LATS1 and LATS2 Phosphorylate CDC26 to Modulate Assembly of the Tetratricopeptide Repeat Subcomplex of APC/C

Masuda, Kenta; Chiyoda, Tatsuyuki; Sugiyama, Naoyuki; Segura‐Cabrera, Aldo; Kabe, Yoshio; Ueki, Arisa; Banno, Kouji; Suematsu, Makoto; Aoki, Daisuke; Ishihama, Yasushi; Saya, Hideyuki; Kuninaka, Shinji

doi:10.1371/journal.pone.0118662

Cited by 12 publications

(13 citation statements)

References 44 publications

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“…135 Multiple studies have linked LATS kinases to mitosis. Both LATS1 and LATS2 can bind to CDC25B 136 and phosphorylate CDC26, 137 master regulators of mitotic exit. Other studies suggest distinct modes of action for LATS1 and LATS2 during mitotic transition.…”

Section: Cell Cycle Regulation and Apoptosismentioning

confidence: 99%

The LATS1 and LATS2 tumor suppressors: beyond the Hippo pathway

2017

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Proper cellular functionality and homeostasis are maintained by the convergent integration of various signaling cascades, which enable cells to respond to internal and external changes. The Dbf2-related kinases LATS1 and LATS2 (LATS) have emerged as central regulators of cell fate, by modulating the functions of numerous oncogenic or tumor suppressive effectors, including the canonical Hippo effectors YAP/TAZ, the Aurora mitotic kinase family, estrogen signaling and the tumor suppressive transcription factor p53. While the basic functions of the LATS kinase module are strongly conserved over evolution, the genomic duplication event leading to the emergence of two closely related kinases in higher organisms has increased the complexity of this signaling network. Here, we review the LATS1 and LATS2 intrinsic features as well as their reported cellular activities, emphasizing unique characteristics of each kinase. While differential activities between the two paralogous kinases have been reported, many converge to similar pathways and outcomes. Interestingly, the regulatory networks controlling the mRNA expression pattern of LATS1 and LATS2 differ strongly, and may contribute to the differences in protein binding partners of each kinase and in the subcellular locations in which each kinase exerts its functions.

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Section: Cell Cycle Regulation and Apoptosismentioning

confidence: 99%

The LATS1 and LATS2 tumor suppressors: beyond the Hippo pathway

2017

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“…AXT cells were lysed with a lysis buffer containing 0.5% Nonidet P-40 (17), and the resulting supernatant was incubated with rotation for 10 minutes at room temperature with antibodies to Rho-GDI (Millipore) and protein G-coupled magnetic Dynabeads (Life Technologies) as mentioned previously (17).…”

Section: Detection Of Rho-gdi and Rhoa Interactionmentioning

confidence: 99%

Simvastatin-Induced Apoptosis in Osteosarcoma Cells: A Key Role of RhoA-AMPK/p38 MAPK Signaling in Antitumor Activity

Kamel

Sugihara

Nobusue

et al. 2017

Molecular Cancer Therapeutics

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Osteosarcoma is the most common type of primary bone tumor, novel therapeutic agents for which are urgently needed. To identify such agents, we screened a panel of approved drugs with a mouse model of osteosarcoma. The screen identified simvastatin, which inhibited the proliferation and migration of osteosarcoma cells in vitro Simvastatin also induced apoptosis in osteosarcoma cells in a manner dependent on inhibition of the mevalonate biosynthetic pathway. It also disrupted the function of the small GTPase RhoA and induced activation of AMP-activated protein kinase (AMPK) and p38 MAPK, with AMPK functioning upstream of p38 MAPK. Inhibitors of AMPK or p38 MAPK attenuated the induction of apoptosis by simvastatin, whereas metformin enhanced this effect of simvastatin by further activation of AMPK. Although treatment with simvastatin alone did not inhibit osteosarcoma tumor growth in vivo, its combination with a fat-free diet induced a significant antitumor effect that was enhanced further by metformin administration. Our findings suggest that simvastatin induces apoptosis in osteosarcoma cells via activation of AMPK and p38 MAPK, and that, in combination with other approaches, it holds therapeutic potential for osteosarcoma. Mol Cancer Ther; 16(1); 182-92. ©2016 AACR.

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“…However, no evidence supports the conservation of such a mechanism in mammals so far. Nevertheless, there is a report showing that LATS1/2 phosphorylates CDC26, which is also in our list of LATS2-interacting proteins identified by TAP, thus regulating APC/C assembly (55). The findings in this report suggest that LATS2 may further regulate APC/C through direct phosphorylation of APC1 or through binding to APC1 to phosphorylate other components of APC/C.…”

Section: Discussionmentioning

confidence: 56%

Deubiquitylase USP9X suppresses tumorigenesis by stabilizing large tumor suppressor kinase 2 (LATS2) in the Hippo pathway

Zhu¹,

Ji²,

Zhang³

et al. 2018

Journal of Biological Chemistry

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The Hippo pathway plays important roles in controlling organ size and in suppressing tumorigenesis through large tumor suppressor kinase 1/2 (LATS1/2)-mediated phosphorylation of YAP/TAZ transcription co-activators. The kinase activity of LATS1/2 is regulated by phosphorylation in response to extracellular signals. Moreover, LATS2 protein levels are repressed by the ubiquitin-proteasome system in conditions such as hypoxia. However, the mechanism that removes the ubiquitin modification from LATS2 and thereby stabilizes the protein is not well understood. Here, using tandem affinity purification (TAP), we found that anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase complex, and USP9X, a deubiquitylase, specifically interact with LATS2. We also found that although APC1 co-localizes with LATS2 to intracellular vesicle structures, it does not regulate LATS2 protein levels and activity. In contrast, USP9X ablation drastically diminished LATS2 protein levels. We further demonstrated that USP9X deubiquitinates LATS2 and thus prevents LATS2 degradation by the proteasome. Furthermore, in pancreatic cancer cells, USP9X loss activated YAP and enhanced the oncogenic potential of the cells. In addition, the tumorigenesis induced by the USP9X ablation depended not only on LATS2 repression, but also on YAP/TAZ activity. We conclude that USP9X is a deubiquitylase of the Hippo pathway kinase LATS2 and that the Hippo pathway functions as a downstream signaling cascade that mediates USP9X's tumor-suppressive activity.

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LATS1 and LATS2 Phosphorylate CDC26 to Modulate Assembly of the Tetratricopeptide Repeat Subcomplex of APC/C

Cited by 12 publications

References 44 publications

The LATS1 and LATS2 tumor suppressors: beyond the Hippo pathway

The LATS1 and LATS2 tumor suppressors: beyond the Hippo pathway

Simvastatin-Induced Apoptosis in Osteosarcoma Cells: A Key Role of RhoA-AMPK/p38 MAPK Signaling in Antitumor Activity

Deubiquitylase USP9X suppresses tumorigenesis by stabilizing large tumor suppressor kinase 2 (LATS2) in the Hippo pathway

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