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Human Molecular Genetics Advance Access originally published online on May 18, 2008
Human Molecular Genetics 2008 17(16):2524-2540; doi:10.1093/hmg/ddn153
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

LAPSER1/LZTS2: a pluripotent tumor suppressor linked to the inhibition of katanin-mediated microtubule severing

Haruka Sudo and Yoshiro Maru*

Department of Pharmacology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan

* To whom correspondence should be addressed. Tel: +81 333538111; Fax: +81 352697417; Email: ymaru{at}research.twmu.ac.jp

Received March 13, 2008; Revised May 2, 2008; Accepted May 14, 2008

Human chromosome region 10q23–24 is one of the most frequently found regions that show loss of heterozygosity in prostate cancers. A candidate tumor suppressor LAPSER1/LZTS2 (LAPSER1) is located in 10q24.3 that has been reported to be deleted as frequently as the neighboring PTEN locus. We previously reported that LAPSER1 binds p80 katanin, a subunit of the katanin heterodimer. In this report, we show that the LAPSER1 C terminal domain inhibits katanin-mediated microtubule severing in vitro and we detected this inhibition at centrosomes by tracing the nucleated de novo, severed, and transported microtubules in cells. This functional association is also supported by the intracellular localization. Centrosomal localization of LAPSER1 was independent of microtubules and was preferential to mother centrioles. In primary cultured neurons, LAPSER1 also colocalizes with p80 katanin. LAPSER1 alters cell proliferation by regulating cytokinesis. As subcellular mechanisms that underlie the tumor suppressive activity, exogenous LAPSER1 expression inhibited central spindle formation by abrogating microtubule transportation and a similar mode of inhibition was found in axogenesis. Katanin knockdown and dominant negative inhibitor of katanin provided similar phenotypes. Prophase LAPSER1 inhibited centrosomal {gamma}-tubulin accumulation, which resulted in retardation of mitotic entry. Furthermore, interphase inhibition of katanin by LAPSER1 expression resulted in prevention of cell motility that was accompanied by the increased acetylated microtubules. LAPSER1 knockdown increased cell migration that was inhibited by the expression of ninein, a microtubule release inhibitor. These results indicate that microtubule severing at centrosomes is a novel tumor-associated molecular subcircuit in cells, in which LAPSER1 is a regulator.


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