Usp7 regulates Hippo pathway through deubiquitinating the transcriptional coactivator Yorkie

Sun, Xuxu; Ding, Yan; Zhan, Meixiao; Li, Yan; Gao, Dongqing; Wang, Guiping; Gao, Yang; Li, Yong; Wu, Shian; Lu, Ligong; Liu, Qingxin; Zhou, Zizhang

doi:10.1038/s41467-019-08334-7

Cited by 66 publications

(61 citation statements)

References 63 publications

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“…In our data, most upstream members of the Hippo signaling pathway showed a trend toward downregulation and these genes were negatively regulated by primarily upregulated miR-NAs, especially the muscle-specific miRNAs miR-1a-3p, miR-206-3p, and miR-133a/b. Moreover, previous studies showed that the activity of Yap1 and Wwtr1 was negatively regulated by the upstream regulatory elements of the Hippo signaling pathway 36,52 . In summary, the differentially expressed miRNAs altered the abundance of Hippo pathway members.…”

Section: Discussionmentioning

confidence: 99%

Chromatin accessibility is associated with the changed expression of miRNAs that target members of the Hippo pathway during myoblast differentiation

Zhou

Xiang

et al. 2020

Cell Death Dis

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miRNAs reportedly participate in various biological processes, such as skeletal muscle proliferation and differentiation. However, the regulation of differentially expressed (DE) miRNAs and their function in myogenesis remain unclear. Herein, miRNA expression profiles and regulation during C2C12 differentiation were analyzed in relation to chromatin states by RNA-seq, ATAC-seq, and ChIP-seq. We identified 19 known and nine novel differentially expressed miRNAs at days 0, 1, 2, and 4. The expression of the differentially expressed miRNAs was related to the chromatin states of the 113 surrounding open chromatin regions defined by ATAC-seq peaks. Of these open chromatin regions, 44.25% were colocalized with MyoD/MyoG binding sites. The remainder of the above open chromatin regions were enriched with motifs of the myoblast-expressed AP-1 family, Ctcf, and Bach2 transcription factors (TFs). Additionally, the target genes of the above differentially expressed miRNAs were enriched primarily in muscle growth and development pathways, especially the Hippo signaling pathway. Moreover, via combining a loss-of-function assay with Q-PCR, western blotting, and immunofluorescence, we confirmed that the Hippo signaling pathway was responsible for C2C12 myoblast differentiation. Thus, our results showed that these differentially expressed miRNAs were regulated by chromatin states and affected muscle differentiation through the Hippo signaling pathway. Our findings provide new insights into the function of these differentially expressed miRNAs and the regulation of their expression during myoblast differentiation.

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Section: Discussionmentioning

confidence: 99%

Chromatin accessibility is associated with the changed expression of miRNAs that target members of the Hippo pathway during myoblast differentiation

Zhou

Xiang

et al. 2020

Cell Death Dis

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“…Despite various types of posttranslational modifications (PTMs) including dephosphorylation (Huang et al, 2013; Liu et al, 2013; Wang et al, 2012; Wilson et al, 2014), ubiquitination (Cho et al, 2020; Sun et al, 2019; Yao et al, 2018), methylation (Fang et al, 2018; Oudhoff et al, 2013), and O-GlcNAcylation (Peng et al, 2017; Zhang et al, 2017) that have been implicated in fine-tuning YAP activity, phosphorylation is regarded as a dominant manner of YAP regulation. The classic Hippo-YAP signaling features sequential phosphorylation of YAP at Ser127 (Zhang et al, 2008, 2015; Zhao et al, 2007) and Ser381/Ser384 (Zhao et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway

Nie

Chen

et al. 2020

Journal of Experimental Medicine

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Hyperactivation of YAP has been commonly associated with tumorigenesis, and emerging evidence hints at multilayered Hippo-independent regulations of YAP. In this study, we identified a new MST4–YAP axis, which acts as a noncanonical Hippo signaling pathway that limits stress-induced YAP activation. MST4 kinase directly phosphorylated YAP at Thr83 to block its binding with importin α, therefore leading to YAP cytoplasmic retention and inactivation. Due to a consequential interplay between MST4-mediated YAP phospho-Thr83 signaling and the classical YAP phospho-Ser127 signaling, the phosphorylation level of YAP at Thr83 was correlated to that at Ser127. Mutation of T83E mimicking MST4-mediated alternative signaling restrained the activity of both wild-type YAP and its S127A mutant mimicking loss of classical Hippo signal. Depletion of MST4 in mice promoted gastric tumorigenesis with diminished Thr83 phosphorylation and hyperactivation of YAP. Moreover, loss of MST4–YAP signaling was associated with poor prognosis of human gastric cancer. Collectively, our study uncovered a noncanonical MST4–YAP signaling axis essential for suppressing gastric tumorigenesis.

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“…About 40 wing discs were lysed in TRIzol (Invitrogen) for RNA isolation according to previous described [ 54 ]. One microgram RNA was used for reverse transcription by HiScript ® Q RT SuperMix with gDNA wiper (Vazyme) according to the instructions.…”

Section: Methodsmentioning

confidence: 99%

Dual functions of Rack1 in regulating Hedgehog pathway

Sun

Gao

et al. 2020

Cell Death Differ

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Hedgehog (Hh) pathway plays multiple roles in many physiological processes and its dysregulation leads to congenital disorders and cancers. Hh regulates the cellular localization of Smoothened (Smo) and the stability of Cubitus interruptus (Ci) to fine-tune the signal outputs. However, the underlying mechanisms are still unclear. Here, we show that the scaffold protein Rack1 plays dual roles in Hh signaling. In the absence of Hh, Rack1 promotes Ci and Cos2 to form a Ci–Rack1–Cos2 complex, culminating in Slimb-mediated Ci proteolysis. In the presence of Hh, Rack1 dissociates from Ci–Rack1–Cos2 complex and forms a trimeric complex with Smo and Usp8, leading to Smo deubiquitination and cell surface accumulation. Furthermore, we find the regulation of Rack1 on Hh pathway is conserved from Drosophila to mammalian cells. Our findings demonstrate that Rack1 plays dual roles during Hh signal transduction and provide Rack1 as a potential drug target for Hh-related diseases.

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Usp7 regulates Hippo pathway through deubiquitinating the transcriptional coactivator Yorkie

Cited by 66 publications

References 63 publications

Chromatin accessibility is associated with the changed expression of miRNAs that target members of the Hippo pathway during myoblast differentiation

Chromatin accessibility is associated with the changed expression of miRNAs that target members of the Hippo pathway during myoblast differentiation

MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway

Dual functions of Rack1 in regulating Hedgehog pathway

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