Jon C. Houtman, PhD

Portrait
Assistant Director for Cancer Education, Holden Comprehensive Cancer Center
Associate Professor of Microbiology and Immunology
Associate Professor of Internal Medicine

Contact Information

Office: 2210 Medical Education and Research Facility
375 Newton Rd
Iowa City, IA 52242
319-335-7780

Lab: 2234B Medical Education and Research Facility
375 Newton Rd
Iowa City, IA 52242
319-335-7597

Education

BA, Biology and Chemistry, University of Minnesota, Morris
PhD, Cellular and Molecular Biology, University of Wisconsin-Madison

Postdoctoral Fellow, Molecular Immunology, National Cancer Institute/NIH/DHHS

Education/Training Program Affiliations

Biomedical Science Program, Department of Microbiology Graduate Program, Interdisciplinary Graduate Program in Immunology, Interdisciplinary Graduate Program in Molecular Medicine, Medical Scientist Training Program

Center, Program and Institute Affiliations

Center for Immunology and Immune-based Diseases, Holden Comprehensive Cancer Center, Institute for Clinical and Translational Science

Research Summary

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.

Publications

Zhang, L., Martini, G. D., Rube, H. T., Kribelbauer, J. F., Rastogi, C., FitzPatrick, V. D., Houtman, J. C., Bussemaker, H. J. & Pufall, M. A. (2017). SelexGLM differentiates androgen and glucocorticoid receptor DNA-binding preference over an extended binding site. Genome research. PMID: 29196557.

McLinden, J. H., Bhattarai, N., Stapleton, J. T., Chang, Q., Kaufman, T. M., Cassel, S. L., Sutterwala, F. S., Haim, H., Houtman, J. C. & Xiang, J. (2017). Yellow Fever Virus, but Not Zika Virus or Dengue Virus, Inhibits T-Cell Receptor-Mediated T-Cell Function by an RNA-Based Mechanism. The Journal of infectious diseases, 216(9), 1164-1175. PMID: 28968905.

Bodle, C. R., Mackie, D. I., Hayes, M. P., Schamp, J. H., Miller, M. R., Henry, M. D., Doorn, J. A., Houtman JCD,, James, M. A. & Roman, D. L. (2017). Natural Products Discovered in a High-Throughput Screen Identified as Inhibitors of RGS17 and as Cytostatic and Cytotoxic Agents for Lung and Prostate Cancer Cell Lines. Journal of natural products, 80(7), 1992-2000. PMID: 28621943.

Wallis, A. M., Wallace, E. C., Hostager, B. S., Yi, Z., Houtman JCD, & Bishop, G. A. (2017). TRAF3 enhances TCR signaling by regulating the inhibitors Csk and PTPN22. Scientific reports, 7(1), 2081. PMID: 28522807.

Vacaflores, A., Freedman, S. N., Chapman, N. M. & Houtman, J. C. (2017). Pretreatment of activated human CD8 T cells with IL-12 leads to enhanced TCR-induced signaling and cytokine production. Mol Immunol, 81, 1-15. PMID: 27883938.

Zhang, M. S., Houtman, J. C. (2016). Human Serum Albumin (HSA) Suppresses the Effects of Glycerol Monolaurate (GML) on Human T Cell Activation and Function. PLoS One, 11(10), e165083. PMID: 27764189.

Hastie, J. L., Williams, K. B., Bohr, L. L., Houtman, J. C., Gakhar, L. & Ellermeier, C. D. (2016). The Anti-sigma Factor RsiV Is a Bacterial Receptor for Lysozyme: Co-crystal Structure Determination and Demonstration That Binding of Lysozyme to RsiV Is Required for sV Activation. PLoS Genet, 12(9), e1006287. PMID: 27602573.

Houtman, C. J., Kitin, P., Houtman, J. C., Hammel, K. E. & Hunt, C. G. (2016). Acridine Orange Indicates Early Oxidation of Wood Cell Walls by Fungi. PLoS One, 11(7), e0159715. PMID: 27454126.

