Plk4 trans-autophosphorylation regulates centriole number by controlling betaTrCP-mediated degradation.
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.
Guderian
Gernot
G
Department of Cell Biology, Max-Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
Westendorf
Jens
J
Uldschmid
Andreas
A
Nigg
Erich A
EA
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002502:Centrioles / Q000378:metabolism*; D018385:Centrosome / Q000378:metabolism; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*
C467559:CCP110 protein, human; C534330:CEP135 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D044844:beta-Transducin Repeat-Containing Proteins; C490219:PLK4 protein, human; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex