Craig M Walsh
Molecular Biology & Biochemistry, School of Biological Sciences
Phone: (949) 824-8487
Email: cwalsh@uci.edu
http://www.faculty.uci.edu/profile.cfm?faculty_id=4617
http://www.faculty.uci.edu/scripts/UCIFacultyProfiles/detailMBB.cfm?ID=4617
mbb.bio.uci.edu
Center for Immunology profile
Craig Walsh
Dr. Walsh’s research focuses on the role apoptotic signal transduction plays in the development, activation and homeostasis of the immune system. Current interests include the study of death-receptors and the regulation of T cell activation. In order to study the role of death-receptor induced apoptosis in T cells, they have generated mice that express inhibitors of certain apoptotic pathways. One line of mice expresses a dominant-negative form of an adapter molecule known as FADD. This adapter protein is involved in activating caspases, cysteine proteases that initiate and execute the death program during apoptosis. Although certain forms of apoptosis are blocked, these and other lines of transgenic mice have provided evidence that multiple apoptotic pathways exist in T cells that are activated during different stages of differentiation. Interestingly, they have found that FADD mutant T cells have defective proliferative responses to normal mitogenic stimulation. Thus, a major focus has been to elucidate the biochemical basis for this proliferative defect. These paradoxical results suggest that T cells utilize similar signal transduction pathways to initiate proliferation and apoptosis and provide a framework for elucidating the homeostatic regulation of T cells that is crucial for a functional immune system. Additionally, these studies are directed at key questions related to cancer biology, as apoptotic and autophagic signaling pathways are important targets of oncogenic transformation.
A second area of investigation regards the signal transduction pathways that regulate the elimination of autoreactive T cells during thymocyte differentiation, a developmental process known as negative selection. Since this stage is thought to involve apoptosis, they are investigating apoptotic pathways that might contribute to this process. During the course of this research, Dr. Walsh’s lab has identified a novel serine-threonine kinase, DRAK2, that is differentially regulated during thymocyte development. Curiously, this kinase induces apoptosis when overexpressed in T cells, and is upregulated in immature thymocytes following T cell receptor ligation. Although the specific function of this kinase is unclear, the lab is currently investigating the role of this kinase in T cell development and activation by generating mice deficient in this kinase. Ultimately, their objective is to investigate the paradigms that regulate immune homeostasis by more fully understanding the intersection of these apoptotic and growth regulatory pathways. Dr. Walsh utilizes proteomics tools, including tandem affinity purification, mass spectrometry and two dimensional gel electrophoresis to aid in their quest to define the biochemical mechanisms that impact immune homeostasis and tolerance, and the ability of the immune system to appropriately respond to microbial and oncogenic targets.
Selected Publications:
Ly, C., Arechiga, A. F., Melo, J. V., Walsh, C. M., and Ong, S. T. (2003). Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. Cancer Res 63(18), 5716-22.
Arechiga, A. F., Bell, B. D., Solomon, J. C., Chu, I. H., Dubois, C. L., Hall, B. E., George, T. C., Coder, D. M., and Walsh, C. M. (2005). Cutting edge: FADD is not required for antigen receptor-mediated NF-kappaB activation. J Immunol 175(12), 7800-4.
Sandu, C., Morisawa, G., Wegorzewska, I., Huang, T., Arechiga, A. F., Hill, J. M., Kim, T., Walsh, C. M., and Werner, M. H. (2006). FADD self-association is required for stable interaction with an activated death receptor. Cell Death and Differentiation 13(12), 2052-2061.
Arechiga, A. F., Bell, B. D., Leverrier, S., Weist, B. M., Porter, M., Wu, Z., Kanno, Y., Ramos, S. J., Ong, S. T., Siegel, R., and Walsh, C. M. (2007). A Fas-associated death domain protein/caspase-8-signaling axis promotes S-phase entry and maintains S6 kinase activity in T cells responding to IL-2. J Immunol 179(8), 5291-300.
Friedrich, M. L., Cui, M., Hernandez, J. B., Weist, B. M., Andersen, H. M., Zhang, X., Huang, L., and Walsh, C. M. (2007). Modulation of DRAK2 autophosphorylation by antigen receptor signaling in primary lymphocytes. J Biol Chem 282(7), 4573-84. |
