Abstract
The key mitotic regulator Polo-like kinase 1 (Plk1) isactivated 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 invitro. Taken together, these results indicate an important role for WAC in promoting Plk1 activation and the timely entry into mitosis.
Highlights
Polo-like kinase 1 (Plk1) plays a key role in many steps of mitotic cell division, ranging from mitotic entry to cytokinesis (Petronczki et al, 2008)
We show that phosphorylation by Cyclin-dependent kinase 1 (Cdk1) primes WAC binding to the polo-box domain (PBD) of Plk1, which promotes Plk1 phosphorylation and activation by Aurora A kinase (AurkA) to ensure timely mitotic entry
WAC Is Phosphorylated by Cdk1 during G2 Phase and Mitosis In our quantitative phospho-proteomics analysis of HeLa cells arrested in mitosis with the spindle microtubule depolymerization drug nocodazole, we noticed that WAC was phosphorylated at multiple serine and threonine residues (Figure S1C)
Summary
Polo-like kinase 1 (Plk1) plays a key role in many steps of mitotic cell division, ranging from mitotic entry to cytokinesis (Petronczki et al, 2008). Plk consists of an N-terminal kinase domain and a C-terminal polo-box domain (PBD) (Figure S1A). Plk can be activated through phosphorylation of its activation loop in the kinase domain by upstream kinases (Jang et al, 2002b), possibly through disrupting its auto-inhibitory interaction with PBD (Xu et al, 2013). Plk activity starts to increase during G2 phase and peaks in mitosis. During G2 phase of human cells, Aurora A kinase (AurkA) cooperates with its co-factor Bora (Hutterer et al, 2006) to phosphorylate Plk at Thr-210 in its activation loop, which is important for Plk activation and the timely entry into mitosis (Macurek et al, 2008; Seki et al, 2008b). The mechanism underlying Plk activation during the G2 to mitosis (G2/M in short) transition remains incompletely understood (Schmucker and Sumara, 2014)
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