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Article ; Online: Cancer lineage-specific regulation of YAP responsive elements revealed through large-scale functional epigenomic screens.

2023 Volume 14, Issue 1, Page(s) 3907

Abstract: YAP is a key transcriptional co-activator of TEADs, it regulates cell growth and is frequently activated in cancer. In Malignant Pleural Mesothelioma (MPM), YAP is activated by loss-of-function mutations in upstream components of the Hippo pathway, while, ...

Abstract	YAP is a key transcriptional co-activator of TEADs, it regulates cell growth and is frequently activated in cancer. In Malignant Pleural Mesothelioma (MPM), YAP is activated by loss-of-function mutations in upstream components of the Hippo pathway, while, in Uveal Melanoma (UM), YAP is activated in a Hippo-independent manner. To date, it is unclear if and how the different oncogenic lesions activating YAP impact its oncogenic program, which is particularly relevant for designing selective anti-cancer therapies. Here we show that, despite YAP being essential in both MPM and UM, its interaction with TEAD is unexpectedly dispensable in UM, limiting the applicability of TEAD inhibitors in this cancer type. Systematic functional interrogation of YAP regulatory elements in both cancer types reveals convergent regulation of broad oncogenic drivers in both MPM and UM, but also strikingly selective programs. Our work reveals unanticipated lineage-specific features of the YAP regulatory network that provide important insights to guide the design of tailored therapeutic strategies to inhibit YAP signaling across different cancer types.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; YAP-Signaling Proteins ; Epigenomics ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Signal Transduction/genetics ; Neoplasms
Chemical Substances	Adaptor Proteins, Signal Transducing ; YAP-Signaling Proteins ; Transcription Factors
Language	English
Publishing date	2023-07-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-39527-w
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Article ; Online: DRUG-seq Provides Unbiased Biological Activity Readouts for Neuroscience Drug Discovery.

ACS chemical biology

2022 Volume 17, Issue 6, Page(s) 1401–1414

Abstract: Unbiased transcriptomic RNA-seq data has provided deep insights into biological processes. However, its impact in drug discovery has been narrow given high costs and low throughput. Proof-of-concept studies with Digital RNA with pertUrbation of Genes ( ... ...

Abstract	Unbiased transcriptomic RNA-seq data has provided deep insights into biological processes. However, its impact in drug discovery has been narrow given high costs and low throughput. Proof-of-concept studies with Digital RNA with pertUrbation of Genes (DRUG)-seq demonstrated the potential to address this gap. We extended the DRUG-seq platform by subjecting it to rigorous testing and by adding an open-source analysis pipeline. The results demonstrate high reproducibility and ability to resolve the mechanism(s) of action for a diverse set of compounds. Furthermore, we demonstrate how this data can be incorporated into a drug discovery project aiming to develop therapeutics for schizophrenia using human stem cell-derived neurons. We identified both an on-target activation signature, induced by a set of chemically distinct positive allosteric modulators of the
MeSH term(s)	Drug Discovery/methods ; Humans ; RNA ; Reproducibility of Results ; Sequence Analysis, RNA/methods ; Transcriptome
Chemical Substances	RNA (63231-63-0)
Language	English
Publishing date	2022-05-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.1c00920
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Article ; Online: Cell adhesion molecule KIRREL1 is a feedback regulator of Hippo signaling recruiting SAV1 to cell-cell contact sites.

Nature communications

2022 Volume 13, Issue 1, Page(s) 930

Abstract: The Hippo/YAP pathway controls cell proliferation through sensing physical and spatial organization of cells. How cell-cell contact is sensed by Hippo signaling is poorly understood. Here, we identified the cell adhesion molecule KIRREL1 as an upstream ... ...

