Abstract
The execution of the mitotic program with high fidelity is dependent upon precise spatiotemporal regulation of posttranslational protein modifications. For example, the timely polyubiquitination of critical mitotic regulators by Anaphase Promoting Complex/Cyclosome (APC/C) is essential for the metaphase to anaphase transition and mitotic exit. The spindle assembly checkpoint prevents unscheduled activity of APC/C-Cdc20 in early mitosis, allowing bipolar attachment of kinetochores to mitotic spindle and facilitating equal segregation of sister chromatids. The critical effector of the spindle checkpoint, Mitotic arrest deficient 2 (Mad2), is recruited to unattached kinetochores forming a complex with other regulatory proteins to efficiently and cooperatively inhibit APC/C-Cdc20. A weakened and/or dysfunctional spindle checkpoint has been linked to the development of genomic instability in both cell culture and animal models, and evidence suggests that aberrant regulation of the spindle checkpoint plays a critical role in human carcinogenesis. Recent studies have illuminated a network of both degradative and non-degradative ubiquitination events that regulate the metaphase to anaphase transition and mitotic exit. Within this context, our recent work showed that the HECT (Homologous to E6-AP C-terminus)-family E3 ligase Smurf2 (Smad specific ubiquitin regulatory factor 2), known as a negative regulator of transforming growth factor-beta (TGF-β) signaling, is required for a functional spindle checkpoint by promoting the functional localization and stability of Mad2. Here we discuss putative models explaining the role of Smurf2 as a new regulator in the spindle checkpoint. The dynamic mitotic localization of Smurf2 to the centrosome and other critical mitotic structures provides implications about mitotic checkpoint control dependent on various ubiquitination events. Finally, deregulated Smurf2 activity may contribute to carcinogenesis by perturbed mitotic control.
Highlights
The spindle assembly checkpoint is a complex signal transduction cascade that inhibits the metaphase to anaphase transition in the presence of unattached or untensed kinetochores
The checkpoint protein Mitotic arrest deficient 2 (Mad2) is recruited to sites of unattached kinetochores in association with Mad1 (Mitotic arrest deficient 1), Bub1 (Budding uninhibited by benzimidazoles 1 homolog) and other components of the Mitotic Checkpoint Complex (MCC)
Available evidence supports that USP44-mediated deubiquitination stabilizes the Cdc20Mad2 complex by removing ubiquitin conjugates from Cdc20 that would otherwise promote disassembly of Importantly, this work strongly implies that the non-degradative ubiquitination of Cdc20 is a prerequisite for the onset of timely Anaphase Promoting Complex/Cyclosome (APC/C) activity
Summary
The spindle assembly checkpoint is a complex signal transduction cascade that inhibits the metaphase to anaphase transition in the presence of unattached or untensed kinetochores. The critical downstream target of the spindle checkpoint is APC/C which, in association with its activator Cdc20, is responsible for the rapid ubiquitin-dependent degradation of mitotic regulatory proteins such as Securin, an inhibitor of sister chromatid segregation, Cyclin B, and Aurora B kinase. Adding to this complexity is our recent study indicating the activity of Smurf2, a HECT family E3 ligase, in the stability of Mad2 and the function of the spindle checkpoint [8].
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