Li, Shawn - Western University London Ontario - Schulich School of Medicine and Dentistry

研究领域

Tyrosine Phosphorylation and the Phosphoproteome The human genome encodes approximately 90 protein tyrosine kinases (PTKs), including both cytoplasmic tyrosine kinases (CTKs) and receptor tyrosine kinases (RTKs), that play a critical role in cell proliferation, differentiation, motility, and apoptosis. Because aberrant tyrosine kinase activation is a main driving force in many cancers, tyrosine kinases are important and proven therapeutic targets. A PTK functions by phosphorylating specific Tyr residues on a substrate, which, in turn, alters the structure, localization or interaction for that substrate. An early step in PTK signaling involves the binding of Src homology 2 or SH2 domain-containing proteins to specific Tyr phosphorylation sites. An important focus in my lab is to decipher the specificity of the 120 SH2 domains encoded by the human genome and the underlying structural basis. Another thrust of our research is to systematically identify tyrosine phosphorylation and the pTyr-mediated protein-protein interaction network in normal and cancer cells or tissues using proteomic techniques such as mass spectrometry and peptide and protein arrays. Protein Methylation and the Lysine Methylome Methylation of Lys and Arg residues has emerged as a prevalent post-translational modification (PTM) occurring on numerous non-histone proteins, thereby drastically extending its role beyond the histone code. We have developed an approach that combines mass spectrometry with peptide arrays and bioinformatics to systematically identify Lys methylation and quantify dynamic changes in the methylproteome associated with tumorigenesis or drug resistance. Our studies to date not only led to the identification of numerous novel methylation sites, but also generated new insights into how protein methylation regulates cellular functions such as the DNA damage repair, apoptosis and drug resistance. With recent advances in mass spectrometry and related proteomic techniques, the stage is now set to decode the methylproteome and to define it functions in health and disease.

