Assistant Director for Cancer Education, Holden Comprehensive Cancer Center
Associate Professor of Microbiology
Associate Professor of
Office: 2210 Medical Education and Research Facility
375 Newton Rd
Iowa City, IA 52242
Lab: 2234B Medical Education and Research Facility
375 Newton Rd
Iowa City, IA 52242
BA, Biology and Chemistry, University of Minnesota, Morris
PhD, Cellular and Molecular Biology, University of Wisconsin-Madison
Post Doctorate, Molecular Immunology, National Cancer Institute/NIH/DHHS
Education/Training Program Affiliations
Department of Microbiology Graduate Program
Interdisciplinary Graduate Program in Immunology
Interdisciplinary Graduate Program in Molecular and Cellular Biology
Medical Scientist Training Program
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. For full stimulation, human T cells require 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. Because of their critical role in T cell activation, it is vital that we understand the regulation, formation and function of these signaling pathways 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 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 proteins GRB2, GADS and GRAP with various ligands and how these interactions facilitate the formation of LAT-mediated complexes and cellular function. 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 investigate how costimulatory and cytokine receptors alter the TCR-induced activation of human T cells. One focus is on the tyrosine kinases Pyk2 and Fak as a node of intersection between the TCR and these 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 costimulatory receptor-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. Finally, we are investigating how IL-12 pretreatment primes human T cells to respond better to subsequent TCR stimulation. 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 T cell function, including autoimmune disorders, human cancers and transplant rejection.
Center, Program and Institute Affiliations
Center for Immunology and Immune-based Diseases
Holden Comprehensive Cancer Center
Institute for Clinical and Translational Science
Regions outside of conserved PxxPxR motifs drive the high affinity interaction of GRB2 with SH3 domain ligands.
Biochim Biophys Acta.
2015 October. 1853(10 Pt A):2560-9.
GADS is required for TCR-mediated calcium influx and cytokine release, but not cellular adhesion, in human T cells.
2015 April. 27(4):841-50.
GRB2 Nucleates T Cell Receptor-Mediated LAT Clusters That Control PLC-γ1 Activation and Cytokine Production.
2015 March 30. 6:141.
Proline-rich tyrosine kinase 2 controls PI3-kinase activation downstream of the T cell antigen receptor in human T cells.
J Leukoc Biol.
2015 February. 97(2):285-96.
Optimization of methods for the genetic modification of human T cells.
Immune Cell Biol.
2015. Epub ahead of print.
TCR-mediated functions are enhanced in activated peripheral blood T cells isolated from leucocyte reduction systems.
J Immunol Methods.
2015 January. 416:137-45.
Prior TLR5 induction in human T cells results in a transient potentiation of subsequent TCR-induced cytokine production.
2014 February. 57(2):161-70.
Focal adhesion kinase negatively regulates lck function downstream of the T cell antigen receptor.
2013 December 15. 191(12):6208-21.
Distinct signaling pathways regulate TLR2 co-stimulatory function in human T cells.
2013 March. 25(3):639-50.
Non-catalytic functions of Pyk2 and Fyn regulate late stage adhesion in human T cells.
Date Last Modified: 06/06/2016 -