Zhong-Yin Zhang, Ph.D.
Robert A. Harris Professor and Chairman
Department of Biochemistry and Molecular Biology
Indiana University School of Medicine
John D. Van Nuys Medical Science Building
635 Barnhill Drive, Room 4053A
Indianapolis, Indiana 46202-5126
B.S., 1984, Nankai University, Tianjin, China
Ph.D., 1990, Purdue University, West Lafayette, IN
Postdoctoral, 1991, The Upjohn Company, Kalamazoo, MI
Postdoctoral, 1994, University of Michigan, Ann Arbor, MI
Area of Study
Chemical biology, signaling mediated by tyrosine dephosphorylation, targeting protein tyrosine phosphatases for the treatment of cancer, diabetes/obesity, autoimmune disorders, and infectious diseases. More details...
Selected Recent Publications
Liu, S., Sun, J.-P., Zhou, B. and Zhang, Z.-Y. "Structural basis of docking interaction between ERK2 and MAP kinase phosphatase 3", Proc. Natl. Acad. Sci. USA 103, 5326-5331 (2006).
Kumar, S., Zhou, B., Liang, F., Yang, H., Wang, W.-Q., and Zhang, Z.-Y. "Global Analysis of Protein Tyrosine Phosphatase Activity with Ultra-Sensitive Fluorescent Probes", J. Proteome Res. 5, 1898-1905 (2006).
Zhou, B., Zhang, J., Liu, S., Reddy, S., Wang, F., and Zhang, Z.-Y. "Mapping ERK2-MKP3 Binding Interfaces by Hydrogen/Deuterium Exchange Mass Spectrometry", J. Biol. Chem. 281, 38834-38844 (2006).
Boutselis, I. G., Yu, X., Zhang, Z.-Y., and Borch, R. "Synthesis and cell-based activity of a potent and selective PTP1B inhibitor prodrug", J. Med. Chem. 50, 856-864 (2007).
Liang, F., Liang, J., Wang, W.-Q., Sun, J.-P., Udho, E., and Zhang, Z.-Y. "PRL3 Promotes Cell Invasion and Proliferation by Down-regulation of Csk Leading to Src Activation", J. Biol. Chem. 282, 5413-5419 (2007).
Sun, J.-P., Luo, Y., Yu, X., Wang, W.-Q., Zhou, B., Liang, F., and Zhang, Z.-Y. "Phosphatase activity, trimerization, and the C-terminal polybasic region are all required for the PRL1-mediated cell growth and migration", J. Biol. Chem. 282, 29043-29051 (2007).
Yu, X., Sun, J.-P., He, Y., Guo, X.-L., Liu, S., Zhou, B., Hudmon, A. and Zhang, Z.-Y. "Structure, inhibitor, and regulatory mechanism of Lyp, a lymphoid-specific tyrosine phosphatase implicated in autoimmune diseases", Proc. Natl. Acad. Sci. USA 104, 19767-19772 (2007)
Cortesio, C. L., Chan, K. T., Perrin, B. J., Burton, N. O., Zhang, S., Zhang, Z.-Y., and Huttenlocher, A. "Calpain 2 and PTP1B function in a novel pathway with Src to regulate invadopodia dynamics and breast cancer invasion" J. Cell Biology 180, 957-971 (2008).
Liang, F., Luo, Y., Dong, Y., Walls, C. D., Liang, J., Jiang, H.-Y., Sanford, J. R., Wek, R. C. and Zhang, Z.-Y. "Translational Control of Csk Expression by the PRL3 Phosphatase", J. Biol. Chem. 283, 10339-10346 (2008).
Boivin, B., Zhang, S., Arbiser, J. L., Zhang, Z.-Y., and Tonks, N. K. "A modified cysteinyl-labeling assay reveals reversible oxidation of protein tyrosine phosphatases in angiomyolipoma cells", Proc. Natl. Acad. Sci. USA 105, 9959-9964 (2008).
Liu, S., Zhou, B., Yang, H., He, Y., Jiang, Z.-X., Kumar, S., Wu, L. and Zhang, Z.-Y. "Aryl vinyl sulfones and sulfonates as active site-directed and mechanism-based probes for protein tyrosine phosphatases", J. Am. Chem. Soc. 130, 8251-8260 (2008).
Abdo, M., Liu, S., Zhou, B., Walls, C. D., Wu, L., Knapp, S. and Zhang, Z.-Y. "Seleninate in Place of Phosphate: Irreversible Inhibition of Protein Tyrosine Phosphatases", J. Am. Chem. Soc. 130, 13196-13197 (2008).
