Protein kinase Cα activation switches YAP1 from TEAD‐mediated signaling to p73‐mediated signaling

Sinclear, Caleb Kwame; Maruyama, Junichi; Nagashima, Shunta; Arimoto-Matsuzaki, Kyoko; Kuleape, Joshua Agbemefa; Iwasa, Hiroaki; Nishina, Hiroshi; Hata, Yoshinobu

doi:10.1111/cas.15285

Cited by 6 publications

(6 citation statements)

References 41 publications

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“…This would clearly demonstrate that cytoplasmic YAP1 promoted autophagic death of breast cancer cells. Activation of the Hippo pathway was crucial to regulating the subcellular localization of YAP1; when the Hippo pathway was activated, the downstream classic molecule YAP1 was phosphorylated and could not enter the nucleus, and thus remained in the cytoplasm [ 3 , 10 , 52 , 53 ]. We used NPASS to screen 48 natural small‐molecule compounds related to the breast cancer cell lines MDA‐MB‐231, MDA‐MB‐468, and MCF7 (Supplementary Figure S3A ).…”

Section: Resultsmentioning

confidence: 99%

“…The functions of YAP1 in inhibiting cell proliferation and promoting apoptosis were partially attenuated but not completely reversed by CQ and siATG7 , indicating that there may be other mechanisms for YAP1 to inhibit breast cancer. It seems that the inhibition of P73 expression by nuclear YAP1 in the literature may provide a partial explanation [ 9 , 10 ]. The impact of YAP1 on breast cancer fate still needs to be further explored.…”

Section: Discussionmentioning

confidence: 99%

“…In the cytoplasm, YAP1 interacted with the Wnt/β‐catenin pathway, inhibiting both the translocation of β‐catenin into the nucleus and subsequent proliferation of tumor cells [ 6 , 8 ]. In the nucleus, YAP1 bound to the tumor suppressor P73, inhibiting ubiquitination and degradation of P73 and thus stabilizing it; this promoted the transcription of P73‐induced apoptotic genes and tumor cell apoptosis [ 9 , 10 , 11 , 12 ]. A recently published pan‐cancer analysis revealed that tumors can be classified based on YAP1 silencing; in the YAP1‐silenced tumors, YAP1 acted as a tumor suppressor, while in the YAP1‐expressed tumors, YAP1 acted as an oncogene [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Cytoplasmic YAP1‐mediated ESCRT‐III assembly promotes autophagic cell death and is ubiquitinated by NEDD4L in breast cancer

Guo

Cui

et al. 2023

Cancer Communications

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Background Nuclear Yes1‐associated transcriptional regulator (YAP1) promotes tumor progression. However, the function of cytoplasmic YAP1 in breast cancer cells and its impact on the survival of breast cancer patients remain unclear. Our research aimed to explore the biological function of cytoplasmic YAP1 in breast cancer cells and the possibility of cytoplasmic YAP1 as a predictive marker of breast cancer survival. Methods We constructed cell mutant models, including NLS‐YAP15SA (nuclear localized), YAP1S94A (incapable of binding to the TEA domain transcription factor family) and YAP1S127D (cytoplasmic localized), and used Cell Counting Kit‐8 (CCK‐8) assays, 5‐ethynyl‐2’‐deoxyuridine (EdU) incorporation assays, and Western blotting (WB) analysis to detect cell proliferation and apoptosis. The specific mechanism of cytoplasmic YAP1‐mediated endosomal sorting complexes required for transport III (ESCRT‐III) assembly was studied by co‐immunoprecipitation, immunofluorescence staining, and WB analysis. Epigallocatechin gallate (EGCG) was used to simulate YAP1 retention in the cytoplasm in in vitro and in vivo experiments to study the function of cytoplasmic YAP1. YAP1 binding to NEDD4‐like E3 ubiquitin protein ligase (NEDD4L) was identified using mass spectrometry and was verified in vitro. Breast tissue microarrays were used to analyze the relationship between cytoplasmic YAP1 expression and the survival of breast cancer patients. Results YAP1 was mainly expressed in the cytoplasm in breast cancer cells. Cytoplasmic YAP1 promoted autophagic death of breast cancer cells. Cytoplasmic YAP1 bound to the ESCRT‐III complex subunits charged multivesicular body protein 2B (CHMP2B) and vacuolar protein sorting 4 homolog B (VPS4B), promoting assembly of CHMP2B‐VPS4B and activating autophagosome formation. EGCG retained YAP1 in the cytoplasm, promoting the assembly of CHMP2B‐VPS4B to promote autophagic death of breast cancer cells. YAP1 bound to NEDD4L, and NEDD4L mediated ubiquitination and degradation of YAP1. Breast tissue microarrays revealed that high levels of cytoplasmic YAP1 were beneficial to the survival of breast cancer patients. Conclusions Cytoplasmic YAP1 mediated autophagic death of breast cancer cells by promoting assembly of the ESCRT‐III complex; furthermore, we established a new breast cancer survival prediction model based on cytoplasmic YAP1 expression.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cytoplasmic YAP1‐mediated ESCRT‐III assembly promotes autophagic cell death and is ubiquitinated by NEDD4L in breast cancer

Guo

Cui

et al. 2023

Cancer Communications

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“…YAP1 does not contain DNA-binding sequences; thus, the binding partners are important for its function. YAP1 binds to TEADs to facilitate the expression of tumor-promoting genes, and YAP1 may switch to bind to TP73 to promote apoptosis of cancer cells ( 19 ). Therefore, we also analyzed the expression of TEADs and TP73 in pan-cancer.…”

Section: Resultsmentioning

confidence: 99%

The role of YAP1 in survival prediction, immune modulation, and drug response: A pan-cancer perspective

Zhang

et al. 2022

Front. Immunol.