Abstract	The Hippo/YAP pathway controls cell proliferation through sensing physical and spatial organization of cells. How cell-cell contact is sensed by Hippo signaling is poorly understood. Here, we identified the cell adhesion molecule KIRREL1 as an upstream positive regulator of the mammalian Hippo pathway. KIRREL1 physically interacts with SAV1 and recruits SAV1 to cell-cell contact sites. Consistent with the hypothesis that KIRREL1-mediated cell adhesion suppresses YAP activity, knockout of KIRREL1 increases YAP activity in neighboring cells. Analyzing pan-cancer CRISPR proliferation screen data reveals KIRREL1 as the top plasma membrane protein showing strong correlation with known Hippo regulators, highlighting a critical role of KIRREL1 in regulating Hippo signaling and cell proliferation. During liver regeneration in mice, KIRREL1 is upregulated, and its genetic ablation enhances hepatic YAP activity, hepatocyte reprogramming and biliary epithelial cell proliferation. Our data suggest that KIRREL1 functions as a feedback regulator of the mammalian Hippo pathway through sensing cell-cell interaction and recruiting SAV1 to cell-cell contact sites.
MeSH term(s)	Adult ; Aged, 80 and over ; Animals ; Cell Communication ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Feedback, Physiological ; Female ; Gene Knockout Techniques ; HEK293 Cells ; Hepatocytes ; Hippo Signaling Pathway ; Humans ; Male ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Mice, Transgenic ; Middle Aged ; YAP-Signaling Proteins/metabolism
Chemical Substances	Cell Cycle Proteins ; KIRREL1 protein, human ; Kirrel1 protein, mouse ; Membrane Proteins ; SAV1 protein, human ; YAP-Signaling Proteins ; YAP1 protein, human
Language	English
Publishing date	2022-02-17
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-28567-3
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Article ; Online: A Genome-wide CRISPR Screen Identifies ZCCHC14 as a Host Factor Required for Hepatitis B Surface Antigen Production.

Hyrina, Anastasia / Jones, Christopher / Chen, Darlene / Clarkson, Scott / Cochran, Nadire / Feucht, Paul / Hoffman, Gregory / Lindeman, Alicia / Russ, Carsten / Sigoillot, Frederic / Tsang, Tiffany / Uehara, Kyoko / Xie, Lili / Ganem, Don / Holdorf, Meghan

Cell reports

2019 Volume 29, Issue 10, Page(s) 2970–2978.e6

Abstract: A hallmark of chronic hepatitis B (CHB) virus infection is the presence of high circulating levels of non-infectious small lipid HBV surface antigen (HBsAg) vesicles. Although rare, sustained HBsAg loss is the idealized endpoint of any CHB therapy. A ... ...

Abstract	A hallmark of chronic hepatitis B (CHB) virus infection is the presence of high circulating levels of non-infectious small lipid HBV surface antigen (HBsAg) vesicles. Although rare, sustained HBsAg loss is the idealized endpoint of any CHB therapy. A small molecule, RG7834, has been previously reported to inhibit HBsAg expression by targeting terminal nucleotidyltransferase proteins 4A and 4B (TENT4A and TENT4B). In this study, we describe a genome-wide CRISPR screen to identify other potential host factors required for HBsAg expression and to gain further insights into the mechanism of RG7834. We report more than 60 genes involved in regulating HBsAg and identify additional factors involved in RG7834 activity, including a zinc finger CCHC-type containing 14 (ZCCHC14) protein. We show that ZCCHC14, together with TENT4A/B, stabilizes HBsAg expression through HBV RNA tailing, providing a potential new therapeutic target to achieve functional cure in CHB patients.
MeSH term(s)	Antigens, Surface/genetics ; Antiviral Agents/pharmacology ; Cell Line, Tumor ; Clustered Regularly Interspaced Short Palindromic Repeats/genetics ; DNA, Viral/genetics ; Genome-Wide Association Study/methods ; Hep G2 Cells ; Hepatitis B Surface Antigens/genetics ; Hepatitis B virus/drug effects ; Hepatitis B virus/genetics ; Hepatitis B, Chronic/drug therapy ; Hepatitis B, Chronic/genetics ; Hepatitis B, Chronic/virology ; Host Microbial Interactions/drug effects ; Host Microbial Interactions/genetics ; Humans ; Nuclear Proteins/genetics ; Polynucleotide Adenylyltransferase/genetics ; Viral Load/drug effects ; Viral Load/genetics
Chemical Substances	Antigens, Surface ; Antiviral Agents ; DNA, Viral ; Hepatitis B Surface Antigens ; Nuclear Proteins ; ZCCHC17 protein, human ; Polynucleotide Adenylyltransferase (EC 2.7.7.19)
Language	English
Publishing date	2019-02-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2019.10.113
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Article ; Online: Genome-wide CRISPR screen identifies protein pathways modulating tau protein levels in neurons.

