Genome-wide RNA interference screening reveals a COPI-MAP2K3 pathway required for YAP regulation

Kim, Yong Joon; Jung, Eun Ji; Shin, Eunbie; Hong, Sin-Hyoung; Jeong, Hui Su; Hur, Gayeong; Jeong, Hye Yun; Lee, Seung‐Hyo; Lee, Ji Eun; Kim, Gun-Hwa; Kim, Joon

doi:10.1073/pnas.1915387117

Cited by 5 publications

(4 citation statements)

References 46 publications

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“…We hypothesized that Hippo-independent regulatory mechanisms could serve as viable targets for suppressing YAP activity in cancer. Previously, we performed kinome 5 and whole-genome siRNA screens 27 in LATS1/2-null RPE1 cells to identify regulators of YAP levels that operate independently of Hippo kinases. Because the main effectors of the Hippo signaling cascade, LATS1/2, were inactivated in these cell lines, the cells exhibited significantly increased YAP activity 5 , and we also used these cell lines to screen for Hippo-independent YAP regulation pathways.…”

Section: Resultsmentioning

confidence: 99%

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Overcoming BRAF and CDK4/6 inhibitor resistance by inhibiting MAP3K3-dependent protection against YAP lysosomal degradation

Park,

Ryu,

Kim

et al. 2024

Exp Mol Med

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Transcriptional programs governed by YAP play key roles in conferring resistance to various molecular-targeted anticancer agents. Strategies aimed at inhibiting YAP activity have garnered substantial interest as a means to overcome drug resistance. However, despite extensive research into the canonical Hippo–YAP pathway, few clinical agents are currently available to counteract YAP-associated drug resistance. Here, we present a novel mechanism of YAP stability regulation by MAP3K3 that is independent of Hippo kinases. Furthermore, we identified MAP3K3 as a target for overcoming anticancer drug resistance. Depletion of MAP3K3 led to a substantial reduction in the YAP protein level in melanoma and breast cancer cells. Mass spectrometry analysis revealed that MAP3K3 phosphorylates YAP at serine 405. This MAP3K3-mediated phosphorylation event hindered the binding of the E3 ubiquitin ligase FBXW7 to YAP, thereby preventing its p62-mediated lysosomal degradation. Robust YAP activation was observed in CDK4/6 inhibitor-resistant luminal breast cancer cells. Knockdown or pharmacological inhibition of MAP3K3 effectively suppressed YAP activity and restored CDK4/6 inhibitor sensitivity. Similarly, elevated MAP3K3 expression supported the prosurvival activity of YAP in BRAF inhibitor-resistant melanoma cells. Inhibition of MAP3K3 decreased YAP-dependent cell proliferation and successfully restored BRAF inhibitor sensitivity. In conclusion, our study reveals a previously unrecognized mechanism for the regulation of YAP stability, suggesting MAP3K3 inhibition as a promising strategy for overcoming resistance to CDK4/6 and BRAF inhibitors in cancer treatment.

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Section: Resultsmentioning

confidence: 99%

“…Our previous RNAi screening studies suggested that MAP3K3 is a potential target for YAP inhibition 5 , 27 . In this study, we demonstrate that MAP3K3 phosphorylates YAP at serine 405 and that this phosphorylation event interferes with YAP polyubiquitination and lysosomal degradation in a LATS-independent manner.…”

Section: Introductionmentioning

confidence: 99%

Overcoming BRAF and CDK4/6 inhibitor resistance by inhibiting MAP3K3-dependent protection against YAP lysosomal degradation

Park,

Ryu,

Kim

et al. 2024

Exp Mol Med

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“…First, we selected genes that fulfill two conditions as candidates ( SI Appendix , Fig. S2 A and Table S1 ): 1) when depleted, they reduce nuclear YAP protein levels but do not affect the nucleocytoplasmic ratio of YAP, based on our previous siRNA library screening data ( 43 , 44 ); and 2) they are frequently overexpressed and/or amplified in HPV − HNSCC patient samples (TCGA data). We examined the mRNA level of YAP 1 after knockdown of each candidate.…”

Section: Resultsmentioning

confidence: 99%

TM4SF19 controls GABP-dependent YAP transcription in head and neck cancer under oxidative stress conditions

