Uncoupling anaphase-promoting complex/cyclosome activity from spindle assembly checkpoint control by deregulating polo-like kinase 1.

Division of Molecular Biology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Molecular and Cellular Biology (Impact Factor: 5.04). 04/2005; 25(5):2031-44. DOI: 10.1128/MCB.25.5.2031-2044.2005
Source: PubMed

ABSTRACT Polo-like kinase 1 (Plk1) plays a role in numerous events in mitosis, but how the multiple functions of Plk1 are separated is poorly understood. We studied regulation of Plk1 through two putative phosphorylation residues, Ser-137 and Thr-210. Using phospho-specific antibodies, we found that Thr-210 phosphorylation precedes Ser-137 phosphorylation in vivo, the latter occurring specifically in late mitosis. We show that expression of two activating mutants of these residues, S137D and T210D, results in distinct mitotic phenotypes. Whereas expression of both phospho-mimicking mutants as well as of the double mutant leads to accelerated mitotic entry, further progression through mitosis is dramatically different: the T210D mutant causes a spindle assembly checkpoint-dependent delay, whereas the expression of the S137D mutant or the double mutant results in untimely activation of the anaphase-promoting complex/cyclosome (APC/C) and frequent mitotic catastrophe. Using nonphosphorylatable Plk1-S137A and Plk1-T210A mutants, we show that both sites contribute to proper mitotic progression. Based on these observations, we propose that Plk1 function is altered at different stages of mitosis through consecutive posttranslational events, e.g., at Ser-137 and Thr-210. Furthermore, our data show that uncontrolled Plk1 activation can uncouple APC/C activity from spindle assembly checkpoint control.

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    ABSTRACT: Abbreviations: BUB1, budding uninhibited by benzimidazole 1 homolog; BUBR1, BUB1 b; IDL, inter domain linker; KD, kinase domain; KT–MT, kinetochore–microtubule; PLK-1, polo-like kinase 1; PBD, polo-box domain; PBIP1, polo-box interacting protein 1; PRC1, protein regulator of cytokinesis 1; SAC, spindle assembly checkpoint Polo-like kinase 1 (PLK1) is a key regulator of eukaryotic cell division. During mitosis, dynamic regulation of PLK1 is crucial for its roles in centrosome maturation, spindle assembly, microtubule–kinetochore attachment, and cytokinesis. Similar to other members of the PLK family, the molecular architecture of PLK1 protein is characterized by 2 domains—the kinase domain and the regulatory substrate-binding domain (polo-box domain)—that cooperate and control PLK1 function during mitosis. Mitotic cells employ many layers of regulation to activate and target PLK1 to different cellular structures in a timely manner. During the last decade, numerous studies have shed light on the precise molecular mechanisms orchestrating the mitotic activity of PLK1 in time and space. This review aims to discuss available data and concepts related to regulation of the molecular dynamics of human PLK1 during mitotic progression.

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