Vacaflores, A., Chapman, N. M., Harty, J. T., Richer, M. J. & Houtman, J. C. (2016). Exposure of Human CD4 T Cells to IL-12 Results in Enhanced TCR-Induced Cytokine Production, Altered TCR Signaling, and Increased Oxidative Metabolism. PLoS ONe, 11(6), e0157175. PMID: 27280403.

Boehm, E. M., Powers, K. T., Kondratick, C. M., Spies, M., Houtman, J. C. & Washington, M. T. (2016). The Proliferating Cell Nuclear Antigen (PCNA)-interacting Protein (PIP) Motif of DNA Polymerase ? Mediates Its Interaction with the C-terminal Domain of Rev1. J Biol Chem, 291(16), 8735-44. PMID: 26903512.

Zhang, M. S., Sandouk, A. & Houtman, J. C. (2016). Glycerol Monolaurate (GML) inhibits human T cell signaling and function by disrupting lipid dynamics. Sci Rep, 6, 30225. PMID: 27456316.

Bilal, M. Y., Zhang, E. Y., Dinkel, B., Hardy, D., Yankee, T. M. & Houtman, J. C. (2015). GADS is required for TCR-mediated calcium influx and cytokine release, but not cellular adhesion, in human T cells. Cell Signal, 27(4), 841-50. PMID: 25636200.

Cadra, S., Gucciardi, A., Valignat, M. P., Theodoly, O., Vacaflores, A., Houtman, J. C. & Lellouch, A. C. (2015). ROZA-XL, an improved FRET based biosensor with an increased dynamic range for visualizing zeta associated protein 70 kD (ZAP-70) tyrosine kinase activity in live T cells. Biochem Biophys Res Commun, 459(3), 405-10. PMID: 25735979.

Tremblay, M. M., Houtman, J. C. (2015). TCR-mediated functions are enhanced in activated peripheral blood T cells isolated from leucocyte reduction systems. J Immunol Methods, 416, 137-45. PMID: 25462023.

Chapman, N. M., Yoder, A. N., Barbón, K. M., Bilal, M. Y., Connolly, S. F. & Houtman, J. C. (2015). Proline-rich tyrosine kinase 2 controls PI3-kinase activation downstream of the T cell antigen receptor in human T cells. J Leukoc Biol, 97(2), 285-96. PMID: 25387834.

Bilal, M. Y., Houtman, J. C. (2015). GRB2 Nucleates T Cell Receptor-Mediated LAT Clusters That Control PLC-?1 Activation and Cytokine Production. Front Immunol, 6, 141. PMID: 25870599.

Bartelt, R. R., Light, J., Vacaflores, A., Butcher, A., Pandian, M., Nash, P. & Houtman, J. C. (2015). Regions outside of conserved PxxPxR motifs drive the high affinity interaction of GRB2 with SH3 domain ligands. Biochim Biophys Acta, 1853(10 Pt A), 2560-9. PMID: 26079855.

Bilal, M. Y., Vacaflores, A. & Houtman, J. C. (2015). Optimization of methods for the genetic modification of human T cells. Immune Cell Biol, 93(10), 896-908. PMID: 26027856.

Hastie, J. L., Williams, K. B., Sepúlveda, C., Houtman, J. C., Forest, K. T. & Ellermeier, C. D. (2014). Evidence of a bacterial receptor for lysozyme: binding of lysozyme to the anti-s factor RsiV controls activation of the ecf s factor sV. PLoS Genet, 10(10), e1004643. PMID: 25275625.

Streeter, J., Schickling, B. M., Jiang, S., Stanic, B., Thiel, W. H., Gakhar, L., Houtman, J. C. & Miller, F. J. (2014). Phosphorylation of Nox1 regulates association with NoxA1 activation domain. Circ Res, 115(11), 911-8. PMID: 25228390.

