Internal Medicine

Jon C. Houtman, PhD

Portrait

Associate Professor of Microbiology
Associate Professor of Internal Medicine

Contact Information

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

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

Email: jon-houtman@uiowa.edu

Education

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

Post Doctoral, Molecular Immunology, National Cancer Institute/NIH/DHHS

Education/Training Program Affiliations

Biosciences Graduate Program
Department of Microbiology Graduate Program
Interdisciplinary Graduate Program in Immunology
Interdisciplinary Graduate Program in Molecular and Cellular Biology
Medical Scientist Training Program

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. 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.

Center, Program and Institute Affiliations

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

All Publications

Streeter J, Schickling B, Jiang S, Stanic B, Thiel W, Gakhar L, Houtman J, Miller F.  Phosphorylation of Nox1 Regulates Association With NoxA1 Activation Domain.  Circ Res.  2014 November 7. 115(11):911-8.
[Link]

Hastie J, Williams K, Sepúlveda C, Houtman J, Forest K, Ellermeier C.  Evidence of a bacterial receptor for lysozyme: binding of lysozyme to the anti-σ factor RsiV controls activation of the ecf σ factor σV.  PLoS Genet.  2014 October 2. 10(10):e1004643.
[Link]

Chapman N, Houtman J.  Functions of the FAK family kinases in T cells: beyond actin cytoskeletal rearrangement.  Immunol Res.  2014 August. 59(1-3):23-34.
[Link]

Cruz-Orcutt N, Vacaflores A, Connolly S, Bunnell S, Houtman J.  Activated PLC-γ1 is catalytically induced at LAT but activated PLC-γ1 is localized at both LAT- and TCR-containing complexes.  Cell Signal.  2014 April. 26(4):797-805.
[Link]

Tremblay M, Bilal M, Houtman J.  Prior TLR5 induction in human T cells results in a transient potentiation of subsequent TCR-induced cytokine production.  Mol Immunol.  2014 February. 57(2):161-70.
[Link]

Chapman N, Yoder A, Barbón K, Bilal M, Connolly S, Houtman J.  Proline-rich tyrosine kinase 2 controls PI3-kinase activation downstream of the T cell antigen receptor in human T cells.  J Leukoc Biol.  2014. Epub ahead of print.
[Link]

Chapman N, Connolly S, Reinl E, Houtman J.  Focal adhesion kinase negatively regulates lck function downstream of the T cell antigen receptor.  J Immunol.  2013 December 15. 191(12):6208-21.
[Link]

Willett J, Tiwari N, Müller S, Hummels K, Houtman J, Fuentes E, Kirby J.  Specificity residues determine binding affinity for two-component signal transduction systems.  MBio.  2013 November 5. 4(6):pii: e00420-13.
[Link]

Coussens N, Hayashi R, Brown P, Balagopalan L, Balbo A, Akpan I, Houtman J, Barr V, Schuck P, Appella E, Samelson L.  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.  2013 November. 33(21):4140-51.
[Link]

Slupe A, Merrill R, Flippo K, Lobas M, Houtman J, Strack S.  A calcineurin docking motif (LXVP) in dynamin-related protein 1 contributes to mitochondrial fragmentation and ischemic neuronal injury.  J Biol Chem.  2013 April 26. 288(17):12353-65.
[Link]

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

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

Dutta S, Li Y, Rock W, Houtman J, Kohen A, Cheatum C.  3-picolyl azide adenine dinucleotide as a probe of femtosecond to picosecond enzyme dynamics.  J Phys Chem B.  2012 January 12. 116(1):542-8.
[Link]

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

Dutta S, Cook R, Houtman J, Kohen A, Cheatum C.  Characterization of azido-NAD+ to assess its potential as a two-dimensional infrared probe of enzyme dynamics.  Anal Biochem.  2010 December 15. 407(2):241-6.
[Link]

