Yingming Zhao, Ph.D.

Research Summary

Laboratory of Proteomics and Protein Post-translational modifications

Overview

Laboratory of Proteomics and Protein Modifications

Post-translational modifications (PTMs) represent a major vehicle to diversify a cellular proteome, the inventory of all protein species in an organism. PTMs have critical roles in all the major cellular pathways and diseases. A protein can be potentially modified by more than 200 types of post-translational modifications, which are catalyzed by enzymes encoded by more than 5% of the genome in higher eukaryotes. A combination of a dozen PTM sites in a substrate protein could lead to more than a million possible protein structures with potentially different functions. Given the high abundance and diversities of PTMs, they are likely the most complex regulatory mechanisms in cells. Despite their critical roles in cells, little is known about their biology, except several most extensively studied PTMs. Functional characterizations of PTMs at the molecular level have been slow, largely due to a lack of suitable information infrastructure and technology infrastructure.

Our research aims to develop mass spectrometry-based proteomics technologies, and to use them to dissect PTM pathways. We are developing new mass spectrometry and bioinformatics tools for reliable, sensitive, and comprehensive analysis of proteins and PTMs. We are interested in dynamics analysis of diverse PTMs in order to understand their functions. We are using proteomics approach to characterize lysine acetylation, lysine propionylation, and lysine butyrylation pathways, the last two of which were recently discovered by us. We have begun applying a new bioinformatics tool, PTMap, also recently developed by us, to investigate PTM cross-talks. We also use powerful proteomics technologies in conjunction with biochemistry, molecular biology, and cell biology to decode PTM networks that have major implications for human health and are not amenable to conventional techniques. 

 

Recent Publications

2012

Xie, Z., Dai, J., Dai, L., Tan, M., Cheng, Z., Wu,Y., Boeke, J. D. , Zhao, Y., Lysine succinylation and lysine malonylation in histones. Mol Cell Proteomics, 2012, 11(5), 100-7. PMCID: PMC3418837

Chen, Y., Zhao, W., Yang, J.S., Cheng, Z., Luo, H., Lu, Z., Tan, M., Gu, W., and Zhao, Y., (2012). Quantitative acetylome analysis reveals the roles of SIRT1 in regulating diverse substrates and cellular pathways. Mol Cell Proteomics In press. PMID: 22826441

Li, N., Kon, N., JIang, L., Tan, M., Ludwig, T., Zhao, Y., Baer, R., W., G., 2012. Tumor suppression in the absence of p53-mediated cell cycle arrest, apoptosis, and senescence. Cell, 149 (6), 1269-1283. PMID: 22682249

Qiang, L., Wang, L., Kon, N., Lee, S., Zhao, Y., Gu, W., Farmer, S.R., Accili, D., 2012. Brown remodeling of white adipocytes by SirT1-dependent deacetylation of PPARγ. Cell, in press. PMCID: PMC3413172

Choi, M.C., Cohen, T.J., Barrientos, T., Wang, B., Simmons, B.J., Li, M., Yang, J.S., Cox, G.A., Zhao, Y., Yao, T.P., 2012. A direct HDAC4-MAP kinase crosstalk activates neurogenic muscle atrophy. Mol. Cell, 47, 1-11. PMCID: PMC3398192

Liu, J., Yan, J., Jiang, S., Wen, J., Chen, L., Zhao, Y., Lin, A.,Site-specific ubiquitination is required for relieving the transcription factor Miz1-mediated suppression on TNF-α-induced JNK activation and inflammation. Proc Natl Acad Sci U S A, 2012, 109(1): p. 191-196. PMCID: PMC3252938

Montellier, E., Rousseaux, S., Zhao, Y., Khochbin S.Histone crotonylation specifically marks the haploid male germ cell gene expression program. Bioessays, 2012, 34(3): p. 187-93. PMID: 22170506

 