Shin,

Kwon,

Jung

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Tobacco and alcohol are risk factors for human papillomavirus–negative head and neck squamous cell carcinoma (HPV − HNSCC), which arises from the mucosal epithelium of the upper aerodigestive tract. Notably, despite the mutagenic potential of smoking, HPV − HNSCC exhibits a low mutational load directly attributed to smoking, which implies an undefined role of smoking in HPV − HNSCC. Elevated YAP (Yes-associated protein) mRNA is prevalent in HPV − HNSCC, irrespective of the YAP gene amplification status, and the mechanism behind this upregulation remains elusive. Here, we report that oxidative stress, induced by major risk factors for HPV − HNSCC such as tobacco and alcohol, promotes YAP transcription via TM4SF19 (transmembrane 4 L six family member 19). TM4SF19 modulates YAP transcription by interacting with the GABP (Guanine and adenine-binding protein) transcription factor complex. Mechanistically, oxidative stress induces TM4SF19 dimerization and topology inversion in the endoplasmic reticulum membrane, which in turn protects the GABPβ1 subunit from proteasomal degradation. Conversely, depletion of TM4SF19 impairs the survival, proliferation, and migration of HPV − HNSCC cells, highlighting the potential therapeutic relevance of targeting TM4SF19. Our findings reveal the roles of the key risk factors of HPV − HNSCC in tumor development via oxidative stress, offering implications for upcoming therapeutic approaches in HPV − HNSCC.

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“…Wong and Thai were also found among the top upregulated ones such as Rap1GAP, CD151, UBE2C and NECTIN2 [30]. MAP2K3 gene (mitogen-activated protein kinase 3) based on the previously published data, has been proposed as a potential drug target due to its activity in lung inflammatory processes (Table 3) [31]. We performed GO (gene ontology) annotation analysis to explore the biological functions of the DEGs in COVID-19 group (Fig.…”

Section: Resultsmentioning

confidence: 99%

Transcriptional Profiles Analysis of COVID-19 and Malaria Patients Reveals Potential Biomarkers in Children

Lambert

Jonas

Rissy

et al. 2022

Preprint

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The clinical presentation overlap between malaria and COVID-19 poses special challenges for rapid diagnosis in febrile children. In this study, we collected RNA-seq data of children with malaria and COVID-19 infection from the public databases as raw data in fastq format paired end files. A group of six, five and two biological replicates of malaria, COVID-19 and healthy donors respectively were used for the study. We conducted differential gene expression analysis to visualize differences in the expression profiles. Using edgeR, we explored particularly the expressed genes in different phenotype groups relative to the healthy samples where 1084 genes and 2495 genes were differentially expressed in the malaria samples and COVID-19 samples respectively. Highly expressed genes in the COVID-19 samples were associated with biological processes such as cell division (CCDC124) and SLC12A5-AS1 a lncRNA gene associated with NK-cell while in the malaria samples were associated with biological processes such as immune response (CTSL), T cell activation (RSAD2) and proteolysis (LAP3). By comparing both malaria and COVID-19, the overlaps of 62 differentially expressed genes patterns were identified. Among the shared genes, the hemoglobin complexes and lipid mediators are highly expressed. We found six genes such as CYB5R3, RSAD2, ALOX15, HBQ1, HBM and PNPLA2 associated with malaria and COVID-19 diseases in children, which can be further validated as potential biomarkers. Our study provided new insights for further investigation of the biological pattern in hosts with malaria and COVID-19 coinfection.

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Genome-wide RNA interference screening reveals a COPI-MAP2K3 pathway required for YAP regulation

Cited by 5 publications

References 46 publications

Overcoming BRAF and CDK4/6 inhibitor resistance by inhibiting MAP3K3-dependent protection against YAP lysosomal degradation

Overcoming BRAF and CDK4/6 inhibitor resistance by inhibiting MAP3K3-dependent protection against YAP lysosomal degradation

TM4SF19 controls GABP-dependent YAP transcription in head and neck cancer under oxidative stress conditions

Transcriptional Profiles Analysis of COVID-19 and Malaria Patients Reveals Potential Biomarkers in Children

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