Communications biology

2021 Volume 4, Issue 1, Page(s) 736

Abstract: Aggregates of hyperphosphorylated tau protein are a pathological hallmark of more than 20 distinct neurodegenerative diseases, including Alzheimer's disease, progressive supranuclear palsy, and frontotemporal dementia. While the exact mechanism of tau ... ...

Abstract	Aggregates of hyperphosphorylated tau protein are a pathological hallmark of more than 20 distinct neurodegenerative diseases, including Alzheimer's disease, progressive supranuclear palsy, and frontotemporal dementia. While the exact mechanism of tau aggregation is unknown, the accumulation of aggregates correlates with disease progression. Here we report a genome-wide CRISPR screen to identify modulators of endogenous tau protein for the first time. Primary screens performed in SH-SY5Y cells, identified positive and negative regulators of tau protein levels. Hit validation of the top 43 candidate genes was performed using Ngn2-induced human cortical excitatory neurons. Using this approach, genes and pathways involved in modulation of endogenous tau levels were identified, including chromatin modifying enzymes, neddylation and ubiquitin pathway members, and components of the mTOR pathway. TSC1, a critical component of the mTOR pathway, was further validated in vivo, demonstrating the relevance of this screening strategy. These findings may have implications for treating neurodegenerative diseases in the future.
MeSH term(s)	Animals ; CRISPR-Associated Protein 9 ; CRISPR-Cas Systems ; Cell Line, Tumor ; Gene Editing ; Genes/genetics ; Genes/physiology ; Genetic Testing/methods ; Genome-Wide Association Study ; Humans ; Metabolic Networks and Pathways/genetics ; Mice ; Neuroblastoma/metabolism ; Neurons/metabolism ; Rats ; TOR Serine-Threonine Kinases/metabolism ; tau Proteins/metabolism
Chemical Substances	tau Proteins ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; CRISPR-Associated Protein 9 (EC 3.1.-)
Language	English
Publishing date	2021-06-14
Publishing country	England
Document type	Journal Article
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-021-02272-1
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Article ; Online: Genome-wide CRISPR screening reveals genetic modifiers of mutant EGFR dependence in human NSCLC.

Zeng, Hao / Castillo-Cabrera, Johnny / Manser, Mika / Lu, Bo / Yang, Zinger / Strande, Vaik / Begue, Damien / Zamponi, Raffaella / Qiu, Shumei / Sigoillot, Frederic / Wang, Qiong / Lindeman, Alicia / Reece-Hoyes, John S / Russ, Carsten / Bonenfant, Debora / Jiang, Xiaomo / Wang, Youzhen / Cong, Feng

eLife

2019 Volume 8

Abstract: EGFR-mutant NSCLCs frequently respond to EGFR tyrosine kinase inhibitors (TKIs). However, the responses are not durable, and the magnitude of tumor regression is variable, suggesting the existence of genetic modifiers of EGFR dependency. Here, we applied ...

Abstract	EGFR-mutant NSCLCs frequently respond to EGFR tyrosine kinase inhibitors (TKIs). However, the responses are not durable, and the magnitude of tumor regression is variable, suggesting the existence of genetic modifiers of EGFR dependency. Here, we applied a genome-wide CRISPR-Cas9 screening to identify genetic determinants of EGFR TKI sensitivity and uncovered putative candidates. We show that knockout of
MeSH term(s)	A549 Cells ; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; CRISPR-Cas Systems ; Carcinoma, Non-Small-Cell Lung/genetics ; Cell Line, Tumor ; Clustered Regularly Interspaced Short Palindromic Repeats ; Cullin Proteins ; ErbB Receptors/genetics ; Female ; Gene Expression Regulation, Neoplastic ; Gene Knockout Techniques ; Guanine Nucleotide Exchange Factors/genetics ; HEK293 Cells ; Humans ; Methionyl Aminopeptidases/metabolism ; Mice ; Mice, Nude ; Receptors, Lysophosphatidic Acid/metabolism ; Signal Transduction ; Transcription Factors/metabolism ; Transcriptome ; Ubiquitin-Protein Ligases/genetics ; rhoA GTP-Binding Protein/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; CUL5 protein, human ; Cullin Proteins ; Guanine Nucleotide Exchange Factors ; LPAR2 protein, human ; Receptors, Lysophosphatidic Acid ; Ric8A protein, human ; Transcription Factors ; YAP1 protein, human ; RHOA protein, human (124671-05-2) ; ARIH2 protein, human (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; EGFR protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; METAP2 protein, human (EC 3.4.11.18) ; Methionyl Aminopeptidases (EC 3.4.11.18) ; rhoA GTP-Binding Protein (EC 3.6.5.2)
Language	English
Publishing date	2019-11-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.50223
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Article ; Online: Bile acid analogues are activators of pyrin inflammasome.

