Control of centriole numbers by Plk4 autophosphorylation and βTrCP-mediated degradation

Guderian, Gernot. Control of centriole numbers by Plk4 autophosphorylation and βTrCP-mediated degradation. 2010, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_9277

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Proper centrosome numbers are imperative for faithful cell division, as aberrant centrosome numbers can lead to chromosomal instability, a hallmark of cancer development (Nigg 2002; Ganem et al., 2009). Hence, initiation of centriole duplication has to be tightly regulated. Recently, we and others demonstrated that Polo-like kinase 4 (Plk4) fulfills a pivotal role in regulating this process (Bettencourt-Dias et al., 2005; Habedanck et al., 2005). Plk4 protein levels and its activity directly correlate with centriole numbers: depletion of Plk4 leads to sequential loss of centrioles in successive cell divisions (Bettencourt-Dias et al., 2005; Habedanck et al., 2005) and its overexpression promotes bona fide overduplication of centrioles (Habedanck et al., 2005; Kleylein-Sohn et al., 2007), while both lead to progressive increase in abnormal spindle formation (reviewed in Nigg 2007). Even though Plk4 is a key regulator of centriole biogenesis and is crucial for maintaining constant centriole number, the mechanisms regulating its activity and expression are only beginning to emerge.
Here, we show that human Plk4 is subject to beta-TrCP-dependent proteasomal degradation, indicating that this pathway is conserved from Drosophila to human (Cunha-Ferreira et al., 2009; Rogers et al., 2009). Unexpectedly, we found that stable overexpression of kinase-dead Plk4 leads to centriole overduplication. Our data indicate that this phenotype depends on the presence of endogenous wild-type Plk4 and that centriole overduplication results from disruption of Plk4 trans-autophosphorylation by kinase-dead Plk4, which then shields endogenous Plk4 from recognition by beta-TrCP. We conclude that active Plk4 promotes its own degradation by catalyzing beta-TrCP binding through trans-autophosphorylation within homodimers which has been independently confirmed by others (Holland et al., 2010). Additionally, we propose that Plk4 autophosphorylation is not sufficient for its degradation and that instead an additional kinase is required for this process.
Advisors:Nigg, Erich A.
Committee Members:Spang, Anne and Hemmings, Brian A.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Cell Biology (Nigg)
UniBasel Contributors:Nigg, Erich A. and Spang, Anne
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:9277
Thesis status:Complete
Number of Pages:85 Bl.
Identification Number:
edoc DOI:
Last Modified:22 Jan 2018 15:51
Deposited On:27 Dec 2010 10:35

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