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IntroductionDysregulation of the Hippo signaling pathway has been implicated in multiple pathologies, including cancer, and YAP1 is the major effector of the pathway. In this study, we assessed the role of YAP1 in prognostic value, immunomodulation, and drug response from a pan-cancer perspective.MethodsWe compared YAP1 expression between normal and cancerous tissues and among different pathologic stages survival analysis and gene set enrichment analysis were performed. Additionally, we performed correlation analyses of YAP1 expression with RNA modification-related gene expression, tumor mutation burden (TMB), microsatellite instability (MSI), immune checkpoint regulator expression, and infiltration of immune cells. Correlations between YAP1 expression and IC50s (half-maximal inhibitory concentrations) of drugs in the CellMiner database were calculated.ResultsWe found that YAP1 was aberrantly expressed in various cancer types and regulated by its DNA methylation and post-transcriptional modifications, particularly m6A methylation. High expression of YAP1 was associated with poor survival outcomes in ACC, BLCA, LGG, LUAD, and PAAD. YAP1 expression was negatively correlated with the infiltration of CD8+ T lymphocytes, CD4+ Th1 cells, T follicular helper cells, NKT cells, and activated NK cells, and positively correlated with the infiltration of myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs) in pan-cancer. Higher YAP1 expression showed upregulation of TGF-β signaling, Hedgehog signaling, and KRAS signaling. IC50s of FDA-approved chemotherapeutic drugs capable of inhibiting DNA synthesis, including teniposide, dacarbazine, and doxorubicin, as well as inhibitors of hypoxia-inducible factor, MCL-1, ribonucleotide reductase, and FASN in clinical trials were negatively correlated with YAP1 expression.DiscussionIn conclusion, YAP1 is aberrantly expressed in various cancer types and regulated by its DNA methylation and post-transcriptional modifications. High expression of YAP1 is associated with poor survival outcomes in certain cancer types. YAP1 may promote tumor progression through immunosuppression, particularly by suppressing the infiltration of CD8+ T lymphocytes, CD4+ Th1 cells, T follicular helper cells, NKT cells, and activated NK cells, as well as recruiting MDSCs and CAFs in pan-cancer. The tumor-promoting activity of YAP1 is attributed to the activation of TGF-β, Hedgehog, and KRAS signaling pathways. AZD2858 and varlitinib might be effective in cancer patients with high YAP1 expression.

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“…To date, a direct link between PKC and PML has not yet been reported, but one study showed that PKC activation resulted in PML-mediated SUMOylation of YAP1 [ 35 ], thus indirectly suggesting that there is (at least) an indirect PKC–PML interaction. Interestingly, sc-3088 is a peptide inhibitor corresponding to amino acids 19-31 of the pseudosubstrate domain expressed in the primary structures of the α, βI, βII, and γ isoforms of PKC and is significantly similar to stretches in the pseudosubstrate domains present in all novel and atypical PKC isoforms [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

LDL Affects the Immunomodulatory Response of Endothelial Cells by Modulation of the Promyelocytic Leukemia Protein (PML) Expression via PKC

Roos

Berkholz

2023

IJMS

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In addition to its function as an intravascular lipid transporter, LDL also triggers signal transduction in endothelial cells (ECs), which, among other things, trigger immunomodulatory cascades, e.g., IL-6 upregulation. However, the molecular mechanisms of how these LDL-triggered immunological responses in ECs are realized are not fully understood. Since promyelocytic leukemia protein (PML) plays a role in promoting inflammatory processes, we examined the relationship between LDL, PML, and IL-6 in human ECs (HUVECs and EA.hy926 cells). RT-qPCR, immunoblotting, and immunofluorescence analyses showed that LDL but not HDL induced higher PML expression and higher numbers of PML-nuclear bodies (PML-NBs). Transfection of the ECs with a PML gene-encoding vector or PML-specific siRNAs demonstrated PML-regulated IL-6 and IL-8 expression and secretion after LDL exposure. Moreover, incubation with the PKC inhibitor sc-3088 or the PKC activator PMA showed that LDL-induced PKC activity leads to the upregulation of PML mRNA and PML protein. In summary, our experimental data suggest that high LDL concentrations trigger PKC activity in ECs to upregulate PML expression, which then increases production and secretion of IL-6 and IL-8. This molecular cascade represents a novel cellular signaling pathway with immunomodulatory effects in ECs in response to LDL exposure.

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Protein kinase Cα activation switches YAP1 from TEAD‐mediated signaling to p73‐mediated signaling

Cited by 6 publications

References 41 publications

Cytoplasmic YAP1‐mediated ESCRT‐III assembly promotes autophagic cell death and is ubiquitinated by NEDD4L in breast cancer

Cytoplasmic YAP1‐mediated ESCRT‐III assembly promotes autophagic cell death and is ubiquitinated by NEDD4L in breast cancer

The role of YAP1 in survival prediction, immune modulation, and drug response: A pan-cancer perspective

LDL Affects the Immunomodulatory Response of Endothelial Cells by Modulation of the Promyelocytic Leukemia Protein (PML) Expression via PKC

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