Cruz-Orcutt, N., Vacaflores, A., Connolly, S. F., Bunnell, S. C. & Houtman, J. C. (2014). Activated PLC-?1 is catalytically induced at LAT but activated PLC-?1 is localized at both LAT- and TCR-containing complexes. Cell Signal, 26(4), 797-805. PMID: 24412752.

Chapman, N. M., Houtman, J. C. (2014). Functions of the FAK family kinases in T cells: beyond actin cytoskeletal rearrangement. Immunol Res, 59(1-3), 23-34. PMID: 24816556.

Tremblay, M. M., Bilal, M. Y. & Houtman, J. C. (2014). Prior TLR5 induction in human T cells results in a transient potentiation of subsequent TCR-induced cytokine production. Mol Immunol, 57(2), 161-70. PMID: 24128895.

Willett, J. W., Tiwari, N., Müller, S., Hummels, K. R., Houtman, J. C., Fuentes, E. J. & Kirby, J. R. (2013). Specificity residues determine binding affinity for two-component signal transduction systems. MBio, 4(6), pii: e00420-13. PMID: 24194534.

Chapman, N. M., Connolly, S. F., Reinl, E. L. & Houtman, J. C. (2013). Focal adhesion kinase negatively regulates lck function downstream of the T cell antigen receptor. J Immunol, 191(12), 6208-21. PMID: 24227778.

Chapman, N. M., Bilal, M. Y., Cruz-Orcutt, N., Knudson, C., Madinaveitia, S., Light, J. & Houtman, J. C. (2013). Distinct signaling pathways regulate TLR2 co-stimulatory function in human T cells. Cell Signal, 25(3), 639-50. PMID: 23219913.

Coussens, N. P., Hayashi, R., Brown, P. H., Balagopalan, L., Balbo, A., Akpan, I., Houtman, J. C., Barr, V. A., Schuck, P., Appella, E. & Samelson, L. E. (2013). Multipoint Binding of the SLP-76 SH2 Domain to ADAP Is Critical for Oligomerization of SLP-76 Signaling Complexes in Stimulated T Cells. Mol Cell Biol, 33(21), 4140-51. PMID: 23979596.

Slupe, A. M., Merrill, R. A., Flippo, K. H., Lobas, M. A., Houtman, J. C. & Strack, S. (2013). A calcineurin docking motif (LXVP) in dynamin-related protein 1 contributes to mitochondrial fragmentation and ischemic neuronal injury. J Biol Chem, 288(17), 12353-65. PMID: 23486469.

Bartelt, R. R., Houtman, J. C. (2013). The adaptor protein LAT serves as an integration node for signaling pathways that drive T cell activation. Wiley Interdiscip Rev Syst Biol Med, 5(1), 101-10. PMID: 23150273.

Chapman, N. M., Yoder, A. N. & Houtman, J. C. (2012). Non-catalytic functions of Pyk2 and Fyn regulate late stage adhesion in human T cells. PLoS One, 7(12), e53011. PMID: 23300847.

Dutta, S., Li, Y. L., Rock, W., Houtman, J. C., Kohen, A. & Cheatum, C. M. (2012). 3-picolyl azide adenine dinucleotide as a probe of femtosecond to picosecond enzyme dynamics. J Phys Chem B, 116(1), 542-8. PMID: 22126535.

Kandasamy, K., Mohan, S. S., Raju, R., Keerthikumar, S., Kumar, G. S., Venugopal, A. K., Telikicherla, D., Navarro, J. D., Mathivanan, S., Pecquet, C., Gollapudi, S. K., Tattikota, S. G., Mohan, S., Padhukasahasram, H., Subbannayya, Y., Goel, R., Jacob, H. K., Zhong, J., Sekhar, R., Nanjappa, V., Balakrishnan, L., Subbaiah, R., Ramachandra, Y. L., Rahiman, B. A., Prasad, T. S., Lin, J. X., Houtman, J. C., Desiderio, S., Renauld, J. C., Constantinescu, S. N., Ohara, O., Hirano, T., Kubo, M., Singh, S., Khatri, P., Draghici, S., Bader, G. D., Sander, C., Leonard, W. J. & Pandey, A. (2010). NetPath: a public resource of curated signal transduction pathways. Genome Biol, 11(1), R3. PMID: 20067622.

