 |
Taolin Yi, Ph.D.
|
Area of general research interest:
Protein tyrosine phosphatases as signaling regulators and therapeutic targets.
Current program:
- Inhibition of protein tyrosine phosphatases by small chemical molecules in cancer treatment.
- The pathogenic role and action mechanism of protein tyrosine phosphatases in malignant diseases.
- Development of refined inhibitors of protein tyrosine phosphatases as novel therapeutics.
Investigators:
- Mingli Cao, Senior Research Technologist
- Keke Fan, Ph.D., Research Fellow
- Suman Kundu, M.S., M.Phil., Research Technologist
Collaborators:
- Ernest Borden, M.D., Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, OH
- Keith English, M.D., University of Tennessee, LeBonheur Children's Medical Cente, Memphis, TN
- James Finke, Ph.D., Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH
- Lenny Platanias, M.D., Northwestern University, Chicago, IL
- Lenny Shultz, Ph.D., Jackson Laboratory, ME
Brief Description:
Protein tyrosine phosphatases are key regulators of intracellular signaling and potential novel targets for therapeutic intervention in human diseases, including malignancies.
Several protein tyrosine phosphatases have oncogenic activity as a result of mutations causing overexpression or activation. These oncogenic phosphatases are attractive targets for developing small chemical inhibitors as novel anticancer therapeutics. Tumor suppressor phosphatases have also been identified. Moreover, some protein tyrosine phosphatases are key negative regulators of anticancer cytokines and immune cells. These negative regulatory phosphatases might also be targeted to improve the efficacy of immune therapy for malignant diseases. So far, few clinically usable inhibitors of protein tyrosine phosphatases have been reported.
We recently identified several small chemical inhibitors for selective protein tyrosine phosphatases. These compounds showed anticancer potential in animal models in connection with phosphatase inhibition. Based on their preclinical activities and tolerance in vivo, these inhibitors are moving into early phases of clinical trials as novel anticancer therapeutics.
Our ongoing studies will (1) use these lead compounds to develop refined inhibitors as potentially more efficacious anticancer agents; (2) elucidate the functional mechanisms of the compounds in phosphatase inhibition and in anticancer action; and (3) identify novel target phosphatases and their signaling mechanisms in human malignancies.
Key References:
Thomassen, M.J., Yi, T., Raychaudhuri, B., Malur, A., and Kavuru, M.S. (2000). Pulmonary alveolar proteinosis Is a disease of decreased availability of GM-CSF rather than an intrinsic cellular defect. Clin. Immunol. 95, 85-92.
Ward, A.C., Oomen, S.P.M.A., Smith, L., Gits, J., van Leeuwen, D., Soede-Bobok, A.A., Erpelinck-Verschueren, C.A.J., Yi, T., and Touw, I.P. (2000). The SH2 domain-containing protein tyrosine phosphatase SHP-1 is induced by granulocyte colony-stimulating factor (G-CSF) and modulates signaling from the G-CSF receptor. Leukemia 14, 1284-1291.
Wu, D.W., Stark, K.C., Dunnington, D., Dillon, S.B., Yi, T., Jones, C., and Pelus, L.M. (2000). SH2-containing protein tyrosine phosphatase-1 (SHP-1) association with Jak2 in UT-7/Epo cells. Blood Cells Mol. Dis. 26, 15-24.
Dong, F., Qiu, Y., Yi, T., Touw, I.P., and Larner, A.C. (2001). The carboxyl terminus of the granulocyte colony-stimulating factor receptor, truncated in patients with severe congenital neutropenia/acute myeloid leukemia, is required for SH2- containing phosphatase-1 suppression of Stat activation. J. Immunol. 167, 6447-6452.
Pathak, M.K., and Yi, T. (2001). Sodium stibogluconate is a potent inhibitor of protein tyrosine phosphatases and augments cytokine responses in hemopoietic cell lines. J. Immunol. 167, 3391-3397.
Vestal, D.J., Yi, T., and Borden, E.C. (2001). Pharmacology of interferons: induced proteins, cell activation, and antitumor activity. In Cancer chemotherapy and biotherapy : principles and practice, Chabner, B. A., and Longo, D. L. eds., (Philadelphia: Lippincott Williams & Wilkins) pp. 752-778.