2011

He, B.-C., Gao, J.-L., Zhang, B.-Q., Luo, Q., Shi, Q., Kim, S.H., Huang, E., Gao, Y., Yang, K., Wagner, E.R., Wang, L., Tang, N., Luo, J., Liu, X., Li, M., Shen, J., Luther, G., Hu, N., Zhou, Q., Luu, H.H., Haydon, R.C., Zhao, Y., He, T.C.,  Tetrandrine Inhibits Wnt/b-Catenin Signaling and Suppresses Tumor Growth of Human Colorectal Cancer. Molecular Pharmacology, 2011, 79(2), p. 211-9. PMCID: PMC3033706

Chu,C., Hou, H., Zhang, J., Phu, L., Loktev, A.V.,  Kirkpatrick, D.S.,  Jackson, P.J., Zhao, Y. and Zou, H., A novel acetylation of β-tubulin by San modulates microtubule polymerization via down-regulating tubulin incorporation, Mol Biol Cell,  2011, 22(4), p. 448-56. PMCID: PMC3038643

Tan, M., Luo, H., Lee, S., Jin, F., Yang, J.-S., Montellier, E., Buchou,T., Cheng, Z., Rousseaux, S., Rajagopal, N., Lu, Z., Ye, Z., Zhu, Q., Wysocka, J., Ye, Y., Khochbin, S., Ren, B., Zhao, Y., Identification of 67 histone marks and histone lysine crotonylation as a new type of Histone modification. Cell, 2011. 146: p.1016-1028. PMCID: PMC3176443

http://www.cell.com/abstract/S0092-8674%2811%2900891-9

Zhang, Z., Tan, M., Xie, Z., Dai, L., Chen, Y., and Zhao, Y., Identification of lysine   succinylation as a new post-translational modification. Nature Chem Biol, 2011. 7(1): p. 58-63.PMCID: PMC3065206

http://www.nature.com/nchembio/journal/v7/n1/pdf/nchembio.495.pdf

Peng, C., Lu, Z., Xie, Z., Cheng, Z., Chen, Y., Tan, M., Luo, H., Zhang, Y., He, W., Yang, K., Zwaans, B.M. M., Tishkoff, D., Ho, L., Lombard, D., He, T.-C., Dai, J., Verdin, E., Ye, Y., Zhao, Y., The first identification of lysine malonylation substrates and its regulatory enzyme. Mol Cell Proteomics, 2011. 10 (12): M111.012658. PMCID: PMC3237090

http://www.mcponline.org/content/10/12/M111.012658

Lu, J.-Y., Lin, Y.-Y., Sheu, J.-C., Wu, J.-T., Lee, F.-J., Chen, Y., Lin M.-I, Chiang, F.-T., Tai, T.-Y., Berger, S. L., Zhao, Y., Tsai K.-S., Zhu, H., Chuang, L.-M., and Boeke, J. D., Acetylation of Yeast AMPK Controls Intrinsic Aging Independently of Caloric Restriction. Cell, 2011. 146: p. 969-979. PMCID: PMC3176974

http://www.cell.com/abstract/S0092-8674%2811%2900888-9

Lu, Z., Cheng, Z., Zhao, Y., Volchenboum ,S.L., Bioinformatic analysis and post-translational modification crosstalk prediction of lysine acetylation. PLoS One, 2011. 6(12): p. e28228. PMCID: PMC3229533

Li, X., Wang, Q., Pan, N., Lee, S., Zhao, Y., Chait, B., Yue, Z. Phosphorylation-Dependent 14-3-3 Binding to LRRK2 Is Impaired by Common Mutations of Familial Parkinson’s Disease. PLoS One, 2011. 6(3): p. e17153. PMCID: PMC3046972 

Ghosh, S., Zhang, J., Zhao, Y., DePamphilis, M.L., and Vassilev, A.P., Assembly of the human origin recognition complex occurs through independent nuclear localization of its components. J Biol Chem, 2011. 286(27): p. 23831-23841. PMCID: PMC3129165

Samant, S.A., Courson, D.S., Sundaresan, N.R., Pillai, V.B., Tan, M., Zhao, Y., Shroff, S.G., Rock, R.S. and Gupta, M.P., HDAC3-dependent reversible lysine acetylation of cardiac myosin heavy chain isoforms modulates their enzymatic and motor activity. J Biol Chem, 2011. 286(7): p. 5567-77. PMCID: PMC3037670