Liu, S., Zeng, L.-F., Wu, L., Yu, X., Xue, T., Gunawan, A., Long, Y.-Q., and Zhang, Z.-Y. "Targeting Inactive Enzyme Conformation: Aryl Diketoacid Derivatives as a New Class of PTP1B Inhibitors", J. Am. Chem. Soc. 130, 17075-17084 (2008).
Luo, Y., Liang, F., and Zhang, Z.-Y. "PRL1 promotes cell migration and invasion by increasing MMP2 and MMP9 expression through Src and ERK1/2 pathways", Biochemistry 48, 1838-1846 (2009).
Arias-Romero, L. E., Saha, S., Villamar-Cruz, O., Yip, S-C., Ethier, S. P., Zhang, Z.-Y., and Chernoff, J. "Activation of Src by protein tyrosine phosphatase 1B is required for ErbB2 transformation of human breast epithelial cells", Cancer Research 69, 4582-4588 (2009).
Zhang, S., Chen, L., Luo, Y., Gunawan, A., Lawrence, D. S. and Zhang, Z.-Y. "Acquisition of a Potent and Selective TC-PTP Inhibitor from a Stepwise Fluorophore-tagged Combinatorial Synthesis and Screening Strategy," J. Am. Chem. Soc. 131, 13072-13079 (2009).
Zhou, B., He, Y., Zhang, X., Xu, J., Luo, Y., Wang, Y., Franzblau, S. G., Yang, Z., Chan, R. J., Liu, Y., Zheng, J. and Zhang, Z.-Y. "Targeting Mycobacterium Protein Tyrosine Phosphatase B for Anti-Tuberculosis Agents" Proc. Natl. Acad. Sci. USA 107, 4573-4578 (2010).
Zhang, X., He, Y., Liu, S., Yu, Z., Jiang, Z.-X., Yang, Z., Dong, Y., Nabinger, S. C., Wu, L., Gunawan, A. M., Wang, L., Chan, R. J., and Zhang, Z.-Y. "A salicylic acid-based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)", J. Med. Chem. 53, 2482-2493 (2010).
Chen, L., Zhou, B., Zhang, S., Wu, L., Wang, Y., Franzblau, S. G. and Zhang, Z.-Y. "Identification and characterization of small molecule inhibitors of mPTPB, an essential virulent phosphatase from Mycobacterium tuberculosis", ACS Med. Chem. Lett. 1, 355-359 (2010).
Liu, S., Yu, Z., Yu, X., Huang, S.-X., Luo, Y., Wu, L., Shen, W., Yang, Z., Wang, L., Gunawan, A. M., Chan, R. J., Shen, B., and Zhang, Z.-Y. "SHP2 is a Target of the Immunosuppressant Tautomycetin" Chemistry and Biology, 18, 101-110 (2011).
Yu, X., Chen, M., Zhang, S., Yu, Z.-H, Sun, J.-P., Wang,L., Liu, S., Imasaki, T., Takagi, Y., and Zhang, Z.-Y. "Substrate specificity of lymphoid-specific tyrosine phosphatase (Lyp) and identification of Src kinase-associated protein of 55 kDa homolog (SKAP-HOM) as a Lyp substrate" J. Biol. Chem. 286, 30526-30534 (2011).
Bai, Y., Luo, Y., Liu, S., Zhang, L., Shen, K., Dong, Y., Walls, C. D., Quilliam, L. A., Wells, C. D., Cao, Y., and Zhang, Z.-Y. "PRL-1 protein promotes ERK1/2 and RhoA activation through a non-canonical interaction with the Src homology 3 domain of p115 Rho GTPase-activating protein", J. Biol. Chem. 286, 42316-42324 (2011).
He, Y., Zeng, L.-F., Yu, Z.-H., He, R., Liu, S. and Zhang, Z.-Y. "Bicyclic benzofuran and indole-based salicylic acids as protein tyrosine phosphatase inhibitors", Bioorg. Med. Chem. 20, 1940-1946 (2012). PMC3297712
Dong, Y., Zhang, L., Zhang, S., Bai, Y., Chen, H., Sun, X., Yong, W., Li, W., Colvin, S. C., Rhodes, S. J., Shou, W., and Zhang, Z.-Y. "Phosphatase of regenerating liver 2 (PRL2) is essential for placenta development by downregulating PTEN (phosphatase and tensin homologue deleted on chromosome 10) and activating Akt protein", J. Biol. Chem 287, 32172-32179 (2012).
Mali, R. S., Ma, P., Zeng, L.-F., Martin, H., Ramdas, B., He, Y., Sims, E., Nabinger, S., Ghosh, J., Sharma, N., Munugalavadla, V., Chatterjee, A., Li, S., Sandusky, G., Craig, A. W., Bunting, K. D., Feng, G.-S., Chan, R. J., Zhang, Z.-Y. and Kapur, R. "Role of SHP2 phosphatase in KIT induced transformation: identification of SHP2 as a druggable target in diseases involving oncogenic KIT" Blood 120, 2669-2678 (2012).