Alimov, Irina / Menon, Suchithra / Cochran, Nadire / Maher, Rob / Wang, Qiong / Alford, John / Concannon, John B / Yang, Zinger / Harrington, Edmund / Llamas, Luis / Lindeman, Alicia / Hoffman, Gregory / Schuhmann, Tim / Russ, Carsten / Reece-Hoyes, John / Canham, Stephen M / Cai, Xinming

The Journal of biological chemistry

2019 Volume 294, Issue 10, Page(s) 3359–3366

Abstract: Bile acids are critical metabolites in the gastrointestinal tract and contribute to maintaining intestinal immune homeostasis through cross-talk with the gut microbiota. The conversion of bile acids by the gut microbiome is now recognized as a factor ... ...

Abstract	Bile acids are critical metabolites in the gastrointestinal tract and contribute to maintaining intestinal immune homeostasis through cross-talk with the gut microbiota. The conversion of bile acids by the gut microbiome is now recognized as a factor affecting both host metabolism and immune responses, but its physiological roles remain unclear. We conducted a screen for microbiome metabolites that would function as inflammasome activators and herein report the identification of 12-oxo-lithocholic acid (BAA485), a potential microbiome-derived bile acid metabolite. We demonstrate that the more potent analogue 11-oxo-12
MeSH term(s)	Bile Acids and Salts/chemistry ; Bile Acids and Salts/immunology ; Epithelial Cells/immunology ; Gastrointestinal Microbiome/immunology ; Humans ; Immunity, Mucosal ; Inflammasomes/immunology ; Intestinal Mucosa/immunology ; Myeloid Cells/immunology ; Pyrin/immunology ; THP-1 Cells
Chemical Substances	Bile Acids and Salts ; Inflammasomes ; MEFV protein, human ; Pyrin
Language	English
Publishing date	2019-01-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA118.005103
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Article ; Online: An iron-dependent metabolic vulnerability underlies VPS34-dependence in RKO cancer cells.

PloS one

2020 Volume 15, Issue 8, Page(s) e0235551

Abstract: VPS34 is a key regulator of endomembrane dynamics and cargo trafficking, and is essential in cultured cell lines and in mice. To better characterize the role of VPS34 in cell growth, we performed unbiased cell line profiling studies with the selective ... ...

