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¹ Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
² Department of Clinical Pharmacology, Research Institute, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
³ PRESTO, Japan Science and Technology Corporation, Tokyo, Japan

LIS1, a causative gene product for type I lissencephaly, binds to and regulates the dynein motor and the centrosome. LIS1 also forms a complex with the catalytic subunits 1 and 2 of type I platelet-activating factor acetylhydrolase [PAF-AH (I)]. However, the cellular function of the catalytic subunits remains unknown. In this study, we showed that over-expression of the catalytic subunits, especially 2, in cultured cells induced dramatic phenotypical changes including nuclear shape change, centrosomal amplification and microtubule disorganization. We examined if these effects were due to the catalytic activity and/or binding of 2 to LIS1. Substitution of a single amino acid Glu39 of murine 1 and 2 by Asp (2-E39D) did not affect catalytic activity but completely abolished LIS1 binding. Over-expression of either 2-E39D or the catalytically inactive 2-S48C revealed that 2-E39D, but not 2-S48C, lost its ability to induce above-mentioned phenotypic changes. Biochemical analyses showed that LIS1 present in the precipitate fraction of murine brain homogenates could be translocated to the soluble fraction by 2, but not by 2-E39D. These results suggest that over-expression of the PAF-AH (I) catalytic subunits induces centrosomal amplification and microtubule disorganization by disturbing intracellular localization of LIS1.

^* Correspondence: E-mail: harai{at}mol.f.u-tokyo.ac.jp