Zhang, S., Liu, S., Tao, R., Wei, D., Chen, L., Shen, W., Yu, Z.-H., Wang, L., Jones, D. R., Dong, X. C. and Zhang, Z.-Y. "A highly selective and potent PTP-MEG2 inhibitor with therapeutic potential for type 2 diabetes" J. Am. Chem. Soc. 134, 18116 18124 (2012).
Meng, F.-G. and Zhang, Z.-Y. "Redox regulation of protein tyrosine phosphatase activity by hydroxyl radical", Biochimica et Biophysica Acta 1834, 464-469 (2013).
He, R., Zeng, L.-F., He, Y., Zhang, S. and Zhang, Z.-Y. "Small molecule tools for functional interrogation of protein tyrosine phosphatases" FEBS J. 280, 731-750 (2013).
He, R., Zeng, L.-F., He, Y., Wu, L., Gunawan, A. M., and Zhang, Z.-Y. "Organocatalytic Multicomponent Reaction for the Acquisition of a Potent and Selective Inhibitor of mPTPB, a Virulence Factor of Tuberculosis", Chem. Commun. 49, 2064-2066 (2013).
He, Y., Xu, J., Yu, Z.-H., Gunawan A. M., Wu, L., Wang, L., and Zhang, Z.-Y. "Discovery and Evaluation of Novel Inhibitors of Mycobacterium Protein Tyrosine Phosphatase B from the 6-Hydroxy-Benzofuran-5-Carboxylic Acid Scaffold", J. Med. Chem. 56, 832-842 (2013).
Yu, Z.-H., Xu, J., Walls, C., Chen, L., Zhang, S., Zhang, R., Wu, L., Wang, L., Liu, S., and Zhang, Z.-Y. "Structural and mechanistic insights into LEOPARD syndrome associated SHP2 mutations" J. Biol. Chem. 288, 10472-10482 (2013).
Zeng, L.-F., Xu, J., He, Y., He, R., Wu, L., Gunawan, A. M., and Zhang, Z.-Y. "A facile hydroxyindole carboxylic acid-based focused library approach for potent and selective inhibitors of Mycobacterium protein tyrosine phosphatase B", ChemMedChem 8, 904-908 (2013).
He, Y., Liu, S., Menon, A., Stanford, S., Oppong, E., Gunawan, A. M., Wu, L., Wu, D. J., Barrios, A. M., Bottini, N., Cato, A. C., and Zhang, Z.-Y. "A potent and selective small molecular inhibitor for the lymphoid-specific tyrosine phosphatase (LYP), a target associated with autoimmune diseases", J. Med. Chem. 56, 4990-5008 (2013).
Dumaual, C. M., Steere, B. A., Walls, C. D., Wang, M., Zhang, Z.-Y., and Randall, S. K. "Integrated analysis of global mRNA and protein expression data in HEK293 cells overexpressing PRL-1", PLoS ONE 8(9):e72977. doi:10.1371/journal.pone.0072977 (2013).
Xu, J., Zeng, L.-F., Shen, W., Turchi, J. J., and Zhang, Z.-Y. "Targeting SHP2 for EGFR inhibitor resistant non small cell lung carcinoma", Biochem. Biophys. Res. Commun. 439, 586-590 (2013).
Walls, C., Iliuk, A., Bai, Y., Wang, M., Tao, A. and Zhang, Z.-Y. "Phosphatase of Regenerating Liver 3 (PRL3) Provokes a Tyrosine Phosphoproteome to Drive Pro-Metastatic Signal Transduction", Molecular and Cellular Proteomics 12, 3759-3777 (2013).
Dong, Y., Zhang, L., Bai, Y., Zhou, H.-M., Campbell, A. M., Chen, H., Yong, W., Zhang, W., Zeng, Q., Shou, W., and Zhang Z.-Y. “Phosphatase of regenerating liver 2 (PRL2) deficiency impairs Kit signaling and spermatogenesis”, J. Biol. Chem. 289, 3799-3810 (2014).
Zeng, L.-F., Zhang, R.-Y., Bai, Y., Wu, L., Gunawan, A. M., and Zhang, Z.-Y. "Hydroxyindole Carboxylic Acid Based Inhibitors for Receptor-Type Protein Tyrosine Protein Phosphatase Beta", Antioxidants & Redox Signaling 20, 2130-2140 (2014).
