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: |
Mechanism of Signal Transduction in Human T Cells
T cell activation is critical for the ability of the human immune system to properly fight an infection by a bacteria, virus or parasite. However, inappropriate or aberrant T cell induction is crucial for the initiation and progression of numerous human diseases, including T cell lymphoma/leukemia, human malignancies, autoimmune disorders, cardiovascular disease and transplant rejection. Human T cells require two signals to become fully stimulated: a primary signal from activation of the T cell receptor (TCR) and a second signal from the induction of one or more costimulatory receptors. Upon TCR and/or costimulatory receptor activation, a number of intracellular signal transduction pathways in the T cell are stimulated, which then control alterations in T cell function. These pathways are regulated by the activation and deactivation of protein tyrosine kinases and phosphatases that control the interactions between receptor, enzymatic effecter proteins and/or non-enzymatic adaptor proteins. Because of their critical role in T cell activation, it is vital that we understand the regulation, formation and function of these signaling complexes in order to develop new treatments for diseases linked to aberrant T cell activation. The goal of my laboratory is to understand the molecular mechanism of the formation of the multiprotein signaling complexes that occur after TCR and/or costimulatory receptor activation. Currently, my laboratory is working on two main projects.
Project 1: The overall goal of this project is to determine the molecular mechanism for the activation and function of the adaptor protein LAT. Upon TCR activation, LAT is phosphorylated on four conserved tyrosines, which then serve as the principle nucleation site for TCR-induced signaling complexes. We are using biochemical and imaging techniques to identify the kinases/phosphatases that regulate the phosphorylation of LAT, characterize the phosphorylation kinetics of individual LAT tyrosines and examine how alterations in these events affect the formation and composition of LAT-mediated complexes. Additionally, we are utilizing highly quantitative biophysical and biochemical tools to characterize the interaction of the adaptor protein Grb2 with various ligands, such as LAT and SOS1, and how these interactions facilitate the formation of LAT-mediated complexes. Ultimately, these studies will allow us to rationally design treatments for diseases linked to the activation of LAT, including human malignancies, autoimmune disorders and cardiovascular disease.
Project 2: The overall focus of this project is to characterize the molecular mechanism for the crosstalk between TCR- and costimulatory receptor-induced signaling pathways. We are interested in how the integrin VLA-4 facilitates the TCR-induced activation of human T cells, with a focus on the tyrosine kinases Pyk2 and Fak as a node of intersection between these two receptors. Fak and Pyk2 are critical for integrating receptor-mediated signals the control the actin cytoskeleton and are frequently overexpressed in human cancers. This project uses biochemical and cell biological techniques to determine the timing and mechanism of the TCR and VLA-4-induced activation of Fak and Pyk2 and characterize the role these kinases play in T cell activation. Additionally, we are examining the function of Toll-like receptors (TLRs) in T cell induction. We are using quantitative cell biological and biochemical methods to examine the molecular mechanism of TLR-induced costimulation. Collectively, these studies will not only allow us to better understand the normal immune response to pathogens, but also help us develop novel treatments for debilitating diseases linked to costimulatory receptor function, including autoimmune disorders, human cancers and transplant rejection.
Holden Comprehensive Cancer Center
Recent publications
Cruz-Orcutt, N. and Houtman, J.C.D. PI3 Kinase Function is Vital for the Function but not Formation of LAT-Mediated Signaling Complexes. Molecular Immunology, 46:2274–2283, 2009.
Bartelt, R., Cruz-Orcutt, N., Collins, M., and Houtman, J.C.D. Comparison of T Cell Receptor-Induced Proximal Signaling and Downstream Functions in Immortalized and Primary T cells. PLoS ONE, 4:e5430, 2009.
Houtman, J.C.D., Brown, P.H., Bowden, B., Yamaguchi, H., Appella, E., Samelson, L.E., and Schuck, P. 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 Science, 16:30-42, 2007.
Houtman, J.C.D., Yamaguchi, H., Barda-Saad, M, Braiman, A., Bowden, B., Appella, E., Schuck, P., and Samelson, L.E. Oligomerization of Signaling Complexes by the Multipoint Binding of Grb2 to both LAT and Sos1. Nature Structural and Molecular Biology, 13:798-805, 2006.
Houtman, J.C.D., Houghtling, R.A., Barda-Saad, M., Toda, Y. and Samelson, L.E. Early Phosphorylation Kinetics of Proteins Involved in Proximal T Cell Receptor-Mediated Signaling Pathways. Journal of Immunology, 175:2449-2458, 2005.