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MKlp2 - a mitotic kinesin and a prime target for cancer therapy (MKlp2-mitosis)
Date du début: 1 nov. 2013, Date de fin: 31 oct. 2015 PROJET  TERMINÉ 

Mklp2, a mitotic kinesin and a prime target for cancer therapyMKlp2 belongs to kinesin 6 family and was first identified as an effector protein of small G protein Rab6A, involving in the retrograde transport between Golgi and ER. While its function in Golgi-ER trafficking awaits further study, MKlp2 has been shown to play crucial role in mitosis. It is essential to relocate chromosomal passenger protein Aurora B and the mitotic regulator Plk1 to the central spindle during anaphase. Depletion of MKlp2 results in failure of cytokinesis. In addition, MKlp2 is overexpressed in several human tumor cells and inhibition of MKlp2 reduces the tumor cell growth. Those properties make MKlp2 a prime target for developing anti cancer drugs.MKlp2 has been shown to interact directly to Plk1 and Mad2, the mitotic checkpoint complex protein. However, the mechanism of MKlp2 motor protein and how those interactions may regulate its function is unknown. In addition, MKlp2 possess unique sequences in its motor domain compared to other kinesins which may render its mechanism of nucleotide/microtubule binding. To understand how MKlp2 functions and how it’s regulated during mitosis, we propose a thorough functional and structural characterization of this interesting motor protein.Aim1. Functional and structural characterization of the motor domain of MKlp2, the kinesin involves in cytokinesis and a potential target for anti-cancer drugsAim2. To study in detail the interaction between MKlp2 and Plk1, its regulation of the function of MKlp2, and to determine the structure of the complexAim3. To characterize the interaction between MKlp2 tail domain and Mad2, the structure of the complex, and the role of the interaction in cytokinesisOur results from this multidisciplinary proposal will provide valuable information on the mechanism of MKlp2, further our understanding on kinesin motors, and allow development of anti-cancer drugs.