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Asterless is a Polo-like kinase 4 substrate that both activates and inhibits kinase activity depending on its phosphorylation state
- Source :
- Molecular Biology of the Cell
- Publication Year :
- 2018
- Publisher :
- American Society for Cell Biology (ASCB), 2018.
-
Abstract
- Centriole assembly initiates when Polo-like kinase 4 (Plk4) interacts with a centriole “targeting-factor.” In Drosophila, Asterless/Asl (Cep152 in humans) fulfills the targeting role. Interestingly, Asl also regulates Plk4 levels. The N-terminus of Asl (Asl-A; amino acids 1-374) binds Plk4 and promotes Plk4 self-destruction, although it is unclear how this is achieved. Moreover, Plk4 phosphorylates the Cep152 N-terminus, but the functional consequence is unknown. Here, we show that Plk4 phosphorylates Asl and mapped 13 phospho-residues in Asl-A. Nonphosphorylatable alanine (13A) and phosphomimetic (13PM) mutants did not alter Asl function, presumably because of the dominant role of the Asl C-terminus in Plk4 stabilization and centriolar targeting. To address how Asl-A phosphorylation specifically affects Plk4 regulation, we generated Asl-A fragment phospho-mutants and expressed them in cultured Drosophila cells. Asl-A-13A stimulated kinase activity by relieving Plk4 autoinhibition. In contrast, Asl-A-13PM inhibited Plk4 activity by a novel mechanism involving autophosphorylation of Plk4’s kinase domain. Thus, Asl-A’s phosphorylation state determines which of Asl-A’s two opposing effects are exerted on Plk4. Initially, nonphosphorylated Asl binds Plk4 and stimulates its kinase activity, but after Asl is phosphorylated, a negative-feedback mechanism suppresses Plk4 activity. This dual regulatory effect by Asl-A may limit Plk4 to bursts of activity that modulate centriole duplication.
- Subjects :
- 0301 basic medicine
PLK4
Cell Cycle Proteins
Polo-like kinase
Protein Serine-Threonine Kinases
Biology
Cell Line
03 medical and health sciences
0302 clinical medicine
otorhinolaryngologic diseases
Animals
Drosophila Proteins
Amino Acid Sequence
Phosphorylation
Kinase activity
Molecular Biology
Cytoskeleton
Centrioles
Kinase
Cell Cycle
Autophosphorylation
Articles
Cell Biology
Cell biology
030104 developmental biology
Protein kinase domain
Drosophila
030217 neurology & neurosurgery
Protein Binding
Centriole assembly
Subjects
Details
- ISSN :
- 19394586 and 10591524
- Volume :
- 29
- Database :
- OpenAIRE
- Journal :
- Molecular Biology of the Cell
- Accession number :
- edsair.doi.dedup.....beafa3eb046e6042f5b9b6ee22879a2a