Cent. Eur. J. Biol. • 4(1) • 2009 • 1–10 DOI: 10.2478/s11535-008-0063-0

Central European Journal of Biology

The tumor suppressor LZTS2 functions through the cellular samurai Katanin

Mini-Review Yoshiro Maru*

Department of Pharmacology, Tokyo Womens Medical University, 162-8666 Tokyo, Japan

Received 10 September 2008; Accepted 16 December 2008

Abstract: The leucine zipper putative tumor suppressor (LZTS) 2 is frequently and specifically found in LOH (loss of heterozygosity) analysis in cancer. Different from other LZTS family members, it regulates the -severing protein Katanin by binding the p80 regulatory subunit of Katanin and inhibiting its interaction with . At specific phases of the cycle, LZTS2 suppresses cell migration and establishes proper central spindle assembly for cytokinesis. Importantly, those biological effects are mediated by the inhibitory activity of LZTS2 on Katanin. LZTS2 binding to Katanin also plays a role in Katanin transport to the midbody to control proper abscis- sion. Therapeutic applications of the interaction between LZTS2 and Katanin in tumor cells are a potential area for future research. Keywords: LAPSER1 • LZTS2 • Katanin • β- • Microtubule • Cancer © Versita Warsaw and Springer-Verlag Berlin Heidelberg.

1. Introduction β- cause resistance to taxanes [2]. Farnesyltransferase inhibitors, which were initially found to inhibit the Ras oncoprotein, can enhance the binding Pharmaceutical discovery has been aided by elucidation between β-tubulin and taxanes to reverse resistance to of mechanisms by which tumor suppressors inhibit taxanes [3]. The genomic region that involves Aurora-A cancer progression. For example, the discovery of is commonly amplified in human tumors with taxane taxanes as microtubule-stabilizing drugs has shown resistance. Overexpression of Aurora-A activates the clinical benefit in a variety of previously intractable spindle assembly checkpoint, causing inappropriate tumors [1]. Taxanes activate mitotic spindle checkpoint entry into despite defective spindle formation, proteins such as Mad1 and Bub1, compensating for which leads to failed cytokinesis [4]. Screening of siRNA the DNA damage checkpoint function of p53 in p53- has revealed that knockdown of a subset of spindle deficient tumors. However, use of taxanes in a program checkpoint proteins decreased taxane sensitivity of order-made therapy, in which specific molecular while knockdown of ceramide-transfer protein (CERT) characteristics of tumors particular to individual patients enhanced sensitivity to taxanes [5]. Our discovery are targeted, will require identification of tumors that are of a direct biochemical interaction between the tumor most sensitive to taxanes. Resistance to taxanes can suppressor LZTS2 and the microtubule-severing protein occur by various means. Taxanes bind the β-tubulin Katanin provides another clue for biomarkers that could subunit of microtubules and antagonize disassembly potentially determine the efficacy of taxanes [6-8]. The of microtubules, which results in metaphase arrest and aim of this mini-review is to summarize current research subsequent apoptosis. Mutations in the binding sites in

* E-mail: [email protected]

