Abstract
Chromosomal instability (CIN) is a driving force for cancer development. The most common causes of CIN include the dysregulation of the spindle assembly checkpoint (SAC), which is a surveillance mechanism that prevents premature chromosome separation during mitosis by targeting anaphase-promoting complex/cyclosome (APC/C). DAB2IP is frequently silenced in advanced prostate cancer (PCa) and is associated with aggressive phenotypes of PCa. Our previous study showed that DAB2IP activates PLK1 and functions in mitotic regulation. Here, we report the novel mitotic phosphorylation of DAB2IP by Cdks, which mediates DAB2IP’s interaction with PLK1 and the activation of the PLK1-Mps1 pathway. DAB2IP interacts with Cdc20 in a phosphorylation-independent manner. However, the phosphorylation of DAB2IP inhibits the ubiquitylation of Cdc20 in response to SAC, and blocks the premature release of the APC/C-MCC. The PLK1-Mps1 pathway plays an important role in mitotic checkpoint complex (MCC) assembly. It is likely that DAB2IP acts as a scaffold to aid PLK1-Mps1 in targeting Cdc20. Depletion or loss of the Cdks-mediated phosphorylation of DAB2IP destabilizes the MCC, impairs the SAC, and increases chromosome missegregation and subsequent CIN, thus contributing to tumorigenesis. Collectively, these results demonstrate the mechanism of DAB2IP in SAC regulation and provide a rationale for targeting the SAC to cause lethal CIN against DAB2IP-deficient aggressive PCa, which exhibits a weak SAC.
Highlights
Chromosome instability (CIN), generated from increased chromosome missegregation in mitosis, is a driving force of human cancer and is, often correlated with poor prognosis, metastasis, and therapeutic resistance in various cancers [1, 2]
DAB2 interactive protein (DAB2IP) depletion accelerates the exit of prostate cancer (PCa) cells from mitosis and promotes the disassembly of anaphase-promoting complex/cyclosome (APC/C)-mitotic checkpoint complex (MCC) Our previous study revealed that the loss of DAB2IP impairs mitotic arrest induced by a microtubule-damaging agent, which suggests a potential role for DAB2IP in spindle assembly checkpoint (SAC) maintenance [32]
Because APC/C activation is determined by its association pattern, we further questioned whether DAB2IP alters mitotic exit via affecting the interaction status of the APC/C-MCC complex
Summary
Chromosome instability (CIN), generated from increased chromosome missegregation in mitosis, is a driving force of human cancer and is, often correlated with poor prognosis, metastasis, and therapeutic resistance in various cancers [1, 2]. In response to unattached kinetochores, the SAC prevents the binding of substrates with APC/ C-Cdc E3 ligase by enhancing the assembly of the mitotic checkpoint complex (MCC), which is a tetrameric protein complex consisting of BubR1, Bub, Mad, and Cdc20 [3]. Monopolar spindle 1 (Mps1) kinase is a master regulator for MCC formation that facilitates the kinetochore localization of several key checkpoint proteins, including Bub, BubR1, Mad, and Mad2 [4,5,6]. Polo-box kinase 1 (PLK1), a key regulator involved in numerous steps during mitotic progression, can phosphorylate Mps on its autophosphorylation sites and enhance its catalytic activity, which contributes to the recruitment of SAC components to kinetochores [12].
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