Kobayashi, M., Bai, Y., Dong, Y., Yu, H., Chen, S., Gao, R., Zhang, L. Yoder, M. C., Kapur, R., Zhang Z.-Y. and Liu, Y. “PRL2/PTP4A2 phosphatase is important for hematopoietic stem cell self-renewal”, Stem Cells 32, 1956-1967 (2014).
Campbell, A. M. and Zhang, Z.-Y. “Phosphatase of Regenerating Liver, a Novel Target for Cancer Therapy”, Expert Opinion on Therapeutic Targets 18, 555-569 (2014).
Yu, Z.-H., Zhang, R.-Y., Walls, C., Chen, L., Zhang, S., Wu, L., Liu, S., and Zhang, Z.-Y. “Molecular Basis for Gain-of-Function LEOPARD Syndrome Associated SHP2 Mutations”, Biochemistry 53, 4136-4151 (2014).
Zeng, L.-F., Zhang, R.-Y., Yu, Z.-H., Liu, S., Wu, L., Gunawan, A. M., Lane, B. S., Mali, R. S., Li, X., Chan, R. J., Kapur, R., Wells, C. D., and Zhang, Z.-Y. “Therapeutic potential of targeting oncogenic SHP2 phosphatase”, J. Med. Chem. 57, 6594-6609 (2014).
He, R., Bai, Y., Yu, Z.-H., Wu, L., Gunawan, A. M., and Zhang, Z.-Y. "Diversity-Oriented Synthesis for Novel, Selective and Drug-like Inhibitors for a Phosphatase from Mycobacterium Tuberculosis", Med. Chem. Commun. 5, 1496-1499 (2014).
Dodd, G., Descherf, S., Loh, K., Simmonds, S., Wiede, F., Balland, E., Merry, T. L., Munzberg, H., Zhang, Z.-Y., Kahn, B. B., Neel, B. G., Bence, K. K., Andrews, Z. B., Cowley, M. A., and Tiganis, T. "Leptin and insulin act on POMC neurons to promote browning of white fat", Cell 160, 88-104 (2015).
He, Y., Guo, X., Yu, Z.-H., Wu, L., Gunawan, A. M., Zhang, Y., Dixon, J. E. and Zhang, Z.-Y. "A potent and selective inhibitor for the UBLCP1 proteasome phosphatase", Bioorganic and Medicinal Chemistry 23, 2798-2809 (2015).
He, R., Yu, Z.-H., Zhang, R.-Y., Wu, L., Gunawan, A., Lane, B. S., Shim, J. S., Zeng, L.-F., He, Y., Chen, L., Wells, C. D., Liu, J. O., and Zhang, Z.-Y. "Exploring the existing drug space for novel pTyr mimetic and SHP2 inhibitors", ACS Medicinal Chemistry Letter 6, in press (2015).
The initial and crucial event for many signaling pathways inside the cell is protein tyrosine phosphorylation/dephosphorylation, which is regulated by two opposing activities catalyzed by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Major insights into protein tyrosine phosphorylation mediated cellular signaling have been derived from studies of PTKs. However, the importance of PTPs has not been fully appreciated until recently. Like PTKs, defective or inappropriate regulation of PTP activity results in aberrant tyrosine phosphorylation, which contributes to the development of many human diseases including cancers, diabetes, inflammation and neurodegenerative diseases. Thus, further understanding of the fundamental role of protein tyrosine phosphorylation in complex and critical signal transduction pathways requires detailed studies of both PTKs and PTPs.
We utilize biochemical, cellular, chemical, structural, and proteomic approaches to probe the roles of PTPs in cellular signaling. Specifically, we carry out detailed mechanistic and kinetic study of PTP catalysis and substrate recognition using physiological substrates (i.e., phosphoproteins). Understanding the molecular basis for tyrosine dephosphorylation by PTPs will open doors to new experimental approaches that will elucidate mechanisms by which these enzymes control cell functions. We employ high-affinity PTP substrate-trapping mutants in combination with mass spectrometry for rapid isolation, identification, and characterization of physiological PTP substrates. Identification and characterization of cellular PTP substrates will help elucidate the function of individual PTPs as well as assignment of PTPs to specific signaling pathways. We design activity-based probes to analyze globally PTP activity both in normal physiology and in pathological conditions. The ability to profile the entire PTP family on the basis of changes in their activity should greatly accelerate both the assignment of PTP function and the identification of potential therapeutic targets. We also develop potent and selective PTP inhibitors using structure-guided, combinatory chemistry and high-throughput screening technologies. Highly potent and selective PTP inhibitors not only serve as powerful tools to delineate the physiological roles of these enzymes in vivo, but also as leads for therapeutic development. Our utmost goal is to use the chemical tools developed in the laboratory together with the classical genetic (e.g. gene knockout and siRNA), cellular and biochemical techniques to define the roles of PTPs in normal physiology and in diseases.