Hu, X., Bu, L.Y., Ma, Y., Wang, Y.J., Jing, B.Q., and Yi, T. (2002). Difference in DNA sequences in SSU rDNAvariable regions among pathogens isolated from different epidemic foci of visceral leishmaniasis in China. Chin. Med. J. (Engl. ) 115, 1457-1459.
Joliat, M.J., Lang, P.A., Lyons, B.L., Burzenski, L., Lynes, M.A., Yi, T., Sundberg, J.P., and Shultz, L.D. (2002). Absence of CD5 dramatically reduces progression of pulmonary inflammatory lesions in SHP-1 protein-tyrosine phosphatase- deficient `viable motheaten' mice. J. Autoimmun. 18, 105-117.
Kant, A.M., De, P., Peng, X., Yi, T., Rawlings, D.J., Kim, J.S., and Durden, D.L. (2002). SHP-1 regulates Fcgamma receptor-mediated phagocytosis and the activation of RAC. Blood 100, 1852-1859.
Nandan, D., Yi, T., Lopez, M., Lai, C., and Reiner, N.E. (2002). Leishmania EF-1alpha activates the Src homology 2 domain containing tyrosine phosphatase SHP-1 leading to macrophage deactivation. J. Biol. Chem. 277, 50190-50197.
Pathak, M.K., Dhawan, D., Lindner, D.J., Borden, E.C., Farver, C., and Yi, T. (2002). Pentamidine is an inhibitor of PRL phosphatases with anticancer activity. Mol. Cancer Ther. 1, 1255-1264.
Pathak, M.K., Hu, X., and Yi, T. (2002). Effects of sodium stibogluconate on differentiation and proliferation of human myeloid leukemia cell lines in vitro. Leukemia 16, 2285-2291.
Yang, W., Tabrizi, M., and Yi, T. (2002). A bipartite NLS at the SHP-1 C-terminus mediates cytokine- induced SHP-1 nuclear localization in cell growth control. Blood Cells Mol. Dis. 28, 63-74.
Yi, T., Pathak, M.K., Lindner, D.J., Ketterer, M.E., Farver, C., and Borden, E.C. (2002). Anticancer activity of sodium stibogluconate in synergy with IFNs. J. Immunol. 169, 5978-5985.
Chen, Y., Wen, R., Yang, S., Schuman, J., Zhang, E.E., Yi, T., Feng, G.S., and Wang, D. (2003). Identification of Shp-2 as a Stat5A phosphatase. J. Biol. Chem. 278, 16520-16527.
Leaman, D.W., Chawla-Sarkar, M., Jacobs, B., Vyas, K., Sun, Y., Ozdemir, A., Yi, T., Williams, B.R., and Borden, E.C. (2003). Novel growth and death related interferon-stimulated genes (ISGs) in melanoma: greater potency of IFN-beta compared with IFN-alpha2. J. Interferon Cytokine Res. 23, 745-756.
Nandan, D., Cherkasov, A., Sabouti, R., Yi, T. and Reiner, N. E. (2003). Molecular cloning, biochemical and structural analysis of elongation factor-1a from leishmania donovani: comparison with mammalian homologue. Biochem. Biophy. Res. Com. 302, 646-652.
Sakamoto S, Qin J, Navarro A, Gamero A, Potla R, Yi T, David M, Baker DP, Feldman G and Larner AC. (2004). Cells previously desensitized to type I IFNs display different mechanisms of activation of Stat-dependent gene expression than naïve cells. J. Biol. Chem. 279, 3324-3253.
Fan, K., Zhou, M., Pathak, M.K., Lindner, D.J., Altuntas, C.Z., Tuohy, V.K., Borden, E.C., and Yi, T. (2005). Sodium stibogluconate interacts with IL-2 in anti-Renca tumor action via a T cell-dependent mechanism in connection with induction of tumor-infiltrating macrophages. J. Immunol. 175, 7003-7008.
Li J, et al. Efficacy of SSG and SSG/IFNa2 against human prostate cancer xenograft tumors in mice: a role for direct growth inhibition in SSG anti-tumor action. Cancer Chemother Pharmacol 2007;60:341-9.