title: The mitosis-regulating and protein-protein interaction activities of astrin are controlled by aurora-A-induced phosphorylation.
abstract: Cells display dramatic morphological changes in mitosis, where numerous factors form regulatory networks to orchestrate the complicated process, resulting in extreme fidelity of the segregation of duplicated chromosomes into two daughter cells. Astrin regulates several aspects of mitosis, such as maintaining the cohesion of sister chromatids by inactivating Separase and stabilizing spindle, aligning and segregating chromosomes, and silencing spindle assembly checkpoint by interacting with Src kinase-associated phosphoprotein (SKAP) and cytoplasmic linker-associated protein-1α (CLASP-1α). To understand how Astrin is regulated in mitosis, we report here that Astrin acts as a mitotic phosphoprotein, and Aurora-A phosphorylates Astrin at Ser(115). The phosphorylation-deficient mutant Astrin S115A abnormally activates spindle assembly checkpoint and delays mitosis progression, decreases spindle stability, and induces chromosome misalignment. Mechanistic analyses reveal that Astrin phosphorylation mimicking mutant S115D, instead of S115A, binds and induces ubiquitination and degradation of securin, which sequentially activates Separase, an enzyme required for the separation of sister chromatids. Moreover, S115A fails to bind mitosis regulators, including SKAP and CLASP-1α, which results in the mitotic defects observed in Astrin S115A-transfected cells. In conclusion, Aurora-A phosphorylates Astrin and guides the binding of Astrin to its cellular partners, which ensures proper progression of mitosis.
authors.affiliation: Graduate Institute of Immunology, China Medical University, Taichung, Taiwan; Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan;
authors.forename: Shao-Chih
authors.initials: SC
authors.lastname: Chiu
authors.affiliation: Department of Applied Chemistry, National Chi Nan University, Puli, Nantou, Taiwan;
authors.forename: Jo-Mei Maureen
authors.initials: JM
authors.lastname: Chen
authors.affiliation: Graduate Institute of Biomedicine and Biomedical Technology, National Chi Nan University, Puli, Nantou, Taiwan; and.
authors.forename: Tong-You Wade
authors.initials: TY
authors.lastname: Wei
authors.affiliation: Graduate Institute of Biochemistry of Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Tai-Shan
authors.initials: TS
authors.lastname: Cheng
authors.affiliation: Department of Applied Chemistry, National Chi Nan University, Puli, Nantou, Taiwan;
authors.forename: Ya-Hui Candice
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Graduate Institute of Biomedicine and Biomedical Technology, National Chi Nan University, Puli, Nantou, Taiwan; and.
authors.forename: Chia-Feng
authors.initials: CF
authors.lastname: Ku
authors.affiliation: Department of Applied Chemistry, National Chi Nan University, Puli, Nantou, Taiwan;
authors.forename: Chiao-Hsuan
authors.initials: CH
authors.lastname: Lian
authors.affiliation: Department of Applied Chemistry, National Chi Nan University, Puli, Nantou, Taiwan;
authors.forename: Chun-Chih Jared
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Department of Applied Chemistry, National Chi Nan University, Puli, Nantou, Taiwan;
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Kuo
authors.affiliation: Department of Applied Chemistry, National Chi Nan University, Puli, Nantou, Taiwan; Graduate Institute of Biomedicine and Biomedical Technology, National Chi Nan University, Puli, Nantou, Taiwan; and ctyu@ncnu.edu.tw.
authors.forename: Chang-Tze Ricky
authors.initials: CT
authors.lastname: Yu
mesh_terms: D064096:Aurora Kinase A / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D060066:Protein Interaction Maps / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; C486663:SPAG5 protein, human; C576917:AURKA protein, human; D064096:Aurora Kinase A
keywords: Astrin; Aurora-A; Separase; phosphorylation; securin