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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay

Published on: May 3, 2018

KIBRA protein phosphorylation is regulated by mitotic kinase aurora and protein phosphatase 1

Ling Xiao1, Yuanhong Chen, Ming Ji

  • 1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.

The Journal of Biological Chemistry
|September 1, 2011
PubMed

Insights

Human KIBRA is a phosphoprotein regulated during mitosis by Aurora kinases and protein phosphatase 1 (PP1). Its phosphorylation impacts mitotic progression and links Hippo signaling to cell division.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Kibra (Kibra homolog) is a novel regulator of the Hippo pathway in Drosophila, controlling tissue growth by modulating cell proliferation and apoptosis.
  • The precise cellular functions and regulation of human KIBRA are not well understood.
  • The Hippo pathway is crucial for organ size control and tumor suppression.

Purpose of the Study:

  • To investigate the regulation and cellular function of human KIBRA.
  • To determine the role of KIBRA phosphorylation in cell cycle progression.
  • To elucidate the relationship between KIBRA, the Hippo pathway, and mitotic machinery.

Main Methods:

  • Phosphoprotein analysis of KIBRA.
  • In vitro and in vivo kinase assays using Aurora-A and Aurora-B.
  • Site-directed mutagenesis to identify phosphorylation sites.
  • Co-immunoprecipitation assays to study protein interactions.
  • Protein phosphatase 1 (PP1) assays.
  • KIBRA depletion studies using siRNA.
  • Association studies with neurofibromatosis type 2/Merlin.

Main Results:

  • KIBRA is a phosphoprotein whose phosphorylation levels peak during mitosis.
  • Mitotic kinases Aurora-A and Aurora-B phosphorylate KIBRA at Serine 539 (Ser539).
  • Protein phosphatase 1 (PP1) dephosphorylates KIBRA, and this interaction is dependent on KIBRA phosphorylation and KIBRA's role in mediating Aurora-A/PP1 interaction.
  • KIBRA interacts with neurofibromatosis type 2/Merlin in a manner dependent on Ser539 phosphorylation.
  • KIBRA phosphorylation at Ser539 is critical for proper mitotic progression.

Conclusions:

  • KIBRA is a physiological substrate of Aurora kinases, linking the Hippo pathway to mitotic regulation.
  • KIBRA phosphorylation by Aurora kinases and subsequent dephosphorylation by PP1 are key regulatory events in mitosis.
  • KIBRA's interaction with Merlin is modulated by its phosphorylation status.
  • These findings reveal a novel connection between KIBRA/Hippo signaling and the cell division machinery, offering new insights into cell cycle control and tumorigenesis.

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