Jon C.D. Houtman, Ph.D.
Ph.D., University of Wisconsin-Madison, 1999 |
Assistant Professor of Microbiology Campus address: 2210 MERF Mailing address: 375 Newton Rd. 2210 Medical Education and Biomedical Research Facility Iowa City, IA 52242 Phone: 319-335-7780 Email: |
Role of Adaptor Proteins in T Cell Activation
An important step in the ability of the human immune system to properly fight an infection by a bacterium, virus or parasite is the activation of a specific type of white blood cell, the human T cell. This occurs when a T cell receptor (TCR) expressed on the surface of T cells is stimulated by an antigen-bound MHC molecule. Upon TCR activation, a number of intracellular signal transduction pathways in the T cell are stimulated, events that ultimately result in changes in T cell function. These pathways are controlled by the activation and deactivation of protein tyrosine kinases and phosphatases that regulate the interactions between receptor, enzymatic effecter proteins and/or non-enzymatic molecules called adaptor proteins, whose sole purpose is to facilitate the formation of signaling complexes. The proper formation and regulation of these multiprotein signaling complexes in human T cells is absolutely required for the response to infections but importantly, is also involved in the progression of a number of disease states. Because of their critical role, it is vital that we understand the regulation, formation and function of these signaling complexes in order to develop new treatments for diseases of the immune system.
The goal of my laboratory is to understand the molecular mechanism of the formation of the multiprotein signaling complexes that occur after TCR activation. Specifically, I am interested in understanding the activation and deactivation mechanism of tyrosine kinases and phosphatases and the role the adaptor proteins play in the regulation and creation of these multiprotein signaling complexes. Currently, my laboratory is focused on three main projects. In the first project, we are focused on understanding the sequence of events that occur during the activation of the adaptor protein LAT, the principle nucleation site for the formation of TCR-induced multiprotein signaling complexes. In the second project, we are characterizing the activation mechanism of the tyrosine kinases Pyk2 and Fak and the role these molecules play in TCR-mediated signaling. In the third project, the function of three members of the Grb2 family of adaptor proteins, Grb2, Gads and Grap in TCR-induced signaling pathways and in the formation of multiprotein signaling complexes at LAT is being examined. These projects employ a range of techniques from biophysical examination of protein-protein interactions to the use of modern imaging techniques to visualize the trafficking of intracellular signaling proteins to the characterization of signaling event in human T cells. Together, these studies will provide novel insights into the regulation, formation and function of TCR-induced signaling complexes. This information will prove vital not only for understanding the normal immune response to pathogen infection, but also for providing potential targets for the treatment and cure of debilitating diseases of the human immune system.
Recent publications
Houtman, J.C.D., P.H. Brown, B. Bowden, H. Yamaguchi, E. Appella, L.E., Samuelson, and P. Schuck. 2007. Studying multi-site binary and ternary protein interactions by global analysis of isothermal titration calorimetry data in SEDPHAT: application to adaptor protein complexes in cell signaling. Protein Sci 16:30-42.
Houtman, J.C.D., H. Yamaguchi, M. Barda-Saad, B. Bowden, E. Appella, P. Schuck, and L.E. Samuelson. 2006. Oligomerization of signaling complexes by the multipoint binding of Grb2 to both LAT and Sos1. Nat Struct Mol Biol, 13:798-805.
Houtman, J.C.D., R.A. Houghtling, M. Barda-Saad, Y. Toda, and L.E. Samuelson. 2005. Early phosphorylation kinetics of proteins involved in proximal T cell receptor-mediated signaling pathways. J Immunol 175:2449-2458.