1 The tumor suppressor LZTS2 functions through the cellular samurai Katanin

into LZTS2 function as a cytokinetic regulator, its action for Katanin activity and the regulatory mechanism by through Katanin to influence microtubule severing, itself could also be conserved throughout evolution. and how its functions relate to cancer. We summarize the results of our recent two papers in the first section 2.2 Binding partners of biological significance (chapter 2), provide new experimental information The mitotic master regulator Polo-like kinase (chapter 3) and outline a potential role for LZTS2 (Plk) 1 [17], LZTS2 [6,7] and its binding in determining sensitivity of cancer cells to taxanes partners, direct or indirect, including γ-tubulin, (chapter 4). mitotic -like protein (Mklp)1 [6,17], β-catenin [18-20] and Katanin [8], are centrosomal proteins. Significantly, binding provides a hierarchical 2. A review of the previously published sequence of protein transport to the midbody during results cytokinesis [17]. Both Plk1 and Mklp1 have a similar subcellular localization during M phase and finally 2.1 A family member concentrate at the midbody during cytokinesis. Assembly Loss of heterozygosity (LOH) in human chromosome of the central spindle is crucial for cytokinesis and 8p22 in patients with cancer revealed the leucine zipper requires a highly conserved complex, centralspindlin, putative tumor suppressor (LZTS) 1 or previously called composed of Mklp1/2 and MgcRacGAP (GTPase Fez1 [9]. BLAST searches for homologous genes and activating protein). Mklp1 is a presumed docking protein subsequent cloning identified LZTS2 with 38% amino for Plk1 and elimination of its Plk1 phosphorylation sites acid homology with LZTS1 [10]. LZTS2 is also known abolishes abscission. Mklp2 but not Mklp1 is required as LAPSER1 for its high (9-10%) content of amino for the chromosomal passenger protein Aurora-B to acids L (leucine), A (alanine), P (proline), S (serine), E translocate from centromeres to the central spindles (glutamic acid) and R (arginine). LZTS2 is on human [21]. We observed colocalization of LZTS2 with chromosome 10q24.3, near the PTEN (phosphatase Aurora-B in the midbody, suggesting that LZTS2 and and tensin homolog) locus. LOH in this region has Aurora-B have the same final destination via different also been documented. The third member LZTS3 routes [6]. In immunostaining, both p80 Katanin and has been identified in silico [11]. The LZTS family is LZTS2 signals are detectable in as well conserved from zebrafish to human. The presence of as non-centrosomal regions within the similar domains such as the leucine zipper (LZ) domain throughout the cell cycle. Co-localization is observed in suggests that they may share some common functions centrosomes and in the midbody, evident from (Figure 1) [12]. Although expression levels are very through to cytokinesis. Katanin transport to the midbody high in brain for LZTS1 and LZTS3, LZTS2 is rather is dependent on LZTS2 transport and LZTS2 transport ubiquitously expressed in human organs as judged by is, in turn, dependent on Mklp1 transport to the midbody oligonucleotide DNA microarray analysis [12], while [6]. Therefore disturbance of Plk1 function upstream in Northern blot analysis showed high abundance in the sequence of regulation is likely to affect microtubule human prostate and testis [10]. severing by Katanin. It should be noted that LZTS2 LZTS2 directly binds the p80 regulatory subunit has two conserved motifs for phosphorylation by Plk1 of Katanin that heterodimerizes with the p60 AAA and/or cyclin-dependent kinase (Cdk)1 in the amino- catalytic subunit [6]. The AAA ATPase family is also terminal half (Figure 1) [22]. The first Plk1 site is T239, conserved from yeast through to humans and severs the found in rat and human LZTS2 but not in other LZTS microtubules that make up mitotic spindles. Two other family members. The second site is targeted by both major AAA family proteins are Spastin whose mutations Plk1 and Cdk1, with phosphorylation occuring on S311 in humans result in hereditary spastic paraplegia [13], in human and rat LZTS2, and on S254 in human and and Fidgetin, natural alterations of which have been rat LZTS1. Deletion of the region containing the motifs reported in fidget mice, where they cause auditory disrupts centrosomal targeting of LZTS2 [6]. The LZ defects [14]. Since regulatory subunits were found in domain in LZTS2 is required for binding to Katanin but Katanin but not in Spastin or Fidgetin, the LZTS family dispensable for transport. Translocation of p60 and members may affect only Katanin. Importantly, not only p80 Katanin subunits to the midbody is also promoted the p60 catalytic subunit but also the p80 non-catalytic by phosphorylation of NudE nuclear distribution gene subunit is conserved in Tetrahymena or Caenorhabditis E homolog (A. nidulans)-like 1 (NDEL1) by Cdk5 or elegans through to mammals [15,16]. Given that Cdk1 [23]. Unphosphorylated NDEL1 is localized to individual knockouts of the p60 and p80 subunit gave centrosomes. The functional relationship between similar phenotypes in Tetrahymena, both are required LZTS2 and NDEL1 awaits further studies.

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Figure 1. Expression and structure of LZTS and three major AAA ATPase family members. Oligonucleotide-based DNA microarray analysis in human organs [12]. Shown are: three LZ domains (orange bars), the third of which is missing in LZTS3; a nuclear export signal (NES, blue triangle) found only in LZTS2; sites that match Plk1 and/or Cdk1 phosphorylation motifs; and the AAA domain (yellow bars) (see details in the text). The homology is shown black when 3 amino acids out of 3 family members are identical, gray when any 2 out of 3 are identical, and white with no match.

