Rho-Signaling-Directed YAP/TAZ Activity Underlies the Long-Term Survival and Expansion of Human Embryonic Stem Cells

Ohgushi, Masatoshi; Minaguchi, Maki; Sasai, Yoshiki

doi:10.1016/j.stem.2015.07.009

Cited by 157 publications

(144 citation statements)

References 39 publications

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“…YAP is believed to be crucial for the self-renewal of embryonic stem cells (Lian et al, 2010;Pan, 2010;Schlegelmilch et al, 2011;Tamm et al, 2011;Liu et al, 2012;Mo et al, 2014;Piccolo et al, 2014;Pijuan-Galito et al, 2014;Varelas, 2014;Yao et al, 2014;Ohgushi et al, 2015). These observations and the high level of YAP in nestin + NSCs led to the hypothesis that YAP might promote NSC self-renewal or proliferation.…”

Section: Normal Nsc Proliferation In Yap-deficient Nscsmentioning

confidence: 99%

“…Upon stimulation, the Hippo pathway subsequently phosphorylates YAP, and phosphorylated YAP undergoes degradation or interacts with 14-3-3 for its cytoplasmic retention. When dephosphorylated, YAP enters the nucleus and interacts with TEAD family proteins to induce the transcription of genes that regulate diverse cellular processes, including cell survival, proliferation and differentiation (Zhao et al, 2007;Lian et al, 2010;Pan, 2010;Schlegelmilch et al, 2011;Tamm et al, 2011;Liu et al, 2012;Yu and Guan, 2013;Mo et al, 2014;Piccolo et al, 2014;Varelas, 2014;Yao et al, 2014;Ohgushi et al, 2015). Although the function of YAP in regulating the development of multiple organs has been investigated, its role in the developing nervous system is less well studied.…”

Section: Introductionmentioning

confidence: 99%

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YAP stabilizes SMAD1 and promotes BMP2-induced neocortical astrocytic differentiation

et al. 2016

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YAP (yes-associated protein), a key transcriptional co-factor that is negatively regulated by the Hippo pathway, is crucial for the development and size control of multiple organs, including the liver. However, its role in the brain remains unclear. Here, we provide evidence for YAP regulation of mouse neocortical astrocytic differentiation and proliferation. YAP was undetectable in neurons, but selectively expressed in neural stem cells (NSCs) and astrocytes. YAP in NSCs was required for neocortical astrocytic differentiation, with no apparent role in self-renewal or neural differentiation. However, YAP in astrocytes was necessary for astrocytic proliferation. Yap (Yap1) knockout, Yap nestin conditional knockout and Yap GFAP conditional knockout mice displayed fewer neocortical astrocytes and impaired astrocytic proliferation and, consequently, death of neocortical neurons. Mechanistically, YAP was activated by BMP2, and the active/nuclear YAP was crucial for BMP2 induction and stabilization of SMAD1 and astrocytic differentiation. Expression of SMAD1 in YAP-deficient NSCs partially rescued the astrocytic differentiation deficit in response to BMP2. Taken together, these results identify a novel function of YAP in neocortical astrocytic differentiation and proliferation, and reveal a BMP2-YAP-SMAD1 pathway underlying astrocytic differentiation in the developing mouse neocortex.

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Section: Normal Nsc Proliferation In Yap-deficient Nscsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

YAP stabilizes SMAD1 and promotes BMP2-induced neocortical astrocytic differentiation

et al. 2016

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“…Ohgushi and colleagues found that this signaling sustains proliferation, growth and pluripotency of human embryonic stem cells. 31 GNAS protein (Guanine nucleotide-binding proteins G protein) function as transducers in numerous signaling pathways including that involved in the activation of adenylyl cyclases. Iglesias-Bartolome and colleagues evidenced that GNAS-PKA pathway has an important role in promoting proper homeostasis of epithelial stem cells in hair follicle by limiting excessive proliferation that may lead to stem cell exhaustion.…”

