Cdk1-phosphorylated CUEDC2 promotes spindle checkpoint inactivation and chromosomal instability

Abstract

Aneuploidy and chromosomal instability are major characteristics of human cancer. These abnormalities can result from defects in the spindle assembly checkpoint (SAC), which is a surveillance mechanism for accurate chromosome segregation through restraint of the activity of the anaphase-promoting complex/cyclosome (APC/C). Here, we show that a CUE-domain-containing protein, CUEDC2, is a cell-cycle regulator that promotes spindle checkpoint inactivation and releases APC/C from checkpoint inhibition. CUEDC2 is phosphorylated by Cdk1 during mitosis. Depletion of CUEDC2 causes a checkpoint-dependent delay of the metaphase-anaphase transition. Phosphorylated CUEDC2 binds to Cdc20, an activator of APC/C, and promotes the release of Mad2 from APC/C-Cdc20 and subsequent APC/C activation. CUEDC2 overexpression causes earlier activation of APC/C, leading to chromosome missegregation and aneuploidy. Interestingly, CUEDC2 is highly expressed in many types of tumours. These results suggest that CUEDC2 is a key regulator of mitosis progression, and that CUEDC2 dysregulation might contribute to tumour development by causing chromosomal instability.

Interleukin-1 Receptor-associated Kinase-2 Genetic Variant rs708035 Increases NF-κB Activity through Promoting TRAF6 Ubiquitination

“…Phosphatase treatment does not cause the WT-IRAK2 to run at the same level as D431E-IRAK2. However, in the same assay, we detected obvious dephosphorylation of CUEDC2 as previously reported (34). These results indicated that the lower band of D431E-IRAK2 was not caused by dephosphorylation.…”

p31comet-mediated extraction of Mad2 from the MCC promotes efficient mitotic exit

“…Second, an ATPdependent process has been implicated in SAC silencing (Teichner et al, 2011), raising the possibility that an ATPase cooperates with p31 comet in the disassembly process. In addition, CUEDC2 has very recently been implicated in dissociating Mad2 from Cdc20 (Gao et al, 2011). Finally, Cdc20 ubiquitylation and degradation also contributes to MCC turnover (Nilsson et al, 2008).…”

The current view for the silencing of the spindle assembly checkpoint

“…43,44 A substrate of mitotic CDK, CEUDC2, also binds to Cdc20 once phosphorylated, and this binding promotes the release of Mad2 from Cdc20 and the subsequent activation of APC/C Cdc20 . 45 However, no evidence indicates the direct link between these mechanisms and kinetochore attachment. It is likely that these mechanisms facilitate the robustness of SAC silencing once cells have initiated the SAC silencing process.…”