Cytokinesis and cell migration both involve dynamic Microtubules are certainly required for cell motility, modulation of cell polarity, and therefore share many but little is known about the molecular mechanisms molecular components and pathways [24]. Cell polarity regulating microtubule dynamics in cell migration. Our is regulated by small GTP-binding proteins such as recent studies suggest Katanin-mediated microtubule Rac and RhoA [25]. Rac plays an essential role in severing and release from centrosomes may play the formation of lamellipodia at the leading edge of a mechanistic role. The microtubule minus ends the migrating cell. A complex containing Rac1, its generated by Katanin are believed to bind cytosolic effector Rac-interacting protein IQ motif containing γ-tubulin. We observed significant reduction of γ-tubulin GAP (IQGAP), and cytoplasmic linker protein 170 accumulation in prophase centrosomes when LZTS2 (CLIP170) accumulates at microtubule plus ends, was overexpressed [7]. LZTS2 also inhibited microtubule linking them with the cortical actin meshwork [26]. RhoA release from centrosomes during . Both regulates contraction of the trailing edge. However, subunits of Katanin have individually been shown to RhoA activation does not always correlate with cell have an affinity for microtubules 28[ ]. We propose that movement, as exemplified in nocodazole-treated cells LZTS2 may disupt microtubule severing by binding the in which RhoA is activated due to microtubule-binding Katanin p80 subunit and blocking its interaction with Rho- GEF (guanine nucleotide exchange factor) release microtubules [7]. The cytoplasmic microtubule network is from depolymerized microtubules [27]. Nocodazole disassembled by increased Katanin activity in prophase, perturbs microtubule dynamics by depolymerization and which then allows for microtubule reassembly to form not only induces ectopic furrows with uncoordinated mitotic spindles. cortical contractions but also inhibits cell migration.

