LAPSER1/LZTS2: a pluripotent tumor suppressor linked to the inhibition of katanin-mediated microtubule severing.
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.
Sudo
Haruka
H
Department of Pharmacology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
Maru
Yoshiro
Y
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000705:Anaphase; D000818:Animals; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D002478:Cells, Cultured; D002503:Centromere / Q000235:genetics / Q000378:metabolism; D048749:Cytokinesis; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D015870:Gene Expression; D000882:Haplorhini; D006801:Humans; D000074201:Katanin; D051379:Mice; D008870:Microtubules / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000502:physiology; D011418:Prophase; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051381:Rats; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C440108:LZTS2 protein, human; D025521:Tumor Suppressor Proteins; D000251:Adenosine Triphosphatases; D000074201:Katanin