title: Molecular Regulation of the Spindle Assembly Checkpoint by Kinases and Phosphatases.
abstract: The spindle assembly checkpoint (SAC) is a surveillance mechanism contributing to the preservation of genomic stability by monitoring the microtubule attachment to, and/or the tension status of, each kinetochore during mitosis. The SAC halts metaphase to anaphase transition in the presence of unattached and/or untensed kinetochore(s) by releasing the mitotic checkpoint complex (MCC) from these improperly-oriented kinetochores to inhibit the anaphase-promoting complex/cyclosome (APC/C). The reversible phosphorylation of a variety of substrates at the kinetochore by antagonistic kinases and phosphatases is one major signaling mechanism for promptly turning on or turning off the SAC. In such a complex network, some kinases act at the apex of the SAC cascade by either generating (monopolar spindle 1, MPS1/TTK and likely polo-like kinase 1, PLK1), or contributing to generate (Aurora kinase B) kinetochore phospho-docking sites for the hierarchical recruitment of the SAC proteins. Aurora kinase B, MPS1 and budding uninhibited by benzimidazoles 1 (BUB1) also promote sister chromatid biorientation by modulating kinetochore microtubule stability. Moreover, MPS1, BUB1, and PLK1 seem to play key roles in APC/C inhibition by mechanisms dependent and/or independent on MCC assembly. The protein phosphatase 1 and 2A (PP1 and PP2A) are recruited to kinetochores to oppose kinase activity. These phosphatases reverse the phosphorylation of kinetochore targets promoting the microtubule attachment stabilization, sister kinetochore biorientation and SAC silencing. The kinase-phosphatase network is crucial as it renders the SAC a dynamic, graded-signaling, high responsive, and robust process thereby ensuring timely anaphase onset and preventing the generation of proneoplastic aneuploidy.
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy. Electronic address: gwenola.manic@gmail.com.
authors.forename: G
authors.initials: G
authors.lastname: Manic
authors.affiliation: Department of Biology, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Corradi
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Sistigu
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy; Department of Biology, University of Rome "Roma Tre", Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Siteni
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy; Department of Biology, University of Rome "Tor Vergata", Rome, Italy. Electronic address: iliovit@gmail.com.
authors.forename: I
authors.initials: I
authors.lastname: Vitale
mesh_terms: D000818:Animals; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints; D008954:Models, Biological; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*
chemical_list: D011494:Protein Kinases; D010744:Phosphoric Monoester Hydrolases
keywords: KMN network; MAD2; chromosome instability; error correction; mitotic kinase; mitotic spindle; protein phosphatase