Song, H., Li, C.-W., Labaff, A.M., Lim, S.-O., Li, L., Kan, S.-F., Chen, Y., Zhang, K., Lang, J., Xie, X., Wang, Y., Huo, L., Hsu, S.-C., Chen, X., Zhao, Y., Hung, M.-C., Acetylation of EGF receptor contributes to tumor cell resistance to Histone deacetylase inhibitors. Biochemical and Biophysical Research Communications, 2011. 404(1): p. 68–73. PMCID: PMC3049249

 

2010

Bajpai, R., Chen, D.A., Rada-Iglesias, A., Zhang, J., Xiong, Y., Helms, J., Chang, C.P., Zhao, Y., Swigut, T., and Wysocka, J., CHD7 cooperates with PBAF to control multipotent neural crest formation. Nature, 2010. 463: p. 958-62. PMCID: PMC2890258

http://www.nature.com/nature/journal/v463/n7283/full/nature08733.html

Kuo, H.P., Lee, D.F., Chen, C.T., Liu, M., Chou, C.K., Lee, H.J., Du, Y., Xie, X., Wei, Y., Xia, W., Zhang, W., Yang, J.-Y., Yen, C.-J., Huang, T.-H., Tan, M., Xing, G., Zhao, Y., Lin, C.-H., Tsai, S.-F., Fidler, I. J., and Hung, M.-C., ARD1 stabilization of TSC2 suppresses tumorigenesis through the mTOR signaling pathway. Sci Signal, 2010. 3(108): p. ra9. PMCID: PMC2874891

http://stke.sciencemag.org/cgi/content/abstract/3/108/ra9

Zhang, J., Chen, Y., Zhang, Z., Xing, G., Wysocka, J., and Zhao, Y., MS/MS/MS reveals false positive identification of histone serine methylation. J Proteome Res, 2010. 9: p. 585-94. PMCID: PMC2801770

http://pubs.acs.org/doi/abs/10.1021/pr900864s

Lee, S., Chen, Y., Luo, H., Wu, A.A., Wilde, M., Schumacker, P., and Zhao, Y., The first global screening of protein substrates bearing protein-bound 3,4-dihydroxyphenylalanine in E. coli and human mitochondria. J Proteome Research, 2010. 9: p. 5705-14. PMCID: PMC2974785

http://pubs.acs.org/doi/abs/10.1021/pr1005179

Zhang, K., Chen, Y., Zhang, Z., Tao, S., Zhu, H., and Zhao, Y., Unrestrictive identification of non-phosphorylation PTMs in yeast kinases by MS and PTMap. Proteomics, 2010. 10: p. 896-903. PMCID: PMC2892973

Li, L., Sun, L., Gao, F., Jiang, J., Yang, Y., Li, C., Gu, J., Wei, Z., Yang, A., Lu, R., Ma, Y., Tang, F., Kwon, S.W., Zhao, Y., Li, J., and Jin, Y., Stk40 links the pluripotency factor Oct4 to the Erk/MAPK pathway and controls extraembryonic endoderm differentiation. Proc Natl Acad Sci U S A, 2010. 107(4): p. 1402-1407. PMCID: PMC2824367

Zeng, S.X., Li, Y., Jin, Y., Zhang, Q., Keller, D.M., McQuaw, C.M., Barklis, E., Stone, S., Hoatlin, M., Zhao, Y., Lu, H., Structure-specific recognition protein 1 facilitates microtubule growth and bundling required for mitosis. Mol Cell Biol, 2010. 30(4): p. 935-947. PMCID: PMC2815565

Heise, C.J., Xu, B.E., Deaton, S.L., Cha, S.K., Cheng, C.J., Earnest, S., Sengupta, S., Juang, Y.C., Stippec, S., Xu, Y., Zhao, Y., Huang, C.L., Cobb. M.H., Serum and glucocorticoid-induced kinase (SGK) 1 and the epithelial sodium channel are regulated by multiple with no lysine (WNK) family members. J Biol Chem, 2010. 285(33): p. 25161-25167. PMCID: PMC2919078

 

