenous Plk4 from recognition by betaTrCP. We conclude that active Plk4 promotes its own degradation by catalyzing betaTrCP binding through trans-autophosphorylation (phosphorylation by the other kinase in the dimer) within homodimers.
Highlights
Centrioles are the main constituents of the mammalian centrosome and act as basal bodies for ciliogenesis (Nigg and Raff, 2009)
Centrosomes organize the cytoplasmic microtubule network during interphase and the mitotic spindle during mitosis, and aberrations in centrosome number have been implicated in chromosomal instability and tumor formation
We show that human Polo-like kinase 4 (Plk4) is subject to TrCP-dependent proteasomal degradation, indicating that this pathway is conserved from Drosophila to human
Summary
Centrioles are the main constituents of the mammalian centrosome and act as basal bodies for ciliogenesis (Nigg and Raff, 2009). Centrosome assembly as well as centriole biogenesis and duplication are crucial processes requiring accurate control (Bornens, 2002; Doxsey et al, 2005; Strnad and Gonczy, 2008; Nigg and Raff, 2009). Echoing earlier studies in invertebrate model organisms (Kirkham et al, 2003; Delattre et al, 2006; Pelletier et al, 2006; Kilburn et al, 2007; Nakazawa et al, 2007; Rodrigues-Martins et al, 2007; Dammermann et al, 2008; Song et al, 2008), Plk4-induced centriole biogenesis in human cells involves the sequential assembly of several essential proteins, including human Sas-6, Cep135, CPAP (human Sas-4) and CP110 (Kleylein-Sohn et al, 2007). Our results lead us to conclude that Plk undergoes autophosphorylation in trans and that this modification is crucial for Plk stability and the maintenance of a constant centriole number
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