3 The tumor suppressor LZTS2 functions through the cellular samurai Katanin

Katanin knockout studies in Tetrahymena suggest and 605 [31]. In contrast to BCR-ABL, BCR, a role in posttranslational modification of microtubules which functions as a GAP for Rac, binds such as acetylation. Anti-p80 Katanin small interfering β-catenin to inhibit its transcriptional activity through the RNA (siRNA) suppressed cell migration and amino-terminal 1-202 amino acids of BCR [32]. Nuclear expression of dominant-negative p60 Katanin induced export of β-catenin takes place in a CRM-1 (chromosome accumulation of acetylated or stabilized microtubules maintenance region 1)-dependent manner, but around centrosomes [7]. By contrast, in migrating independently of APC. The carboxy-terminus of LZTS2 cells, acetylated microtubules are absent in the leading has a functional nuclear export signal (NES) (Figure 1) edges. Our understanding is that microtubule polymer and binds β-catenin [33]. The NES is conserved in mass reduction by Katanin stimulates microtubule neither LZTS1 nor LZTS3. Overexpression of LZTS2 dynamics in the cell body and assembly is stimulated results in reduced expression levels of β-catenin in in different cellular compartments, as exemplified in both cytoplasm and nucleus by enhancement of its cilia in Tetrahymena [15]. One of the physiological nuclear export and in repression of β-catenin-mediated substrates of histone deacetylase (HDAC) 6 is α-tubulin. transcriptional activity. Overexpression of HDAC6 stimulates cell migration and Wnt signaling stimulates cell migration HDAC6 inhibitors inhibit cell migration [29]. in PC3 prostate cancer cells [34]. APC and β-catenin may have roles in the regulation of cell migration, and are transported along microtubules from 3. New experimental information their minus ends to growing plus ends through interaction with kinesin superfamily motor proteins [35]. Therefore 3.1 LZTS2 and β-catenin suppression of cell migration by LZTS2 overexpression We observed that both β-catenin and LZTS2 colocalize might also be explained by its potential influence on in the early mitotic phase to spindle poles, comprising the β-catenin. and a portion of spindle containing minus ends (data not shown). We could also detect LZTS2 3.2 Mitotic aster assembly signals in both cytoplasm and nucleus in interphase cells Both astral and central spindle microtubules are by immunostaining. Although the biological significance responsible for induction of furrowing in cytokinesis. of the interaction in awaits further investigation, LZTS2 overexpression enhances astral acetylated it raises intriguing issues since β-catenin plays essential tubulin signals [6]. As stated above, LZTS2 and roles in at least 3 biological settings: (1) cell-cell adhesion, β-catenin are colocalized in spindle poles. A small linking cadherin to the cortical actin cytoskeleton in population of cytoplasmic BCR is also detectable in adherens junctions, (2) Wnt-stimulated transcription of spindle poles (data not shown). Deletion or stabilization genes for cell growth including c-Myc and cyclin D1 and of β-catenin has been reported to induce monopolar (3) establishment of the bipolar mitotic spindle. It has spindles with unseparated centrosomes or multipolar been proposed that the adenomatous polyposis coli spindles with centrosomal splitting, respectively [20]. (APC) tumor suppressor binds β-catenin and Axin to Recently an involvement of β-catenin in Nek2 (never in form a destruction complex and that β-catenin is targeted mitosis gene A-related kinase 2)-regulated centrosomal to proteasomal degradation. When APC is mutated in separation has been clearly shown. β-catenin activity colon cancer or Wnt signaling is stimulated, glycogen can be experimentally upregulated by overexpression synthase kinase (GSK) 3β-mediated phosphorylation of stabilized β-catenin [20], or by expression of the of β-catenin at the amino-terminal serine 33, 37 and artificial fusion protein β-Engrailed, in which the carboxy- threonine 41 is inhibited and β-catenin is stabilized and terminal transactivation domain of β-catenin is replaced accumulates in cells shuttling between the cytoplasm with the transcriptional repression domain of Drosophila and nucleus. Another mechanism of β-catenin Engrailed. Expression of β-Engrailed specifically stabilization is through its phosphorylation of tyrosine 86 enhances β-catenin protein-protein interactions, but and 654 by the BCR-ABL oncoprotein of chronic myeloid not β-catenin-mediated transcription [36]. Under these leukemia, which enables β-catenin to escape interaction conditions we could observe defocused, tripolar, or with the APC/Axin/GSK3β destruction complex [30]. multipolar poles in approximately 15% of cells. This was Recently, mechanisms of regulating β-catenin nuclear accompanied by spindle assembly checkpoint activation localization by Wnt signaling have been reported to as judged by the localization of Mad2 (data not shown). involve Phosphoinositide 3-kinase (PI3K)-Rac1-c-Jun We tried to analyze LZTS2 and Katanin directly in N-terminal kinase (JNK)2 pathway-dependent those overexpressers. However, it was occasionally phosphorylation of β-catenin on serine 191 difficult to take convincing and consistent images of

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Figure 2. An in vitro aster formation assay. Cell lysates from synchronized PC3 cells were subjected to mitotic aster assembly assays with ATP and taxol as described [37]. Images were obtained with anti-α-tubulin (clone DM1A) (left panels). The middle panels show cells stained with anti-NuMa (Monosan), anti-LZTS2 [6], anti-p80 Katanin (Geneway), anti-β-catenin (BD Biosciences) and anti-BCR (Santa Cruz Biotechnology) . The right panels are merged images. Scale bars are 5 μm.

5 The tumor suppressor LZTS2 functions through the cellular samurai Katanin

β-catenin, LZTS2, BCR and Katanin. This may be due to aberrant expression and localization of these proteins in this particular setting. Therefore we tried to examine the assembly of mitotic asters from synchronized cells in a cell free system. This assay enables us to take a convenient glance at interactions between components of spindles independently of centrosomes [37]. In intact PC3 cells, while both the p80 subunit of Katanin and β-catenin show a similar localization to the microtubule organizer NuMa protein (Nuclear protein that associates with the mitotic apparatus) that targets microtubule minus ends and concentrate at the central core, BCR and LZTS2 displayed no particular pattern (Figure 2). This pattern was not significantly altered in overexpression of β-catenin or β-Engrailed.