2009

Chen, Y., Chen, W., Cobb, M.H. and Zhao, Y., PTMap--a sequence alignment software for unrestricted, accurate, and full-spectrum identification of post-translational modification sites. Proc Natl Acad Sci U S A, 2009. 106(3): p. 761-6. PMCID: PMC2630079

http://www.pnas.org/content/106/3/761.full

Cheng, Z., Tang, Y., Chen, Y., Kim, S., Liu, H., Li, S.S., Gu, W. and Zhao, Y., Molecular characterization of propionyllysines in non-histone proteins. Mol Cell Proteomics, 2009. 8(1): p. 45-52. PMCID: PMC2621001

http://www.mcponline.org/content/8/1/45.abstract

Zhang, J., Sprung, R., Pei, J., Tan, X., Kim, S., Zhu, H., Liu, C.F., Grishin, N.V. and Zhao, Y., Lysine acetylation is a highly abundant and evolutionarily conserved modification in Escherichia coli. Mol Cell Proteomics, 2009. 8(2): p. 215-25. PMCID: PMC2634580

http://www.mcponline.org/content/8/2/215.abstract

Lin, Y.Y., Lu, J.Y., Zhang, J., Walter, W., Dang, W., Wan, J., Tao, S.C., Qian, J., Zhao, Y., Boeke, J.D., Berger, S.L. and Zhu, H., Protein acetylation microarray reveals that NuA4 controls key metabolic target regulating gluconeogenesis. Cell, 2009. 136(6): p. 1073-84. PMCID: PMC2696288

http://www.cell.com/abstract/S0092-8674%2809%2900081-6

Peng, J.C., Valouev, A., Swigut, T., Zhang, J., Zhao, Y., Sidow, A. and Wysocka, J., Jarid2/Jumonji coordinates control of PRC2 enzymatic activity and target gene occupancy in pluripotent cells. Cell, 2009. 139(7): p. 1290-302. PMCID: PMC2911953

http://www.cell.com/abstract/S0092-8674%2809%2901506-2

Chan, D.W., Wang, Y., Wu, M., Wong, J., Qin, J. and Zhao, Y., Unbiased proteomic screen for binding proteins to modified lysines on histone H3. Proteomics, 2009. 9(9): p. 2343-54. PMCID: PMC2914554

Zhang, K., Chen, Y., Zhang, Z. and Zhao, Y., Identification and verification of lysine propionylation and butyrylation in yeast core histones using PTMap software. J Proteome Res, 2009. 8(2): p. 900-6. PMCID: PMC2921183

Chen, Y., Zhang, J., Xing, G. and Zhao, Y., Mascot-derived false positive peptide identifications revealed by manual analysis of tandem mass spectra. J Proteome Res, 2009. 8(6): p. 3141-7. PMCID: PMC2720604

Zhao, Y. and Jensen, O.N., Modification-specific proteomics: Strategies for characterization of post-translational modifications using enrichment techniques. Proteomics, 2009. 9(20): p. 4632-41. PMCID: PMC2892724

Basu, A., Rose, K.L., Zhang, J., Beavis, R.C., Ueberheide, B., Garcia, B.A., Chait, B., Zhao, Y., Hunt, D.F., Segal, E., Allis, C.D. and Hake, S.B., Proteome-wide prediction of acetylation substrates. Proc Natl Acad Sci U S A, 2009. 106(33): p. 13785-13790. PMCID: PMC2728972

Rosse, C., Formstecher, E., Boeckeler, K., Zhao, Y., Kremerskothen, J., White, M.D., Camonis, J.H. and Parker, P.J., An aPKC-exocyst complex controls paxillin phosphorylation and migration through localised JNK1 activation. PLoS Biol, 2009. 7(11): p. e1000235. PMCID: PMC2762617

Chon, H., Vassilev, A., DePamphilis, M.L., Zhao, Y., Zhang, J., Burgers, P.M., Crouch, R.J. and Cerritelli, S.M., Contributions of the two accessory subunits, RNASEH2B and RNASEH2C, to the activity and properties of the human RNase H2 complex. Nucleic Acids Res, 2009. 37(1): p. 96-110. PMCID: PMC2615623