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Huadong Liu, Haiming Huang, Courtney Voss, Tomonori Kaneko, Wentao Qin, Sachdev Sidhu and Shawn Shun-Cheng Li (2019) Surface loops in a single SH2 domain are capable of encoding the spectrum of specificity of the SH2 family. Mol Cell Proteomics. in press [ PubMed ] Jie Deng, An-Dong Liu, Guo-Qing Hou, Xi Zhang, Kun Ren, Xuan-Zuo Chen, Shawn S. C. Li, Yao-Song Wu and Xuan Cao (2019) N-acetylcysteine decreases malignant characteristics of glioblastoma cells by inhibiting Notch2 signaling. J Exp Clin Cancer Res. 2019 Jan 3;38(1):2 [ PubMed ] Gianluca Veggiani, Haiming Huang, Bradley P. Yates, Jiefei Tong, Tomonori Kaneko, Rakesh Joshi, Shawn S-C Li, Michael F. Moran, Gerald Gish, Sachdev S. Sidhu (2019) Engineered SH2 domains with tailored specificities and enhanced affinities for phosphoproteome analysis. Protein Science. Feb;28(2):403-413 [ PubMed ] Steven F. Gameiro, Wyatt W. Anderson, Ahmed F. Yousef, Wen T. Qin, Shawn S. C. Li and Joe S. Mymryk (2018) The Transcriptional Repressor BS69 is a Conserved Target of the E1A Proteins from Several Human Adenovirus Species. Viruses, 10, 662 [ PubMed ] Rui Wang, Mei Huang, Linting Li, Tomonori Kaneko, Courtney Voss, Liang Zhang, Jiang Xia, and Shawn S.C. Li (2018) Affinity Purification of Methyllysine Proteome by Site-Specific Covalent Conjugation. Anal. Chem. 90, 23, 13876-13881 [ PubMed ] Tomonori Kaneko, Peter J. Stogios, Xiang Ruan, Courtney Voss, Elena Evdokimova, Tatiana Skarina, Amy Chung, Xiaoling Liu, Lei Li, Alexei Savchenko, Alexander W. Ensminger & Shawn S.-C. Li (2018) Identification and characterization of a large family of superbinding bacterial SH2 domains. Nature Communications 9:4549 [ PubMed ] Enhui Wu, Kun Feng, Rui Shi, Rui Lv, Fuzhong Ouyang, Shawn S. C. Li, Jun Zhong and Jian Liu (2018) Hybrid CuCoO–GO enables ultrasensitive detection of antibiotics with enhanced laser desorption/ionization at nano-interfaces. Chem. Sci. [ Link ] Ran Wei, Tomonori Kaneko, Xuguang Liu, Huadong Liu, Lei Li, Courtney Voss, Eric Liu, Ningning He, Shawn S.-C. Li (2018) Interactome mapping uncovers a general role for Numb in protein kinase regulation. Mol Cell Proteomics. Nov;17(11):2216-2228. [ PubMed ] Claudia Walliser, Martin Wist, Elisabeth Hermkes, Yuan Zhou, Anja Schade, Jennifer Haas, Julia Deinzer, Laurent Désiré, Shawn S.C. Li, Stephan Stilgenbauer, Joshua D. Milner and Peter Gierschik (2018) Functional characterization of phospholipase C-γ2 mutant protein causing both somatic ibrutinib resistance and a germline monogenic autoinflammatory disorder. Oncotarget. 9:34357-34378. [ PubMed ] Nileeka Balasuriya, McShane McKenna, Xuguang Liu, Shawn S. C. Li and Patrick O’Donoghue (2018) Phosphorylation-Dependent Inhibition of Akt1. Genes (Basel). Sep 7;9(9). pii: E450. [ PubMed ] Bizhu Chu, An He, Yeteng Tian, Wan He, Peizhong Chen, Jintao Hu, Ruilian Xu, Wenbin Zhou, Mingjie Zhang, Pengyuan Yang, Shawn S. C. Li, Ying Sun, Pengfei Li, Tony Hunter, and Ruijun Tian (2018) Photoaffinity-engineered protein scaffold for systematically exploring native phosphotyrosine signaling complexes in tumor samples. Proc Natl Acad Sci U S A. Sep 18;115(38):E8863-E8872. [ PubMed ] Rui Wang, Pete Y. M. Leung, Feng Huang, Qingzhuang Tang, Tomonori Kaneko, Mei Huang, Zigang Li, Shawn S. C. Li, Yi Wang, and Jiang Xia (2018) Reverse Binding Mode of Phosphotyrosine Peptides with SH2 Protein. Biochemistry. Sep 4;57(35):5257-5269. [ PubMed ] An-dong Liu, Hui Xu, Ya-nan Gao, Dan-ni Luo, Zhao-feng Li, Courtney Voss, Shawn S. C. Li and Xuan Cao (2018) (Arg)9-SH2 superbinder: a novel promising anticancer therapy to melanoma by blocking phosphotyrosine signaling. J Exp Clin Cancer Res. Jul 5;37(1):138. [ PubMed ] Nileeka Balasuriya, Maya T. Kunkel, Xuguang Liu, Kyle K. Biggar, Shawn S.-C. Li, Alexandra C. Newton and Patrick O'Donoghue (2018) Genetic code expansion and live cell imaging reveal that Thr-308 phosphorylation is irreplaceable and sufficient for Akt1 activity. J Biol Chem. Jul 6;293(27):10744-10756. [ PubMed ] Sahil S. Singal, Karen Nygard, Manthan R. Dhruv, Kyle Biggar, Majida A. Shehab, Shawn S.-C. Li, Thomas Jansson, and Madhulika B. Gupta (2018) Co-Localization of Insulin-Like Growth Factor Binding Protein-1, Casein Kinase-2β, and Mechanistic Target of Rapamycin in Human Hepatocellular Carcinoma Cells as Demonstrated by Dual Immunofluorescence and in Situ Proximity Ligation Assay. Am J Pathol. Jan;188(1):111-124. [ PubMed ] Jinwei Zhu, Qingqing Zhou, Yuan Shang, Hao Li, Mengjuan Peng, Xiao Ke, Zhuangfeng Weng, Rongguang Zhang, Xuhui Huang, Shawn S.C. Li, Guoping Feng, Youming Lu, and Mingjie Zhang. (2017) Synaptic Targeting and Function of SAPAPs Mediated by Phosphorylation-Dependent Binding to PSD-95 MAGUKs. Cell Rep. Dec 26;21(13):3781-3793 [ PubMed ] Kyle K. Biggar, Zhentian Wang, and Shawn S.-C. Li (2017) SnapShot: Lysine Methylation beyond Histones. Mol Cell. 2017 Dec 7;68(5):1016-1016.e1 [ PubMed ] Majida Abu Shehab, Kyle Biggar, Sahil Sagar Singal, Karen Nygard, Shawn Shun-Cheng Li, Thomas Jansson, Madhulika B. Gupta (2017) Exposure of decidualized HIESC to low oxygen tension and leucine deprivation results in increased IGFBP-1 phosphorylation and reduced IGF-I bioactivity. Mol Cell Endocrinol. Sep 5;452:1-14. [ PubMed ] Palaniraja Thandapani, Anthony M. Couturier, Zhenbao Yu, Xing Li, Jean-François Couture, Shawn Li, Jean-Yves Masson and Stéphane Richard (2017) Lysine methylation of FEN1 by SET7 is essential for its cellular response to replicative stress. Oncotarget. May 22;8(39):64918-64931 [ PubMed ] Zhenzhen Deng, Mingming Dong, Yan Wang, Jing Dong, Shawn S.-C. Li, Hanfa Zou, and Mingliang Ye (2017) Biphasic Affinity Chromatographic Approach for Deep Tyrosine Phosphoproteome Analysis. Anal Chem. Feb 21;89(4):2405-2410 [ PubMed ]