Molecular Mechanisms and Cellular Function for the Aurora-A Induced SLAN Phosphorylation.

• Main Authors: WAN, CHANG-XIN, 萬長鑫
• Other Authors: YU, CHANG-TZE
• Format: Others
• Language: zh-TW
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/86b2ws

碩士 === 國立暨南國際大學 === 應用化學系 === 106 === Aurora-A is an oncogenic serine/threonine kinase upregulated in mitosis. Overexpression or silence of Aurora-A induces cytokinesis failure and thereby production of multiple nuclei, implying the engagement of Aurora-A in the control of cytokinesis. Aurora-A is documented phosphorylating cytoplasmic unidentified factors at spindle midzone, and responsible for the spindle midzone- or metaphase plate- targeting of these factors, indicating that Aurora-A likely controls cytokinesis via phosphorylating and in turn midzone localization of its downstream substrates. To search for these factors, we noticed SLAN, a potential tumor suppressor and mitotic regulator guiding mitosis progression and cytokinesis through unknown mechanisms. The previous study in our laboratory shows that SLAN interacts with Aurora-A, and Aurora-A phosphorylates SLAN in an in vitro kinase. Moreover, overexpression of SLAN induces the formation of multiple nuclei, these observations fueling us to speculate a plausible hypothesis where Aurora-A controls cytokinesis through phosphorylation of SLAN. Hence, the thesis focuses itself on testing this hypothesis by proposing several aims, including identifying the molecular mechanisms by which Aurora-A phosphorylates SLAN, mapping the Aurora-A-catalyzed phosphorylation sites on SLAN, determining the potential regulatory effects of SLAN phosphorylation on cytokinesis, and unraveling how Aurora-A/SLAN cascade regulates cytokinesis. The study based on a series of analyses shows that Aurora-A interacts with and phosphorylates SLAN via the help of the scaffold protein 14-3-3, and Aurora-A phosphorylates SLAN at T573, which greatly stimulates M phase arrest and the formation of multiple nuclei. Further mechanistic analyses reveal the involvement of RhoA as one of the key factors downstream to Aurora-A/SLAN axis during cytokinesis. Taken together, the study demonstrates Aurora-A/SLAN/14-3-3 as a novel regulatory axis controlling cytokinesis.