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

Barda-Saad M, Shirasu N, Pauker M, Hassan N, Perl O, Balbo A, Yamaguchi H, Houtman J, Appella E, Schuck P, Samelson L.  Cooperative interactions at the SLP-76 complex are critical for actin polymerization.  EMBO J.  2010 July 21. 29(14):2315-28.
[Link]

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

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

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

Kandasamy K, Mohan S, Raju R, Keerthikumar S, Kumar G, Venugopal A, Telikicherla D, Navarro J, Mathivanan S, Pecquet C, Gollapudi S, Tattikota S, Mohan S, Padhukasahasram H, Subbannayya Y, Goel R, Jacob H, Zhong J, Sekhar R, Nanjappa V, Balakrishnan L, Subbaiah R, Ramachandra Y, Rahiman B, Prasad T, Lin J, Houtman J, Desiderio S, Renauld J, Constantinescu S, Ohara O, Hirano T, Kubo M, Singh S, Khatri P, Draghici S, Bader G, Sander C, Leonard W, Pandey A.  NetPath: a public resource of curated signal transduction pathways.  Genome Biol.  2010 January 12. 11(1):R3.
[Link]

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

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

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

Wen K, McKane M, Houtman J, Rubenstein P.  Control of the ability of profilin to bind and facilitate nucleotide exchange from G-actin.  J Biol Chem.  2008 April 4. 283(14):9444-53.
[Link]

Pigge F, Dighe M, Houtman J.  Mono-, bis-, and tris(crown ether)s assembled around 1,3,5-triaroylbenzene scaffolds.  J Org Chem.  2008 April 4. 73(7):2760-7.
[Link]

Johnston J, Coussens N, Allen S, Houtman J, Turner K, Zaleski A, Ramaswamy S, Gibson B, Apicella M.  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.  2008 January 11. 283(2):855-65.
[Link]

Houtman J, Brown P, Bowden B, Yamaguchi H, Appella E, Samelson L, Schuck P.  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.  2007 January. 16(1):30-42.
[Link]

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

Houtman J, Barda-Saad M, Samelson L.  Examining multiprotein signaling complexes from all angles.  FEBS J.  2005 November. 272(21):5426-35.
[Link]

Houtman J, Houghtling R, Barda-Saad M, Toda Y, Samelson L.  Early phosphorylation kinetics of proteins involved in proximal TCR-mediated signaling pathways.  J Immunol.  2005 August 15. 175(4):2449-58.
[Link]

Houtman J, Higashimoto Y, Dimasi N, Cho S, Yamaguchi H, Bowden B, Regan C, Malchiodi E, Mariuzza R, Schuck P, Appella E, Samelson L.  Binding specificity of multiprotein signaling complexes is determined by both cooperative interactions and affinity preferences.  Biochemistry.  2004 April 13. 43(14):4170-8.
[Link]

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

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

Houtman J, Wiepz G, Bertics P.  The coordinate regulation of preadipocyte growth and differentiation by EGF and growth hormone.  Biomedical and Health Research, IOS Press, Amsterdam, Netherlands.  2000 January. 37.

Kim S, Houtman J, Jiang J, Ruppert J, Bertics P, Frank S.  Growth hormone-induced alteration in ErbB-2 phosphorylation status in 3T3-F442A fibroblasts.  J Biol Chem.  1999 December 10. 274(50):36015-24.
[Link]

Zhang Y, Li D, Houtman J, Witiak D, Seltzer J, Bertics P, Lauhon C.  Design, combinatorial chemical synthesis and in vitro characterization of novel urea based gelatinase inhibitors.  Bioorg Med Chem Lett.  1999 October 4. 9(19):2823-6.
[Link]

Wiepz G, Houtman J, Cha D, Bertics P.  Growth hormone attenuation of epidermal growth factor-induced mitogenesis.  J Cell Physiol.  1997 October. 173(1):44-53.
[Link]

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

Date Last Modified: 06/07/2014 - 21:56:23