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2018年中国质谱学术大会（CMSC2018）

作者： Shujuan Wang Cunjie Zhang Adrian Pasculescu Pan Zhang Sihui Li Xiaojing Wu Xiao Li Rita Das Qing Sheng Lorne Taylor Vivian Nguyen Tony Pawson Carl Uli Bialucha Karen Colwill Yong Zheng State Key Laboratory of Proteomics Beijing Proteome Research CenterNational Center for Protein Sciences (Beijing)Beijing Institute of Lifeomics Lunenfeld Tanenbaum Research Institute Mount Sinai Hospital McGill University Health Centre Department of Molecular Genetics University of Toronto

The SHC1 adaptor protein directly binds to all members of the HER/ERBB receptor tyrosine kinase family and forms a critical link between the receptors and downstream effectors1,2. Since SHC1 only binds to receptors in their activated states, it is well positioned to monitor the translation of signals from the receptors to downstream targets which is of critical importance in ERBB-driven cancers. We affinity purified SHC1 followed by parallel reaction monitoring(PRM)-based quantification to measure changes in SHC1 complex formation in 19 cancer cell lines with various ERBB levels1. We targeted 35 SHC interactors for quantitation. Our data showed that the cell lines varied significantly in the type and number of proteins(from 6 to 32 proteins) that were recruited to SHC1. We further captured temporal profiles of the SHC1 complexes before and during EGF stimulation in four ERBB2/HER2 positive breast cancer cell lines(SKBR3, BT-474, HCC-1954, HCC-1419) with different sensitivity towards trastzumab3, a clinical inhibitor for ERBB2/HER2. We detected significantly stronger association of promitogenic components of SHC1 complexes at basal level in drug-sensitive cells over drug-resistant cells. This pattern is not observed for components involved in negatively regulation ERBB signaling. Moreover, the duration, but not the maximum level, of the association for pro-mitogenic components is apparently longer in drug-sensitive cells, suggesting defects in signal down regulation in these cells. Not all of these observations could be predicted from either m RNA or protein expression levels. Taking together, our analysis of dynamic SHC1 complex formation supports SHC1 as a function-base probe for monitoring ERBB activation status and a potential diagnostic tool for drug sensitivity prediction.

关键词： quantitative mass spectrometry Drug resistance Dynamic Signaling Breast cancer cell

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Identifi cation and functional analysis of phosphorylation residues of the Arabidopsis BOTRYTIS-INDUCED KINASE1

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Protein & Cell 2013年第10期4卷 771-781页

作者： Jinhua Xu Xiaochao Wei Limin Yan Dan Liu Yuanyuan Ma Yu Guo Chune Peng Honggang Zhou Cheng Yang Zhiyong Lou Wenqing Shui College of Life Sciences and Tianjin State Laboratory of Protein Science Nankai UniversityTianjin 300071China High-throughput Molecular Drug Discovery Center Tianjin Joint Academy of Biotechnology and MedicineTianjin 300457China Laboratory of Structural Biology and MOE Laboratory of Protein Science School of Medicine and Life SciencesTsinghua UniversityBeijing 100084China College of Pharmacy and State Key Laboratory of Medicinal Chemical Biology Nankai UniversityTianjin 300071China

Arabidopsis BOTRYTIS-INDUCED KINASE1(BIK1)is a receptor-like cytoplasmic kinase acting early in multiple signaling pathways important for plant growth and innate *** is known to form a signaling complex with a cell-surface receptor FLS2 and a co-receptor kinase BAK1 to transduce signals upon perception of pathogen-asso-ciated molecular patterns(PAMPs).Although site-specifi c phosphorylation is speculated to mediate the activation and function of BIK1,few studies have been devoted to complete profiling of BIK1 phosphorylation ***,we identified nineteen in vitro autophosphoryla-tion sites of BIK1 including three phosphotyrosine sites,thereby proving BIK1 is a dual-specifi city kinase for the fi rst *** kinase activity of BIK1 substitution mutants were explicitly assessed using quantitative mass spec-trometry(MS).Thr-237,Thr-242 and Tyr-250 were found to most signifi cantly affect BIK1 activity in autophosphoryla-tion and phosphorylation of BAK1 in vitro.A structural model of BIK1 was built to further illustrate the molecular functions of specifi c phosphorylation *** also mapped new sites of FLS2 phosphorylation by BIK1,which are different from those by *** in vitro results could provide new hypotheses for more in-depth in vivo studies leading to deeper understanding of how phosphorylation contributes to BIK1 activation and medi-ates downstream signaling specifi city.

关键词： phosphorylation BIK1 receptor-like cytop-lasmic kinase quantitative mass spectrometry

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Multiple Signaling Roles of CD3ε and Its Application in CAR-T Cell Therapy

Multiple Signaling Roles of CD3ε and Its Application in CAR...

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第十四届全国免疫学学术大会

作者： Wei Wu Qiuping Zhou Takeya Masubuchi Xiaoshan Shi Hua Li Xinyi Xu Min Huang Li Meng Xing He Hengyu Zhu Shuaixin Gao Nan Zhang Ruirui Jing Jie Sun Haopeng Wang Enfu Hui Catherine Chiulan Wong Chenqi Xu the First Hospital of Jilin University State Key Laboratory of Molecular Biology Shanghai Institute of Biochemistry and Cell Biology Center for Excellence in Molecular Cell Science Chinese Academy of Sciences Section of Cell & Developmental Biology Division of Biological Sciences University of California Center for Precision Medicine Multi-omics Research Peking University Health Science Center Peking University First Hospital Bone Marrow Transplantation Center of the First Affiliated Hospital and Department of Cell Biology Zhejiang University School of Medicine School of Life Science and Technology ShanghaiTech University

A T cell receptor(TCR) mediates antigen-induced signaling through its associated CD3ε, δ, γ, and ζ, but the contributions of different CD3 chains remain elusive. Using quantitative mass spectrometry, we simultaneously quantitated the phosphorylation of the immunoreceptor tyrosine-based activation motif(ITAM) of all CD3 chains upon TCR stimulation. A subpopulation of CD3ε ITAMs was mono-phosphorylated, owing to Lck kinase selectivity, and specifically recruited the inhibitory Csk kinase to attenuate TCR signaling, suggesting that TCR is a self-restrained signaling machinery containing both activating and inhibitory motifs. Moreover, we found that incorporation of the CD3ε cytoplasmic domain into a second-generation chimeric antigen receptor(CAR) improved antitumor activity of CAR-T cells. Mechanistically, the Csk-recruiting ITAM of CD3ε reduced CAR-T cytokine production whereas the basic residue rich sequence(BRS) of CD3ε promoted CAR-T persistence via p85 recruitment. Collectively, CD3ε is a built-in multifunctional signal tuner, and increasing CD3 diversity represents a strategy to design next-generation CAR.

关键词： CAR-T therapy Csk ITAM T cell receptor TCR cancer cell persistence cytokine release p85 phosphorylation pattern quantitative mass spectrometry

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