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Large tumor suppressor 2,LATS2,activates iNK in kinase-independent mechanism through ASK1

Journal of molecular Cell Biology 2018年第6期10卷 549-558页

作者： Lauren Rusnak Cong Tang Qi Qi xiulei mo Haian Fu Graduate Program in Cancer Biology Emory UniversityAtlantaGA 30322USA Department of Pharmacology and Emory Chemical Biology Discovery Center Emory UniversityAtlantaGA 30322USA The First Affiliated Hospital Medical School of Xi'an Jiaotong UniversityXi'an 710061China Winship Cancer Institute Emory UniversityAtlantaGA 30322USA Department of Hematology and Medical Oncology Emory UniversityAtlantaGA 30322USA

Apoptosis signal-regulating kinase 1 (ASK1)is an important mediator of the cell stress response *** of its central role in regulating cell death,the activity of ASK1 is tightly regulated by protein-protein interactions and post-translational *** of ASK1 activity has been linked to human diseases,such as neurological disorders and *** we describe the identification and characterization of large tumor suppressor 2 (LATS2)as a novel binding partner for ***2 is a core kinase in the Hippo signaling pathway and is commonly downregulated in *** found that LATS2 interacts with ASK1 and increases ASK1-mediated signaUng to promote apoptosis and activate the iNK mitogen-activated protein kinase (MAPK).This change in MAPK signaling is dependent on the catalytic activity of ASK1 but does not require LATS2 kinase activity. This work identifies a novel role for LATS2 as a positive regulator of the ASK1-MKK-JNK signaling pathway and establishes a kinase-independent function of LATS2 that may be part of the intricate regulatory system for cellular response to diverse stress signals.

关键词： ASK1 LATS2 kinase regulation signal transduction mitogen-activated protein kinase

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A multiplexed time-resolved fluorescence resonance energy transfer ultrahigh-throughput screening assay for targeting the SMAD4–SMAD3–DNA complex

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Journal of molecular Cell Biology 2023年第11期15卷 21-32页

作者： Wukun Ouyang Qianjin Li Qiankun Niu Min Qui Haian Fu Yuhong Du xiulei mo Department of Pharmacology and Chemical Biology Emory University School of MedicineAtlantaGA 30322USA Emory Chemical Biology Discovery Center Emory University School of MedicineAtlantaGA 30322USA Department of Hematology and Medical Oncology and Winship Cancer Institute Emory UniversityAtlantaGA 30322USA

The transforming growth factor-beta(TGFβ)signaling pathway plays crucial roles in the establishment of an immunosuppressive tumor microenvironment,making anti-TGFβagents a significant area of interest in cancer ***,the clinical translation of current anti-TGFβagents that target upstream cytokines and receptors remains ***,the development of small-molecule inhibitors specifically targeting SMAD4,the downstream master regulator of the TGFβpathway,would offer an alternative approach with significant therapeutic potential for anti-TGFβ*** this study,we present the development of a cell lysate-based multiplexed time-resolved fluorescence resonance energy transfer(TR-FRET)assay in an ultrahigh-throughput screening(uHTS)1536-well plate *** assay enables simultaneous monitoring of the protein–protein interaction between SMAD4 and SMAD3,as well as the protein–DNA interaction between SMADs and their consensus DNA-binding *** multiplexed TR-FRET assay exhibits high sensitivity,allowing the dynamic analysis of the SMAD4–SMAD3–DNA complex at single-amino acid ***,the multiplexed uHTS assay demonstrates robustness for screening small-molecule *** a pilot screening of an FDA-approved bioactive compound library,we identified gambogic acid and gambogenic acid as potential hit *** proof-of-concept findings underscore the utility of our optimized multiplexed TR-FRET platform for large-scale screening to discover small-molecule inhibitors that target the SMAD4–SMAD3–DNA complex as novel antiTGFβsignaling agents.

关键词： TGFβ/SMAD4 signaling high-throughput screening TR-FRET

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Development of a miniaturized 3D organoid culture platform for ultra-high-throughput screening

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Journal of molecular Cell Biology 2020年第8期12卷 630-643页

作者： Yuhong Du Xingnan Li Qiankun Niu xiulei mo Min Qui Tingxuan Ma Calvin J.Kuo Haian Fu Department of Pharmacology and Chemical Biology and Emory Chemical Biology Discovery Center Emory University School of MedicineAtlantaGAUSA Department of Medicine Division of HematologyStanford University School of MedicineStanfordCAUSA

The recent advent of robust methods to grow human tissues as 3D organoids allows us to recapitulate the 3D architecture of tumors in an in vitro setting and offers a new orthogonal approach for drug ***,organoid culturing with extracellular matrix to support 3D architecture has been challenging for high-throughput screening(HTS)-based drug discovery due to technical *** genetically engineered human colon organoids as a model system,here we report our effort to miniaturize such 3D organoid culture with extracellular matrix support in high-density plates to enable *** first established organoid culturing in a 384-well plate format and validated its application in a cell viability HTS assay by screening a 2036-compound *** further miniaturized the 3D organoid culturing in a 1536-well ultra-HTS format and demonstrated its robust performance for large-scale primary compound *** miniaturized organoid culturing method may be adapted to other types of *** leveraging the power of 3D organoid culture in a high-density plate format,we provide a physiologically relevant screening platform to model tumors to accelerate organoid-based research and drug discovery.

关键词： human colon organoids KRAS^G12D 3D culture 384-well plate high-throughput screening(HTS) 1536-well plate ultra-HTS(uHTS)

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TMPRSS2 and SARS-CoV-2 SPIKE interaction assay for uHTS

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Journal of molecular Cell Biology 2023年第3期15卷 32-43页

作者： Danielle Cicka Qiankun Niu Min Qui Kun Qian Eric Miller Dacheng Fan xiulei mo Andrey AIvanov Stefan GSarafianos Yuhong Du Haian Fu Department of Pharmacology and Chemical Biology Emory University School of MedicineAtlantaGA 30322USA Graduate Program in molecular and Systems Pharmacology Laney Graduate School of Emory UniversityAtlantaGA 30322USA Emory Chemical Biology Discovery Center Emory University School of MedicineAtlantaGA 30322USA Winship Cancer Institute of Emory University AtlantaGA 30322USA Laboratory of Biochemical Pharmacology Department of PediatricsEmory University School of MedicineAtlantaGA 30322USA

SARS-CoV-2,the coronavirus that causes the disease COVID-19,has claimed millions of lives over the past 2 *** demands rapid development of effective therapeutic agents that target various phases of the viral replication *** interaction between host transmembrane serine protease 2(TMPRSS2)and viral SPIKE protein is an important initial step in SARS-CoV-2 infection,offering an opportunity for therapeutic development of viral entry ***,we report the development of a time-resolved fluorescence/Förster resonance energy transfer(TR-FRET)assay for monitoring the TMPRSS2–SPIKE interaction in lysate from cells co-expressing these *** assay was configured in a 384-well-plate format for high-throughput screening with robust assay *** enable large-scale compound screening,we further miniaturized the assay into 1536-well ultrahigh-throughput screening(uHTS)format.A pilot screen demonstrated the utilization of the assay for *** optimized TR-FRET uHTS assay provides an enabling platform for expanded screening campaigns to discover new classes of small-molecule inhibitors that target the SPIKE and TMPRSS2 protein–protein interaction.

关键词： SARS-CoV-2 COVID-19 protein-protein interaction TMPRSS2 SPIKE high-throughput screening TR-FRET

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