Agassandian, M., Chen, B. B., Schuster, C. C., Houtman, J. C. & Mallampalli, R. K. (2010). 14-3-3zeta escorts CCTalpha for calcium-activated nuclear import in lung epithelia. FASEB J, 24(4), 1271-83. PMID: 20007511.

Collins, M., Tremblay, M., Chapman, N., Curtiss, M., Rothman, P. B. & Houtman, J. C. (2010). The T cell receptor-mediated phosphorylation of Pyk2 tyrosines 402 and 580 occurs via a distinct mechanism than other receptor systems. J Leukoc Biol, 87(4), 691-701. PMID: 20028775.

Collins, M., Bartelt, R. R. & Houtman, J. C. (2010). T cell receptor activation leads to two distinct phases of Pyk2 activation and actin cytoskeletal rearrangement in human T cells. Mol Immunol, 47(9), 1665-74. PMID: 20381867.

Dutta, S., Cook, R. J., Houtman, J. C., Kohen, A. & Cheatum, C. M. (2010). Characterization of azido-NAD+ to assess its potential as a two-dimensional infrared probe of enzyme dynamics. Anal Biochem, 407(2), 241-6. PMID: 20705046.

Guseva, N. V., Fullenkamp, C. A., Naumann, P. W., Shey, M. R., Ballas, Z. K., Houtman, J. C., Forbes, C. A., Scalzo, A. A. & Heusel, J. W. (2010). Glycosylation contributes to variability in expression of murine cytomegalovirus m157 and enhances stability of interaction with the NK-cell receptor Ly49H. Eur J Immunol, 40(9), 2618-31. PMID: 20662096.

Barda-Saad, M., Shirasu, N., Pauker, M. H., Hassan, N., Perl, O., Balbo, A., Yamaguchi, H., Houtman, J. C., Appella, E., Schuck, P. & Samelson, L. E. (2010). Cooperative interactions at the SLP-76 complex are critical for actin polymerization. EMBO J, 29(14), 2315-28. PMID: 20562827.

Cruz-Orcutt, N., Houtman, J. C. (2009). PI3 kinase function is vital for the function but not formation of LAT-mediated signaling complexes. Mol Immunol, 46(11-12), 2274-83. PMID: 19427038.

Bartelt, R. R., Cruz-Orcutt, N., Collins, M. & Houtman, J. C. (2009). Comparison of T cell receptor-induced proximal signaling and downstream functions in immortalized and primary T cells. PLoS One, 4(5), e5430. PMID: 19412549.

Picollo, A., Malvezzi, M., Houtman, J. C. & Accardi, A. (2009). Basis of substrate binding and conservation of selectivity in the CLC family of channels and transporters. Nat Struct Mol Biol, 16(12), 1294-301. PMID: 19898476.

Johnston, J. W., Coussens, N. P., Allen, S., Houtman, J. C., Turner, K. H., Zaleski, A., Ramaswamy, S., Gibson, B. W. & Apicella, M. A. (2008). Characterization of the N-acetyl-5-neuraminic acid-binding site of the extracytoplasmic solute receptor (SiaP) of nontypeable Haemophilus influenzae strain 2019. J Biol Chem, 283(2), 855-65. PMID: 17947229.

Pigge, F. C., Dighe, M. K. & Houtman, J. C. (2008). Mono-, bis-, and tris(crown ether)s assembled around 1,3,5-triaroylbenzene scaffolds. J Org Chem, 73(7), 2760-7. PMID: 18331059.