Abstract	VPS34 is a key regulator of endomembrane dynamics and cargo trafficking, and is essential in cultured cell lines and in mice. To better characterize the role of VPS34 in cell growth, we performed unbiased cell line profiling studies with the selective VPS34 inhibitor PIK-III and identified RKO as a VPS34-dependent cellular model. Pooled CRISPR screen in the presence of PIK-III revealed endolysosomal genes as genetic suppressors. Dissecting VPS34-dependent alterations with transcriptional profiling, we found the induction of hypoxia response and cholesterol biosynthesis as key signatures. Mechanistically, acute VPS34 inhibition enhanced lysosomal degradation of transferrin and low-density lipoprotein receptors leading to impaired iron and cholesterol uptake. Excess soluble iron, but not cholesterol, was sufficient to partially rescue the effects of VPS34 inhibition on mitochondrial respiration and cell growth, indicating that iron limitation is the primary driver of VPS34-dependency in RKO cells. Loss of RAB7A, an endolysosomal marker and top suppressor in our genetic screen, blocked transferrin receptor degradation, restored iron homeostasis and reversed the growth defect as well as metabolic alterations due to VPS34 inhibition. Altogether, our findings suggest that impaired iron mobilization via the VPS34-RAB7A axis drive VPS34-dependence in certain cancer cells.
MeSH term(s)	Cell Hypoxia ; Cell Line, Tumor ; Cell Proliferation ; Cholesterol/biosynthesis ; Cholesterol/genetics ; Class III Phosphatidylinositol 3-Kinases/genetics ; Class III Phosphatidylinositol 3-Kinases/metabolism ; Endosomes/metabolism ; HEK293 Cells ; Humans ; Iron/metabolism ; Lysosomes/metabolism ; Neoplasms/metabolism ; Receptors, LDL/metabolism ; Transferrin/metabolism ; rab GTP-Binding Proteins/genetics ; rab GTP-Binding Proteins/metabolism
Chemical Substances	Receptors, LDL ; Transferrin ; rab7 protein (152989-05-4) ; Cholesterol (97C5T2UQ7J) ; Iron (E1UOL152H7) ; Class III Phosphatidylinositol 3-Kinases (EC 2.7.1.137) ; rab GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2020-08-24
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0235551
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Article ; Online: Autophagy-Independent Lysosomal Targeting Regulated by ULK1/2-FIP200 and ATG9.

Goodwin, Jonathan M / Dowdle, William E / DeJesus, Rowena / Wang, Zuncai / Bergman, Philip / Kobylarz, Marek / Lindeman, Alicia / Xavier, Ramnik J / McAllister, Gregory / Nyfeler, Beat / Hoffman, Gregory / Murphy, Leon O

Cell reports

2017 Volume 20, Issue 10, Page(s) 2341–2356

Abstract: Iron is vital for many homeostatic processes, and its liberation from ferritin nanocages occurs in the lysosome. Studies indicate that ferritin and its binding partner nuclear receptor coactivator-4 (NCOA4) are targeted to lysosomes by a form of ... ...

Abstract	Iron is vital for many homeostatic processes, and its liberation from ferritin nanocages occurs in the lysosome. Studies indicate that ferritin and its binding partner nuclear receptor coactivator-4 (NCOA4) are targeted to lysosomes by a form of selective autophagy. By using genome-scale functional screening, we identify an alternative lysosomal transport pathway for ferritin that requires FIP200, ATG9A, VPS34, and TAX1BP1 but lacks involvement of the ATG8 lipidation machinery that constitutes classical macroautophagy. TAX1BP1 binds directly to NCOA4 and is required for lysosomal trafficking of ferritin under basal and iron-depleted conditions. Under basal conditions ULK1/2-FIP200 controls ferritin turnover, but its deletion leads to TAX1BP1-dependent activation of TBK1 that regulates redistribution of ATG9A to the Golgi enabling continued trafficking of ferritin. Cells expressing an amyotrophic lateral sclerosis (ALS)-associated TBK1 allele are incapable of degrading ferritin suggesting a molecular mechanism that explains the presence of iron deposits in patient brain biopsies.
MeSH term(s)	Autophagy/genetics ; Autophagy/physiology ; Autophagy-Related Protein-1 Homolog/genetics ; Autophagy-Related Protein-1 Homolog/metabolism ; Autophagy-Related Proteins/genetics ; Autophagy-Related Proteins/metabolism ; Cell Line ; Cell Line, Tumor ; DNA, Complementary/genetics ; Ferritins/genetics ; Ferritins/metabolism ; HEK293 Cells ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Lysosomes/metabolism ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Protein-Tyrosine Kinases/genetics ; Protein-Tyrosine Kinases/metabolism ; Vesicular Transport Proteins/genetics ; Vesicular Transport Proteins/metabolism
Chemical Substances	ATG9A protein, human ; Autophagy-Related Proteins ; DNA, Complementary ; Intracellular Signaling Peptides and Proteins ; Membrane Proteins ; Neoplasm Proteins ; RB1CC1 protein, human ; TAX1BP1 protein, human ; Vesicular Transport Proteins ; Ferritins (9007-73-2) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Autophagy-Related Protein-1 Homolog (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; TBK1 protein, human (EC 2.7.11.1) ; ULK1 protein, human (EC 2.7.11.1) ; Ulk2 protein, human (EC 2.7.11.1)
Language	English
Publishing date	2017-08-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2017.08.034
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Article ; Online: Tankyrase Inhibitor Sensitizes Lung Cancer Cells to Endothelial Growth Factor Receptor (EGFR) Inhibition via Stabilizing Angiomotins and Inhibiting YAP Signaling.

