WAC Promotes Polo-like Kinase 1 Activation for Timely Mitotic Entry

Cell Rep. 2018 Jul 17;24(3):546-556. doi: 10.1016/j.celrep.2018.06.087.

Abstract

The key mitotic regulator Polo-like kinase 1 (Plk1) is activated during G2 phase by Aurora A kinase (AurkA)-mediated phosphorylation of its activation loop, which is important for timely mitotic entry. The mechanism for Plk1 activation remains incompletely understood. Here, we report that the activation of Plk1 requires WAC, a WW domain-containing adaptor protein with a coiled-coil region that predominantly localizes to the nucleus in interphase. Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry. These defects are rescued by exogenous expression of wild-type WAC, but not the Plk1-binding-deficient mutant. WAC also binds AurkA and can enhance Plk1 phosphorylation by AurkA in vitro. Taken together, these results indicate an important role for WAC in promoting Plk1 activation and the timely entry into mitosis.

Keywords: Aurora A; Cyclin A/Cdk1; Cyclin B/Cdk1; G2/M transition; Plk1; WAC; mitotic entry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / metabolism*
  • CDC2 Protein Kinase / metabolism
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism*
  • Enzyme Activation
  • G2 Phase
  • HeLa Cells
  • Humans
  • Metaphase
  • Mitosis*
  • Phosphorylation
  • Polo-Like Kinase 1
  • Protein Binding
  • Protein Domains
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Proto-Oncogene Proteins
  • WAC protein, human
  • Protein Serine-Threonine Kinases
  • CDC2 Protein Kinase