3.3 LZTS1 and LZTS2 Although both LZTS1 and LZTS2 cause G2/M arrest when overexpressed, they may act via distinct mechanisms. A difference between LZTS1 and LZTS2 comes from studies on LZTS1-null mice [9]. LZTS1 binds to and reduces ubiquitination of Cdc25C in mitotic cells, which in turn facilitates Cdc25C- mediated activation and dephosphorylation of Cdk1. In LZTS2-overexressing cells, we observed mild but appreciable accumulation of active Cdk1, although we could hardly detect Cdk1 in the anti-LZTS2 immunoprecipitates [6]. However, given the overall homology, particularly in the LZ domain, between LZTS1 and LZTS2, LZTS2 might also affect Cdk1 via a similar mechanism. Two striking features of LZTS2- overexpressing cells are central spindle defects, and binucleation that is enhancable by nocodazole, both of which are mediated by Katanin. Analysis of the interaction between bacterially produced and purified GST-tagged carboxy-terminal half of LZTS2 (GST-LZTS2-LZ) and the His-tagged con80 of

Katanin (con80) yielded a KD of 30 nM [6]. Yeast two- hybrid assays with the same binding partners gave positive signals, supporting the results of the in vitro binding assay. However, two-hybrid assay of con80 and the corresponding region of LZTS1 (LZTS1-LZ) showed a dramatically reduced number of colonies (Figure 3). Quantification of β-galactosidase activity Figure 3. Yeast two-hybrid analysis to detect the interaction between LZTS2 and p80 Katanin (con80). Bait vec- in yeast expressing the two-hybrid constructs tors containing the full-length rat LZTS2 (Full) origi- revealed that mean activities were 14.67 ± 0.45 Miller nally used for library screening [6], the carboxy- terminal half containing the LZ domains and NES units (LZTS2-full vs. con80), 7.77 ± 0.03 (LZTS2- (LZ), the corresponding region of LZTS1 and con- LZ vs. con80), 3.71 ± 0.06 (LZTS1 vs. con80), and trol vector alone were co-expressed in yeast with prey vectors containing our initial isolate con80 1.36 ± 0.30 (vector alone vs. con80). An established Katanin [6] in synthetic dropout (SD) medium -2 positive control for interaction is the binding of NADPH (SD-2; -Leu, -Trp) or -4 (SD-4; -Leu, -Trp, -His, -Ade- oxidase components p22 and p47, with β-galactosidase nine). The β-galactosidase activities for each combina- tion were also measured as described previously [6,45] activity of yeast expressing p22 and p47 two-hybrid (n=6). constructs measured at 9.97 ± 0.91, and for which

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Figure 4. Hypothetical scheme for LZTS2 functions. LZTS2 (L) appears to have two functions: (1) it downregulates microtubule severing by Katanin (K) and (2) it might be a centrosomal protein responsible for the prophase checkpoint. In this model, the status of LZTS2- Katanin interaction determines the amounts of stabilized and acetylated microtubules around centrosomes, and controls the level of γ-tubulin. Microtubules that are severed and released into the cytoplasm play essential roles in abscission in the midbody as well as in the establishment of leading edges of migrating cells. Excessive severing affects abundance of molecules around centrosomes that might be recognized by LZTS2, which in turn causes a negative feedback on Katanin. Under conditions of LZTS2 deficiency, negative feedback is inadequate, resulting in Katanin activation. In addition, LZTS2 deficiency may allow aberrant mitotic entry into prophase (Pro). Taxane-mediated stabilization of microtubules induces spindle assembly checkpoint activation (SACA). Combined stabilization (combined) by taxanes and the ECM (see text) might cause relative LZTS2 deficiency that allows prophase entry followed by SACA. These ideas explain both resistance and sensitivity of taxanes. Pro (P), pro/meta (P/M), meta (M), Ana (A), telo (T) and interphases (Inter) and cytokinesis (C). C = centrosome. Green triangles = acetylation on tubulin. Blue circles = γ-tubulin.

