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Pathology & Immunology

Houston, Texas

Pathology and Immunology
Pathology & Immunology
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Tse-Hua Tan, Ph.D. - Faculty

Tse-Hua Tan photoProfessor, Department of Pathology & Immunology and Program in Cell and Molecular Biology
Leukemia Society of America Scholar

Ph.D., Princeton University
Postdoctoral, Rockefeller University

E-mail: ttan@bcm.edu

Training Grant Postdoctoral Research Opportunity

Research Interests: Signal Transduction Mechanisms of Lymphocyte Activation and Apoptosis

Our research interests involve the molecular mechanisms of gene regulation and signal transduction during cell growth and apoptosis (programmed cell death). Specifically, we are studying the signaling pathways (protein kinases and phosphatases) leading to the activation of the c-Jun N-terminal kinase (JNK) and the c-Rel/NF-kB family of transcription factors. The Rel/NF-kB family of transcription factors are potent transactivators of many viral and cellular genes. They are pleiotropic mediators of various inflammatory and mitogenic responses. We are currently characterizing the kinases and phosphatases that regulate Rel/NF-kB function. JNK protein kinases and the Rel/NF-kB factors are involved in T-cell receptor and CD28 costimulation. CD28 is a pivotal T-cell costimulatory molecule that plays important roles in T-cell activation, HIV-1 pathogenesis, and the induction and maintenance of peripheral tolerance and autoimmunity. Understanding the T-cell receptor and CD28 costimulatory signaling pathways is one major focus of our research. These studies will ultimately lead to a better understanding of the molecular basis for cellular decisions leading to lymphocyte proliferation, differentiation, anergy or apoptosis.

JNK belongs to the mitogen-activated protein kinase (MAPK) superfamily. JNK plays a crucial role in inflammatory responses, stress responses, cell proliferation, apoptosis, and tumorigenesis. JNK kinase activity can be activated by various stimuli, including the proinflammatory cytokines (TNF-alpha and interleukin-1), lymphocyte costimulatory receptors (CD28 and CD40), DNA-damaging chemicals, radiation, and Fas signaling. Results from the JNK knockout mice indicate that JNK is involved in apoptosis induction and T helper cell differentiation. The JNK kinase cascade has been established as follows: Receptors --> adaptors (HIP-55, Nck, Gads, Grb2, Crk) --> MAP4K (HPK1, GCK, GLK, KHS, HGK/NIK) --> MAP3K (MEKK1, TAK1, MLK3) --> MAP2K (MKK4, MKK7) --> JNK --> transcription factors --> cell proliferation and apoptosis. We are presently characterizing various JNK-mediated signaling pathways during cell growth and apoptosis in lymphocytes and cancer cells using various biochemical, molecular, and genetic knockout approaches. HPK1 (hematopoietic progenitor kinase-1; MAP4K1), an upstream activator of JNK and NF-kB, is involved in T- and B-cell antigen receptor signaling. HPK1 interacts with several SH3-domain-containing adaptor proteins, including Nck, Grb2, Crk, Gads, and HIP-55. HIP-55 is a novel F-actin-binding adaptor protein, which is localized to the T cell-APC (antigen-presenting cell) contact site (immunological synapse). HIP-55 regulates T-cell activation and endocytosis by connecting the TCR signaling complex to actin cytoskeleton. We are using HPK1 and HIP-55 knockout mice to study the functions of HPK1 and HIP-55 in lymphocyte activation, immune responses, innate immunity and autoimmunity.

The serine/threonine protein phosphatase 4 (PP4) is highly related to PP2A, which is important in the control of cell proliferation, cell cycle, and tumorigenesis. PP4 associates with and regulates Rel/NF-kB and JNK kinase cascade in the TNF-alpha signaling pathway. PP4 also regulates microtubule nucleation at centrosomes. We are presently characterizing PP4-mediated TNF-alpha cell signaling, as well as its role in breast tumorigenesis, insulin receptor signaling and insulin resistance, centrosome function, and cell cycle regulation by various biochemical (proteomic) and genetic (siRNA, T-cell specific conditional knockout mice) approaches. JNK pathway-associated phosphatase (JKAP) is a novel dual-specificity MAP kinase phosphatase (MKP). Intriguingly, JKAP stimulates JNK kinase activity, and the JNK activation by TNF-alpha or TGF-beta is abolished in JKAP knockout cells. We will continue to characterize JKAP and additional novel dual-specificity MAP kinase phosphatases (MKPs) that regulate the JNK signaling pathways.

Our specific research interests are as follows:

  • Signal transduction in lymphocyte activation, apoptosis, immune responses, innate immunity, and autoimmunity
  • Signal transduction by NF-kB and stress-activated MAP kinases and phosphatases
  • Cancer cell signaling pathways and mechanisms of tumorigenesis
  • Generation and characterization of HPK1, HIP-55 and PP4 knockout mice

JNK Signaling Cascade Illustration


Selected Publications:
A more complete listing of Dr. Tan's publications visit PubMed.