Section: Muse Cells Secrete Factors That May Play a Role In Stem Cellmentioning

confidence: 99%

The secretome of MUSE cells contains factors that may play a role in regulation of stemness, apoptosis and immunomodulation

et al. 2016

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Mesenchymal stromal cells (MSCs) are a heterogeneous population, which contain several cell phenotypes: mesenchymal stem cells, progenitor cells, fibroblasts and other type of cells. Previously, we identified unique stem cells that we named multilineage-differentiating stress enduring (Muse) cells as one to several percent of MSCs of the bone marrow, adipose tissue and dermis. Among different cell populations in MSCs, Muse cells, positive for pluripotent surface marker SSEA-3, may represent cells responsible for pluripotent-like property of MSCs, since they express pluripotency genes, able to differentiated into triploblastic cells from a single cells and are self-renewable.MSCs release biologically active factors that have profound effects on local cellular dynamics. A thorough examination of MSC secretome seems essential for understanding the physiological functions exerted by these cells in our organism and also for rational cellular therapy design. In this setting, studies on secretome of Muse cells may shed light on pathways that are associated with their specific features.Our findings evidenced that secretomes of MSCs and Muse cells contain factors that regulate extracellular matrix remodeling, ox-redox activities and immune system. Muse cells appear to secrete factors that may preserve their stem cell features, allow survival under stress conditions and may contribute to their immunomodulation capacity.In detail, the proteins belonging to protein kinase A signaling, FXR/RXR activation and LXR/RXR activation pathways may play a role in regulation of Muse stem cell features. These last 2 pathways together with proteins associated with antigen presentation pathway and coagulation system may play a role in immunomodulation.

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“…The Rho family members RhoA and CDC42 are small GTPases that could modulate cell migration and actin cytoskeleton reorganization [19, 20]. Furthermore, inactivating Rho GTPase could prevent cell migration and cancer cells stemness [21, 22]. Notably, recent research has shown that Up-regulation of GTPBP4 in colorectal carcinoma is responsible for tumor metastasis, and GTPBP4 may disorganize actin cytoskeleton through repressing RhoA signaling [11].…”

Section: Discussionmentioning

confidence: 99%

GTPBP4 Promotes Gastric Cancer Progression via Regulating P53 Activity

Pang

Zhu

et al. 2018

Cell Physiol Biochem

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Background/Aims: gastric cancer is a serious health concern with high morbidity and mortality. Therefore, it is urgent to find novel targets for gastric cancer diagnosis and treatment. Methods: qRT-PCR and immunohistochemistry assays were used to detect GTPBP4 expression in gastric cancer tissues, and gastric cancer and gastric epithelial cells. Lentivirus infection was used to construct GTPBP4 stable knockdown cells. Annexin V/PI apoptosis, CCK8, EdU incorporation and cell clone formation analysis were performed to evaluate the effects of GTPBP4 on gastric cancer cell proliferation and apoptosis. Further RNA-based high-throughput sequencing and co-IP assays were constructed to explore the related mechanisms contributing to GTPBP4-mediated effects. Results: GTPBP4 expression was significantly increased in gastric cancer tissues compared with that in adjacent normal tissues, and positively correlated with gastric cancer stages. Meanwhile, GTPBP4 level was markedly upregulated in gastric cancer cells than in gastric epithelial cells. Additionaly, stable knockdown of GTPBP4 inhibited cell proliferation and promoted cell apoptosis. Mechanistically, p53 and its related signaling were significantly activated in GTPBP4 stable knockdown cells. And GTPBP4 interacted with p53 in gastric cancer cells. Conclusions: our results provide insights into mechanistic regulation and linkage of the GTPBP4-p53 in gastric cancer, and also a valuable potential target for gastric cancer.

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Rho-Signaling-Directed YAP/TAZ Activity Underlies the Long-Term Survival and Expansion of Human Embryonic Stem Cells

Cited by 157 publications

References 39 publications

YAP stabilizes SMAD1 and promotes BMP2-induced neocortical astrocytic differentiation

YAP stabilizes SMAD1 and promotes BMP2-induced neocortical astrocytic differentiation

The secretome of MUSE cells contains factors that may play a role in regulation of stemness, apoptosis and immunomodulation

GTPBP4 Promotes Gastric Cancer Progression via Regulating P53 Activity

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