a biochemical analysis gives KD 0.34 µM) [38] These literature are re-evaluated, looking for the PTEN numbers are comparable to those observed for the (10q23.3)-independent LOH region that contains LZTS2 LZTS2-Katanin interaction, suggesting that LZTS2 (10q24.3), we found 8 out of 19 cases in small cell lung is indeed one of the major interacting molecules of cancer [39], 3 out of 23 cases in prostate cancer [40] and Katanin. 3 out of 17 cases in squamous cell lung cancer [41]. Enhanced cell growth and migration are the two major biological phenotypes of malignant tumor cells. 4. Cancer and hypothesis Overexpression of LZTS2 inhibits both phenotypes in transformed cells and its knockdown enhances cell Tumor suppressor genes are not only of diagnostic migration. LZTS2 might also induce genomic instability significance but also valuable for predicting resistance and subsequent acquisition of mutations, since both or efficacy of pharmaceutical therapy. For example, overexpression and knockdown cause binucleation due Plk1 overexpression is believed to be a poor- to central spindle defect-mediated failure of cytokinesis prognostic marker in a variety of tumors. When LOH [6]. Mechanistically, all of these activities are possibly analyses of lung and prostate cancers reported in mediated through Katanin regulation by LZTS2.

7 The tumor suppressor LZTS2 functions through the cellular samurai Katanin

Overexpression of LZTS2 also renders tumor cells stated earlier, Aurora-A overexpression in cancer cells resistant to taxanes [7]. This is in agreement with the can override the spindle assembly checkpoint, thereby results of lentiviral short hairpin RNA (shRNA) library evading apoptosis and causing taxane resistance [4]. screening of lung cancer cells that revealed a group If both the ECM and paclitaxel stabilize microtubules of genes including LZTS2 whose downregulation synergistically, a resulting suppression of LZTS2- conferred taxane sensitivity [42]. LZTS1-null cells are mediated negative feedback on Katanin could mimic also sensitive to taxanes [9]. Knockdown of LZTS2 LZTS2 deficit, leading to apoptosis via mitotic stress. activates Katanin by disinhibition with subsequent Thus, discovery of competitors for binding between and rearrangement, and leads LZTS2 and the p80 subunit of Katanin or Katanin to enhanced cell migration. This indicates that genetic agonists might be of therapeutic value. analysis of the LZTS2 locus could provide not only a In addition to the LZTS2 effects on cell growth stated diagnostic tool but also a good criterion for predicting above, we have found mitotic catastrophe when LZTS2 sensitivity to taxanes. is overexpressed in v-Fps-transformed cells [6]. This What determines the efficacy of taxanes in tumor phenomenon is only partially dependent on Katanin [6] cells? Paclitaxel is a microtubule stabilizer that primarily and observed neither in BCR-ABL-transformed cells in targets polymerized microtubules. The extracellular which β-catenin is stabilized nor in cells transformed by matrix (ECM) proteins such as TGFBI (transforming v-Src or v-Ras. v-Fps is an activated retroviral version of growth factor beta induced) and fibronectin stabilize the cellular Fes/Fps and activated Fes was reported to microtubules and sensitize cells to taxanes in a FAK- be localized in centrosomes and to bind mitotic spindles and Rho-dependent manner [43]. However, molecules during metaphase [44]. Elucidation of mechanisms downstream of FAK are not known. We hypothesize involved in v-Fps/LZTS2-induced mitotic cell death may that LZTS2 at centrosomes might play a role as a provide clues for further strategies for cancer therapy. guardian for antephase or prophase checkpoints, monitoring maturation of centrosomes and microtubule dynamics around centrosomes (Figure 4). Severing by Acknowledgments Katanin releases microtubules into the cytoplasm from centrosomes, and changes around the centrosomes This study was partly supported by Grants-in-Aid for might be monitored by LZTS2. The rate of severing Scientific Research (No. 20013041) to Y.M. I thank Dr could be kept in check by LZTS2-mediated suppression F.J. McNally (University of California Davis) for Katanin of the enzymatic activity of Katanin (Figure 4). LZTS2 DNA, Dr A.I.M. Barth (Stanford University) for stabilized deficiency enhances microtubule severing, and may β-catenin DNA, Dr P.D. McCrea (University of Texas allow premature mitotic entry resulting in abnormal M.D. Anderson Cancer Center) for β-Engrailed DNA, Dr cytokinesis. If paclitaxel induces mitotic stress by Y.Yamamoto and Mr T. Omori for technical help, and Dr microtubule stabilization in the absence of LZTS2, cells H. Sudo for two original papers on which this manuscript may then enter pro/meta and metaphase, becoming totally depends. apoptotic by spindle assembly checkpoint activation. As

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9 The tumor suppressor LZTS2 functions through the cellular samurai Katanin

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