A novel Chk1/2–Lats2–14-3-3 signaling pathway regulates P-body formation in response to UV damage

Okada, Nobuhiro; Yabuta, Norikazu; Suzuki, Hirokazu; Aylon, Yael; Oren, Moshe; Nishimura, Hiroshi

doi:10.1242/jcs.072918

Cited by 32 publications

(31 citation statements)

References 42 publications

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“…Importantly, the 14-3-3 family participates in the formation/maintenance of processing bodies (Okada et al, 2011) and stress granules (Stoecklin et al, 2004). These observations, together with our present results, suggest that 14-3-3 may have functional interplay with heat shock proteins, either cooperatively or separately, during formation of these cell structures.…”

Section: Discussionsupporting

confidence: 75%

14-3-3 proteins sequester a pool of soluble TRIM32 ubiquitin ligase to repress autoubiquitination and cytoplasmic body formation

Ichimura

Taoka

Shoji

et al. 2013

Journal of Cell Science

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SummaryDeregulated expression of tripartite motif-containing protein 32 (TRIM32, an E3 ubiquitin-protein ligase) contributes to various diseases. Here we report, using quantitative proteomics and biochemistry, that 14-3-3 proteins bind to phosphorylated TRIM32 and prevent TRIM32 autoubiquitylation and the formation of TRIM32-containing cytoplasmic bodies, which are potential autoregulatory mechanisms that can reduce the concentration of soluble free TRIM32. The 14-3-3-TRIM32 interaction is dependent on protein-kinase-A-catalyzed phosphorylation of TRIM32 at Ser651. We found that the inhibitory effect of 14-3-3 is, in part, a consequence of disrupting the propensity of TRIM32 to undergo higher-order self-association without affecting its dimerization. Consequently, dimerized TRIM32 bound to 14-3-3 was sequestered in a distinct cytoplasmic pool away from the microtubule network, whereas a TRIM32 mutant that cannot bind 14-3-3 underwent multimerization and was unavailable to facilitate cell growth. Our results reveal a novel connection between ubiquitylation and phosphorylation pathways, which could modulate a variety of cell events by stimulating the formation of the 14-3-3-TRIM32 signaling complex.

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Section: Discussionsupporting

confidence: 75%

14-3-3 proteins sequester a pool of soluble TRIM32 ubiquitin ligase to repress autoubiquitination and cytoplasmic body formation

Ichimura

Taoka

Shoji

et al. 2013

Journal of Cell Science

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“…The putative roles of these proteins in regulating P-body dynamics are also supported by several recent studies showing that binding of 14-3-3 proteins to EDC3, a P-body component, altered P-body morphology, inhibited miRNA-mediated gene silencing, and changed EDC3's PPIs (Larance et al 2010). Furthermore, phosphorylated 14-3-3g protein (YWHAG) translocates to P-bodies, and knocking down 14-3-3g protein blocks P-body formation after UV damage (Okada et al 2011). It is known that 14-3-3 proteins bind to protein ligands with phosphorylated serine or threonine residues, which, in turn, physically prevent molecular interactions or modulate the accessibility of a target protein to modifying enzymes such as kinases, phosphatases, and proteases (Mhawech 2005;Johnson et al 2010).…”

Section: Discussionmentioning

confidence: 67%

Unraveling regulation and new components of human P-bodies through a protein interaction framework and experimental validation

Zheng

Chen²,

Shyu³

2011

RNA

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The cellular factors involved in mRNA degradation and translation repression can aggregate into cytoplasmic domains known as GW bodies or mRNA processing bodies (P-bodies). However, current understanding of P-bodies, especially the regulatory aspect, remains relatively fragmentary. To provide a framework for studying the mechanisms and regulation of P-body formation, maintenance, and disassembly, we compiled a list of P-body proteins found in various species and further grouped both reported and predicted human P-body proteins according to their functions. By analyzing protein-protein interactions of human P-body components, we found that many P-body proteins form complex interaction networks with each other and with other cellular proteins that are not recognized as P-body components. The observation suggests that these other cellular proteins may play important roles in regulating P-body dynamics and functions. We further used siRNA-mediated gene knockdown and immunofluorescence microscopy to demonstrate the validity of our in silico analyses. Our combined approach identifies new P-body components and suggests that protein ubiquitination and protein phosphorylation involving 14-3-3 proteins may play critical roles for post-translational modifications of P-body components in regulating P-body dynamics. Our analyses provide not only a global view of human P-body components and their physical interactions but also a wealth of hypotheses to help guide future research on the regulation and function of human P-bodies.

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“…We, and others, showed that the Nterminal regions are phosphorylated by several kinases, including Cdc2/cyclin B (S613 of Lats1), NUAK1 (S464 of Lats1), PKCd (S464 of Lats1), Aurora-A (S83 and S380 of Lats2) and Chk1/2 (S408 of Lats2), whereas the C-terminus is phosphorylated by Mst1/2 (S909 and T1079 of Lats1; S872 and T1041 of Lats2). These findings indicate that the N-terminal regions of Lats1/2 contribute to the physiological regulation of these proteins, including subcellular localization, protein stability, or enzymatic activity (Morisaki et al, 2002;Chan et al, 2005;Takahashi et al, 2006;Humbert et al, 2010;Okada et al, 2011;Yabuta et al, 2011).…”

Section: Introductionmentioning

confidence: 83%

N-terminal truncation of Lats1 causes abnormal cell growth control and chromosomal instability

Yabuta

Mukai

Okamoto

et al. 2013

Journal of Cell Science

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SummaryThe tumor suppressors Lats1 and Lats2 are mediators of the Hippo pathway that regulates tissue growth and proliferation. Their N-terminal non-kinase regions are distinct except for Lats conserved domains 1 and 2 (LCD1 and LCD2), which may be important for Lats1/2-specific functions. Lats1 knockout mice were generated by disrupting the N-terminal region containing LCD1 (Lats1 DN/DN). Some Lats1 DN/DN mice were born safely and grew normally. However, mouse embryonic fibroblasts (MEFs) from Lats1 DN/DN mice displayed mitotic defects, centrosomal overduplication, chromosomal misalignment, multipolar spindle formation, chromosomal bridging and cytokinesis failure. They also showed anchorage-independent growth and continued cell cycles and cell growth, bypassing cell-cell contact inhibition similar to tumor cells. Lats1 DN/DN MEFs produced tumors in nude mice after subcutaneous injection, although the tumor growth rate was much slower than that of ordinary cancer cells. Yap, a key transcriptional coactivator of the Hippo pathway, was overexpressed and stably retained in Lats1 DN/DN MEFs in a cell density independent manner, and Lats2 mRNA expression was downregulated. In conclusion, N-terminally truncated Lats1 induced Lats2 downregulation and Yap protein accumulation, leading to chromosomal instability and tumorigenesis.

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A novel Chk1/2–Lats2–14-3-3 signaling pathway regulates P-body formation in response to UV damage

Cited by 32 publications

References 42 publications

14-3-3 proteins sequester a pool of soluble TRIM32 ubiquitin ligase to repress autoubiquitination and cytoplasmic body formation

14-3-3 proteins sequester a pool of soluble TRIM32 ubiquitin ligase to repress autoubiquitination and cytoplasmic body formation

Unraveling regulation and new components of human P-bodies through a protein interaction framework and experimental validation

N-terminal truncation of Lats1 causes abnormal cell growth control and chromosomal instability

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