  • Hu, M.C.-T., W. Qiu, X. Wang, C.F. Meyer, and T.-H. Tan. 1996. Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade. Genes & Development 10:2251-2264. [ABSTRACT]

  • Chen, Y.-R., X. Wang, D. Templeton, R.J. Davis, and T.-H. Tan. 1996. The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma radiation: duration of JNK activation may determine cell death and proliferation. Journal of Biological Chemistry 271:31929-31936. [PDF] [HTML]

  • Yao, Z., G. Zhou, X.S. Wang, A. Brown, K. Diener, H. Gan, and T.-H. Tan. 1999. A novel human STE20-related protein kinase, HGK, that specifically activates the c-Jun N-terminal kinase signaling pathway. Journal of Biological Chemistry 274:2118-2125. [ABSTRACT] [HTML] [PDF]

  • Ling, P., Z. Yao, C.F. Meyer, X.S. Wang, W. Oehl, S.M. Feller, and T.-H. Tan. 1999. Interaction of HPK1 with the adaptor proteins Crk and CrkL leads to synergistic activation of c-Jun N-terminal kinase (JNK). Molecular & Cellular Biology 19:1359-1368. [ABSTRACT] [HTML] [PDF]

  • Zhou, G., S.C. Lee, Z. Yao, and T.-H. Tan. 1999. Hematopoietic progenitor kinase 1 is a component of transforming growth factor beta-induced c-Jun N-terminal kinase signaling cascade. Journal of Biological Chemistry 274:13133-13138. [ABSTRACT] [HTML] [PDF]

  • Ensenat, D., Z. Yao, X.S. Wang, R. Kori, S.C. Lee, and T.-H. Tan. 1999. A novel SH3 domain-containing adaptor protein, HIP-55, that interacts with hematopoietic progenitor kinase 1 (HPK1). Journal of Biological Chemistry 274:33945-33950. [ABSTRACT] [HTML][PDF]

  • Ling, P., C.F. Meyer, L. P. Redmond, J.-W. Shui, B. Davis, R.R. Rich, M.C.-T. Hu, R.L. Wange, and T.-H. Tan. 2001. Involvement of hematopoietic progenitor kinase 1 in T-cell receptor signaling. Journal of Biological Chemistry 276: 18908-18914. [ABSTRACT] [HTML] [PDF]

  • Zhou, G., K.A. Mihindukulasuria, R.A. MacCorkle-Chosnek, A. Van Hooser, M. C.-T. Hu, B.R. Brinkley, and T.-H. Tan. 2002. Protein phosphatase 4 is involved in tumor necrosis factor-alpha-induced activation of c-Jun N-terminal kinase. Journal of Biological Chemistry 277:6391-6398. [ABSTRACT] [HTML] [PDF]

  • Han, J., R. Kori, J.-W. Shui, Y.-R. Chen, Z. Yao, and T.-H. Tan. 2003. The SH3 domain-containing adaptor HIP-55 mediates c-Jun N-terminal kinase activation in T cell receptor signaling. Journal of Biological Chemistry 278:52195-52202.
    [ABSTRACT] [HTML] [PDF]

  • Shui, J.-W., and T.-H. Tan. 2004. Germline transmission and efficient DNA recombination in mouse embryonic stem cells mediated by adenoviral-Cre transduction. Genesis 39:217-223. [ABSTRACT] [PDF]

  • MacCorkle, R.A., and T.-H. Tan. 2004. Inhibition of JNK2 disrupts anaphase and produces aneuploidy in mammalian cells. Journal of Biological Chemistry 279:40112-40121. [ABSTRACT] [HTML] [PDF]

  • Mihindukulasuriya, K.A., G. Zhou, J. Qin, and T.-H. Tan. 2004. Protein phosphatase 4 interacts with and down-regulates insulin receptor substrate 4 following tumor necrosis factor-alpha stimulation. Journal of Biological Chemistry 279:46588-46594. [ABSTRACT] [HTML] [PDF]

  • Zhou, G., J.S. Boomer, and T.-H. Tan. 2004. Protein phosphatase 4 is a positive regulator of hematopoietic progenitor kinase 1. Journal of Biological Chemistry 279:49551-49561. [ABSTRACT] [HTML] [PDF]


    For a complete list of Dr. Tan's publications, visit PubMed.


Contact Information:
    Tse-Hua Tan, Ph.D.
    Department of Pathology & Immunology
    Baylor College of Medicine
    (Room N903.01, Alkek Bldg.)
    One Baylor Plaza, BCM245
    Houston, Texas 77030
Phone: 713-798-4665
Fax: 713-798-3033
E-mail: ttan@bcm.edu

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