 Chen, W., Chen, Y., Xu, B.E., Juang, Y.C., Stippec, S., Zhao, Y. and Cobb, M.H., Regulation of a third conserved phosphorylation site in SGK1. J Biol Chem, 2009. 284(6): p. 3453-60. PMCID: PMC2635031

 

2008

Tang, Y., Zhao, W., Chen, Y., Zhao, Y. and Gu, W., Acetylation is indispensable for p53 activation. Cell, 2008. 133(4): p. 612-26. PMCID: PMC2914560

http://www.cell.com/abstract/S0092-8674%2808%2900441-8

Xing, G., Zhang, J., Chen, Y. and Zhao, Y., Identification of four novel types of in vitro protein modifications. J Proteome Res, 2008. 7(10): p. 4603-8. PMCID: PMC2911956

http://pubs.acs.org/doi/abs/10.1021/pr800456q

Sprung, R., Chen, Y., Zhang, K., Cheng, D., Zhang, T., Peng, J. and Zhao, Y., Identification and validation of eukaryotic aspartate and glutamate methylation in proteins. J Proteome Res, 2008. 7(3): p. 1001-6. PMCID: PMC2921173

http://pubs.acs.org/doi/abs/10.1021/pr0705338

Lin, Y.Y., Qi, Y., Lu, J.Y., Pan, X., Yuan, D.S., Zhao, Y., Bader, J.S. and Boeke, J.D., A comprehensive synthetic genetic interaction network governing yeast histone acetylation and deacetylation. Genes Dev, 2008. 22(15): p. 2062-74. PMCID: PMC2492751

Jung, S.Y., Li, Y., Wang, Y., Chen, Y., Zhao, Y. and Qin, J., Complications in the assignment of 14 and 28 Da mass shift detected by mass spectrometry as in vivo methylation from endogenous proteins. Anal Chem, 2008. 80(5): p. 1721-9. PMCID: PMC2920732

 Deng, H., Yu, F., Chen, J., Zhao, Y., Xiang, J. and Lin, A., Phosphorylation of Bad at Thr-201 by JNK1 promotes glycolysis through activation of phosphofructokinase-1. J Biol Chem, 2008. 283(30): p. 20754-60. PMCID: PMC2475697

 

2007

Chen, Y., Sprung, R., Tang, Y., Ball, H., Sangras, B., Kim, S.C., Falck, J.R., Peng, J., Gu, W. and Zhao, Y., Lysine propionylation and butyrylation are novel post-translational modifications in histones. Mol Cell Proteomics, 2007. 6(5): p. 812-9. PMCID: PMC2911958

http://www.mcponline.org/content/6/5/812.short

Lee, J., Xu, Y., Chen, Y., Sprung, R., Kim, S.C., Xie, S. and Zhao, Y., Mitochondrial phosphoproteome revealed by an improved IMAC method and MS/MS/MS. Mol Cell Proteomics, 2007. 6(4): p. 669-76. PMCID: PMC2902983

http://www.mcponline.org/content/6/4/669.abstract

Xu, Y., Sprung, R., Kwon, S.W., Kim, S.C. and Zhao, Y., Isolation of phosphopeptides by pI-difference-based electrophoresis. J Proteome Res, 2007. 6(3): p. 1153-7. PMID: 17330948

http://pubs.acs.org/doi/abs/10.1021/pr060498p

Chang, B., Chen, Y., Zhao, Y. and Bruick, R.K., JMJD6 is a histone arginine demethylase. Science, 2007. 318(5849): p. 444-7. PMID: 17947579

http://www.sciencemag.org/content/318/5849/444.short

Kang, J., Chen, Y., Zhao, Y. and Yu, H., Autophosphorylation-dependent activation of human Mps1 is required for the spindle checkpoint. Proc Natl Acad Sci U S A, 2007. 104(51): p. 20232-7. PMCID: PMC2154414

Raman, M., Earnest, S., Zhang, K., Zhao, Y. and Cobb, M.H., TAO kinases mediate activation of p38 in response to DNA damage. Embo J, 2007. 26(8): p. 2005-14. PMCID: PMC1852793