Wen, K. K., McKane, M., Houtman, J. C. & Rubenstein, P. (2008). Control of the ability of profilin to bind and facilitate nucleotide exchange from G-actin. J Biol Chem, 283(14), 9444-53. PMID: 18223293.

Houtman, J. C., Brown, P. H., Bowden, B., Yamaguchi, H., Appella, E., Samelson, L. E. & Schuck, P. (2007). Studying multisite 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(1), 30-42. PMID: 17192587.

Houtman, J. C., Yamaguchi, H., Barda-Saad, M., Braiman, A., Bowden, B., Appella, E., Schuck, P. & Samelson, L. E. (2006). Oligomerization of signaling complexes by the multipoint binding of GRB2 to both LAT and SOS1. Nat Struct Mol Biol, 13(9), 798-805. PMID: 16906159.

Houtman, J. C., Houghtling, R. A., Barda-Saad, M., Toda, Y. & Samelson, L. E. (2005). Early phosphorylation kinetics of proteins involved in proximal TCR-mediated signaling pathways. J Immunol, 175(4), 2449-58. PMID: 16081816.

Houtman, J. C., Barda-Saad, M. & Samelson, L. E. (2005). Examining multiprotein signaling complexes from all angles. FEBS J, 272(21), 5426-35. PMID: 16262684.

Houtman, J. C., Higashimoto, Y., Dimasi, N., Cho, S., Yamaguchi, H., Bowden, B., Regan, C., Malchiodi, E. L., Mariuzza, R., Schuck, P., Appella, E. & Samelson, L. E. (2004). Binding specificity of multiprotein signaling complexes is determined by both cooperative interactions and affinity preferences. Biochemistry, 43(14), 4170-8. PMID: 15065860.

Cho, S., Velikovsky, C. A., Swaminathan, C. P., Houtman, J. C., Samelson, L. E. & Mariuzza, R. A. (2004). Structural basis for differential recognition of tyrosine-phosphorylated sites in the linker for activation of T cells (LAT) by the adaptor Gads. EMBO J, 23(7), 1441-51. PMID: 15029250.

Yamaguchi, H., Houtman, J. C., Samelson, L. E. & Appella, E. (2003). Synthesis and application of large phosphopeptides from the Linker for Activation of T cells (LAT) protein. Biopolymers, 71, P503.

Houtman, J. C., Wiepz, G. J. & Bertics, P. J. (2000). The coordinate regulation of preadipocyte growth and differentiation by EGF and growth hormone. In J. M. Ntambi (Eds.) Adipocyte biology and hormone signaling. Biomedical and Health Research, IOS Press, Amsterdam, Netherlands.

Zhang, Y., Li, D., Houtman, J. C., Witiak, D. T., Seltzer, J., Bertics, P. J. & Lauhon, C. T. (1999). Design, combinatorial chemical synthesis and in vitro characterization of novel urea based gelatinase inhibitors. Bioorg Med Chem Lett, 9(19), 2823-6. PMID: 10522699.

Kim, S. O., Houtman, J. C., Jiang, J., Ruppert, J. M., Bertics, P. J. & Frank, S. J. (1999). Growth hormone-induced alteration in ErbB-2 phosphorylation status in 3T3-F442A fibroblasts. J Biol Chem, 274(50), 36015-24. PMID: 10585492.

Wiepz, G. J., Houtman, J. C., Cha, D. & Bertics, P. J. (1997). Growth hormone attenuation of epidermal growth factor-induced mitogenesis. J Cell Physiol, 173(1), 44-53. PMID: 9326448.

Lee, D., Szumlanski, C., Houtman, J. C., Honchel, R., Rojas, K., Overhauser, J., Wieben, E. D. & Weinshilboum, R. M. (1995). Thiopurine methyltransferase pharmacogenetics. Cloning of human liver cDNA and a processed pseudogene on human chromosome 18q21.1. Drug Metab Dispos, 23(3), 398-405. PMID: 7628307.