Wang, Hui / Lu, Bo / Castillo, Johnny / Zhang, Yue / Yang, Zinger / McAllister, Gregory / Lindeman, Alicia / Reece-Hoyes, John / Tallarico, John / Russ, Carsten / Hoffman, Greg / Xu, Wenqing / Schirle, Markus / Cong, Feng

The Journal of biological chemistry

2016 Volume 291, Issue 29, Page(s) 15256–15266

Abstract: YAP signaling pathway plays critical roles in tissue homeostasis, and aberrant activation of YAP signaling has been implicated in cancers. To identify tractable targets of YAP pathway, we have performed a pathway-based pooled CRISPR screen and identified ...

Abstract	YAP signaling pathway plays critical roles in tissue homeostasis, and aberrant activation of YAP signaling has been implicated in cancers. To identify tractable targets of YAP pathway, we have performed a pathway-based pooled CRISPR screen and identified tankyrase and its associated E3 ligase RNF146 as positive regulators of YAP signaling. Genetic ablation or pharmacological inhibition of tankyrase prominently suppresses YAP activity and YAP target gene expression. Using a proteomic approach, we have identified angiomotin family proteins, which are known negative regulators of YAP signaling, as novel tankyrase substrates. Inhibition of tankyrase or depletion of RNF146 stabilizes angiomotins. Angiomotins physically interact with tankyrase through a highly conserved motif at their N terminus, and mutation of this motif leads to their stabilization. Tankyrase inhibitor-induced stabilization of angiomotins reduces YAP nuclear translocation and decreases downstream YAP signaling. We have further shown that knock-out of YAP sensitizes non-small cell lung cancer to EGFR inhibitor Erlotinib. Tankyrase inhibitor, but not porcupine inhibitor, which blocks Wnt secretion, enhances growth inhibitory activity of Erlotinib. This activity is mediated by YAP inhibition and not Wnt/β-catenin inhibition. Our data suggest that tankyrase inhibition could serve as a novel strategy to suppress YAP signaling for combinatorial targeted therapy.
MeSH term(s)	Adaptor Proteins, Signal Transducing/antagonists & inhibitors ; Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Antineoplastic Agents/pharmacology ; CRISPR-Cas Systems ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/metabolism ; Cell Line, Tumor ; Down-Regulation ; ErbB Receptors/antagonists & inhibitors ; Erlotinib Hydrochloride/pharmacology ; Gene Knockout Techniques ; HEK293 Cells ; Humans ; Intercellular Signaling Peptides and Proteins/chemistry ; Intercellular Signaling Peptides and Proteins/genetics ; Intercellular Signaling Peptides and Proteins/metabolism ; Lung Neoplasms/drug therapy ; Lung Neoplasms/metabolism ; Membrane Proteins/chemistry ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Microfilament Proteins ; Phosphoproteins/antagonists & inhibitors ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; Protein Interaction Domains and Motifs ; Protein Stability/drug effects ; RNA, Small Interfering/genetics ; Signal Transduction/drug effects ; Tankyrases/antagonists & inhibitors ; Tankyrases/chemistry ; Tankyrases/genetics ; Transcription Factors ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	AMOT protein, human ; Adaptor Proteins, Signal Transducing ; Antineoplastic Agents ; Intercellular Signaling Peptides and Proteins ; Membrane Proteins ; Microfilament Proteins ; Phosphoproteins ; RNA, Small Interfering ; Transcription Factors ; YAP1 protein, human ; Erlotinib Hydrochloride (DA87705X9K) ; RNF146 protein, human (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; TNKS2 protein, human (EC 2.4.2.30) ; Tankyrases (EC 2.4.2.30) ; TNKS protein, human (EC 2.4.4.30) ; EGFR protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1)
Language	English
Publishing date	2016-05-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M116.722967
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