Bartz, R., Zehmer, J.K., Zhu, M., Chen, Y., Serrero, G., Zhao, Y. and Liu, P., Dynamic activity of lipid droplets: protein phosphorylation and GTP-mediated protein translocation. J Proteome Res, 2007. 6(8): p. 3256-65. PMID: 17608402

Ganesan, A.K., Kho, Y., Kim, S.C., Chen, Y., Zhao, Y. and White, M.A., Broad spectrum identification of SUMO substrates in melanoma cells. Proteomics, 2007. 7(13): p. 2216-2221. PMID: 17549794

Li, H., Zhang, Z., Wang, B., Zhang, J., Zhao, Y. and Jin, Y., The Wwp2-mediated Ubiquitination of the RNA Polymerase II Large Subunit in Mouse Embryonic Pluripotent Stem Cells. Mol Cell Biol, 2007. 27(15): p. 5296-5305. PMCID: PMC1952083

 

2006

Kim, S.C., Sprung, R., Chen, Y., Xu, Y., Ball, H., Pei, J., Cheng, T., Kho, Y., Xiao, H., Xiao, L., Grishin, N.V., White, M., Yang, X.J. and Zhao, Y., Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol Cell, 2006. 23(4): p. 607-18. PMID: 16916647

http://www.cell.com/molecular-cell/abstract/S1097-2765%2806%2900454-0

Nandi, A., Sprung, R., Barma, D.K., Zhao, Y., Kim, S.C., Falck, J.R. and Zhao, Y., Global identification of O-GlcNAc-modified proteins. Anal Chem, 2006. 78(2): p. 452-8. PMID: 16408927

http://pubs.acs.org/doi/abs/10.1021/ac051207j

Chien, Y., Kim, S., Bumeister, R., Loo, Y.M., Kwon, S.W., Johnson, C.L., Balakireva, M.G., Romeo, Y., Kopelovich, L., Gale, M., Jr., Yeaman, C., Camonis, J.H., Zhao, Y. and White, M.A., RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival. Cell, 2006. 127(1): p. 157-70. PMID: 17018283

http://www.cell.com/abstract/S0092-8674%2806%2901155-X

Qiu, Y., Zhao, Y., Becker, M., John, S., Parekh, B.S., Huang, S., Martinez, E.D., Chen, Y., Lu, H., Adkins, N.L., Georgel, P.T., Schiltz, P.L. and Hager, G.L., HDAC1 Acetylation is Linked to Progressive Modulation of Steroid Receptor Induced Gene Transcription. Mol Cell, 2006. 22(5): p. 669-679. PMID: 16762839

http://www.cell.com/molecular-cell/abstract/S1097-2765%2806%2900267-X

Kim, S.C., Chen, Y., Mirza, S., Xu, Y., Lee, J., Liu, P. and Zhao, Y., A clean, more efficient method for in-solution digestion of protein mixtures without detergent or urea. J Proteome Res, 2006. 5(12): p. 3446-52. PMID: 17137347

Anselmo, A.N., Earnest, S., Chen, W., Juang, Y.C., Kim, S.C., Zhao, Y. and Cobb, M.H., WNK1 and OSR1 regulate the Na+, K+, 2Cl- cotransporter in HeLa cells. Proc Natl Acad Sci U S A, 2006. 103(29): p. 10883-8. PMCID: PMC1544143

McMahon, K.A., Zhu, M., Kwon, S.W., Liu, P., Zhao, Y. and Anderson, R.G., Detergent-free caveolae proteome suggests an interaction with ER and mitochondria. Proteomics, 2006. 6(1): p. 143-52. PMID: 16294311

Radichev, I., Kwon, S.W., Zhao, Y., DePamphilis, M.L. and Vassilev, A., Genetic analysis of human Orc2 reveals specific domains that are required in vivo for assembly and nuclear localization of the origin recognition complex. J Biol Chem, 2006. 281(32): p. 23264-73. PMID: 16762929

Binns, D., Januszewski, T., Chen, Y., Hill, J., Markin, V.S., Zhao, Y., Gilpin, C., Chapman, K.D., Anderson, R.G. and Goodman, J.M., An intimate collaboration between peroxisomes and lipid bodies. J Cell Biol, 2006. 173(5): p. 719-31. PMCID: PMC2063889