A human homolog of <i>Drosophila</i> warts tumor suppressor, h‐warts, localized to mitotic apparatus and specifically phosphorylated during mitosis

Nishiyama, Yasuyuki; Hirota, Toru; Morisaki, Tsuyoshi; Hara, Tadayuki; Marumoto, Tomotoshi; Iida, Susumu; Makino, Keishi; Yamamoto, Hideyuki; Hiraoka, Takehisa; Kitamura, Nobuo; Saya, Hideyuki

doi:10.1016/s0014-5793(99)01224-7

Cited by 99 publications

(105 citation statements)

References 35 publications

(43 reference statements)

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“…Of particular interest is Lats1, which shares 52% overall sequence identity with Lats2, with 85% sequence identity over the kinase domain (Yabuta et al 2000). Lats1 also resides on interphase centrosomes (Nishiyama et al 1999;Hirota et al 2000). Indeed, overexpression of kinase-dead Lats1, presumably acting in a dominant-negative fashion, causes prolonged mitotic delay and impairment of the G1 tetraploidy checkpoint as a result of inefficient p53 induction (Iida et al 2004).…”

Section: Discussionmentioning

confidence: 99%

A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization

Aylon¹,

Michael²,

Shmueli³

et al. 2006

Genes Dev.

257

296

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Damage to the mitotic spindle and centrosome dysfunction can lead to cancer. To prevent this, cells trigger a succession of checkpoint responses, where an initial mitotic delay is followed by slippage without cytokinesis, spawning tetraploid G1 cells that undergo a p53-dependent G1/S arrest. We describe the importance of Lats2 (Large Tumor Suppressor 2) in this checkpoint response. Lats2 binds Mdm2, inhibits its E3 ligase activity, and activates p53. Nocodazole, a microtubule poison that provokes centrosome/mitotic apparatus dysfunction, induces Lats2 translocation from centrosomes to the nucleus and p53 accumulation. In turn, p53 rapidly and selectively up-regulates Lats2 expression in G2/M cells, thereby defining a positive feedback loop. Abrogation of Lats2 promotes accumulation of polyploid cells upon exposure to nocodazole, which can be prevented by direct activation of p53. The Lats2-Mdm2-p53 axis thus constitutes a novel checkpoint pathway critical for the maintenance of proper chromosome number.[Keywords: Lats2; Mdm2; p53; tetraploidy checkpoint] Supplemental material is available at http://www.genesdev.org.

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Section: Discussionmentioning

confidence: 99%

A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization

Aylon¹,

Michael²,

Shmueli³

et al. 2006

Genes Dev.

257

296

View full text Add to dashboard Cite

show abstract

“…However, no known Rabs have been shown to be required for mitotic exit or cytokinesis. Interestingly, the kinase domain of Warts/Lats1 exhibits a significant degree of sequence identity to Dbf2 (34%) and localizes to the interphase centrosomes and mitotic midbody (Nishiyama et al, 1999;Tao et al, 1999;Hirota et al, 2000). A conserved nuclear protein kinase Ndr2 (Millward et al, 1995(Millward et al, , 1999 is also closely related to Dbf2 (35% identity).…”

Section: Cytokinesismentioning

confidence: 99%

Yeast polo-like kinases: functionally conserved multitask mitotic regulators

et al. 2005

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The polo-like kinases (Plks) are a conserved subfamily of Ser/Thr protein kinases that play pivotal roles in regulating various cellular and biochemical events at multiple stages of M phase. Genetic and biochemical data revealed that both the budding yeast and the fission yeast polo kinase homologs (Cdc5 and Plo1, respectively) bear remarkable functional similarities with those in metazoan organisms, suggesting that the role of Plks is largely conserved throughout evolution. Thus, studies on Plks in genetically amenable lower eucaryotic organisms may yield valuable insights into the function of Plks in higher eucaryotic organisms. In this review, common properties and distinct functions of Cdc5 and Plo1 will be discussed and compared to properties and functions of Plks in higher eucaryotic organisms.

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“…A mammalian homolog of the Drosophila tumorsuppressor protein warts, known as WARTS (or large tumor-suppressor 1 (LATS1)), was identified (Nishiyama et al, 1999;Tao et al, 1999) and found to have functions similar to its activity in Drosophila: mice deficient in WARTS (WTS)/LATS1 develop malignant tumors . WTS encodes a serine-threonine kinase that shares a high degree of sequence homology with members of the myotonic dystrophy protein kinase (DMPK) family, many of which participate in mitotic events.…”

Section: Introductionmentioning

confidence: 99%

Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation

et al. 2006

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The serine protease Omi/HtrA2 was initially regarded as a proapoptotic molecule that proteolyses several proteins to induce cell death. Recent studies, however, indicate that loss of Omi protease activity increases susceptibility to stress-induced cell death. These complicated findings suggest that the protease activity of Omi is involved not only in apoptosis but also in cellular homeostasis. However, the targets which Omi uses to mediate this novel process are unknown. Previously, we showed that WARTS (WTS)/large tumor-suppressor 1 mitotic kinase interacts with the protein/discs-large protein/zonula (PDZ) domain of Omi and promotes its protease activity. We now report that WTS is a substrate for Omi protease activity, thus it is not only a regulator but also a downstream target of this protease. Interaction with Omi PDZ domain is required for WTS to be proteolysed. When caspase-9-deficient mouse embryonic fibroblasts (MEFs) were treated with staurosporine, WTS was proteolysed by activated endogenous Omi without induction of cell death. Therefore, protease activity of Omi and proteolysis of WTS are not necessarily required for cell death. We found that depletion of Omi from HeLa cells results in accelerated cell proliferation despite no significant change in the duration of mitosis. The depletion of WTS showed the same effect on S phase progression. Therefore, WTS proteolytic fragment(s) generated by Omi may act as an inhibitor of G1/S progression. Our data reveal a role for Omi-mediated processing of WTS in negative regulation of cell cycle progression at interphase, suggesting a novel function of Omi other than apoptosis.

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A human homolog of Drosophila warts tumor suppressor, h‐warts, localized to mitotic apparatus and specifically phosphorylated during mitosis

Cited by 99 publications

References 35 publications

A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization

A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization

Yeast polo-like kinases: functionally conserved multitask mitotic regulators

Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation

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