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MICaB Faculty

Yoji Shimizu
Yoji Shimizu, Ph.D.

Distinguished University Teaching Professor
Department of Laboratory Medicine and Pathology
Director, Medical Scientist Training Program (MD/PhD)
Associate Dean, Graduate School
Director, Graduate School Diversity Office

University of Wisconsin - Madison, 1987, Ph.D.

612-626-6849 - office
612-626-6713 - lab

Research Interests:

Signal transduction, lymphocyte activation, cell adhesion and migration

The generation of an antigen-specific immune response requires the coordinated interaction of the various cellular constituents of the immune system with each other and with components of the extracellular environment found in tissue.  These adhesive events are critical to the efficient trafficking of lymphocytes through the body, the interaction of T lymphocytes with antigen-presenting cells that initiates and sustains T cell activation, and the influx of leukocytes into sites of inflammation. Dr. Shimizu's laboratory is investigating the intracellular signal transduction events that regulate the strength of these adhesive interactions and the functional significance of these molecular mechanisms of cell adhesion and migration on the ability of the immune system to respond to pathogens and tumors.  Specific areas of investigation projects include: 1) analysis of the biochemical signaling events by which the antigen-specific T cell receptor regulates the functional activity of integrins, a family of cell adhesion receptors that mediates the adhesion of cells to other cells and to extracellular matrix molecules; 2) mechanisms of receptor “cross-talk” that regulate integrin function; 3) the function of adapter proteins in regulating T cell gene transcription and cytoskeletal reorganization; 4) elucidation of pathways mediating the migration and retention of tumor-specific T cells into sites of tumor growth; and 5) analysis of the function of the lipid kinase p110gamma in regulating the inflammatory response and T cell-dependent immune responses to vaccinia virus.    Dr. Shimizu’s laboratory combines molecular and biochemical approaches with genetic models in the mouse where the impact of altering signaling pathways on the generation of antigen-specific and tumor-specific immune responses can be assessed.  The long-term objective is to provide the knowledge base necessary to specifically modulate the immune response by targeting these mechanisms of cell adhesion and migration.

Dr. Shimizu's lab

lSelected Recent Publications:

  • Domae, E., Hirai, Y., Ikeo, T., Goda, S., and Shimizu, Y.: Cytokine-mediated activation of human ex vivo-expanded Vg9Vd2 T cells. Oncotarget 2017; 8:45928-45942.
  • Banek, C.T., Kneupfer, M.M., Foss, J.D., Fiege, J.K., Asirvatham-Jeyaraj, N., Van Helden, D., Shimizu, Y., and Osborn, J.W. Resting afferent renal nerve discharge and renal inflammation: elucidating the role of afferent and efferent renal nerves in deoxycorticosterone acetate salt hypertension. Hypertension 2016; 68:1415-1423.
  • Asirvatham-Jeyaraj, N., Fiege, J.K., Han, R., Foss, J., Banek, C.T., Burbach, B.J., Razzoli, M., Bartolomucci, A., Shimizu, Y., Panoskaltsis-Mortari, A., and Osborn, J.W.: Renal denervation normalizes arterial pressure with no effect on glucose metabolism or renal inflammation in obese hypertensive mice. Hypertension 2016; 68:929-936.
  • Wang, H., Kwak, D., Fassett, J., Hou, L., Xu, X., Burbach, B., Thenappan, T., Xu, Y., Ge, J., Shimizu, Y., Bache, R., and Chen, Y.: CD28/B7 deficiency attenuates systolic overload-induced congestive heart failure, myocardial and pulmonary inflammation, and activated T-cell accumulation in the heart and lungs. Hypertension 2016; 68:688-696.
  • Fiege, J.K., Beura, L.K. and Shimizu, Y.: Adhesion and degranulation promoting adapter protein (ADAP) promotes CD8 T cell differentiation and resident memory formation and function during an acute infection. J. Immunol. 2016; 197: 2079-2089.
  • Fiege, J.K., Burbach, B.J. and Shimizu, Y.: Negative regulation of memory phenotype CD8 T cell conversion by adhesion and degranulation promoting adapter protein (ADAP). J. Immunol. 2015; 191:3119-3128.
  • Zumwalde, N.A., Domae, E., Mescher, M.F. and Shimizu, Y. 2013. ICAM-1 dependent homotypic aggregates regulate CD8 T cell effector function and differentiation during T cell activation. J. Immunol. 191:3683-3693.
  • Mitchell, J.S., Burbach, B.J., Srivastava, R., Fife, B.T. and Shimizu, Y. 2013. Multi-stage T cell-dendritic cell interactions control optimal CD4 T cell activation through the ADAP-SKAP55 signaling module. J. Immunol. 191:2372-2383.
  • Srivastava, R., Burbach, B.J., Mitchell, J.S., Pagan, A.J. and Shimizu, Y. 2012. ADAP regulates cell cycle progression of T cells via control of cyclin E and cdk2 expression through distinct CARMA-dependent signaling pathways. Mol. Cell. Biol. 32:1907-1918.  
  • Bunnell, T.M., Burbach, B.J., Shimizu, Y. and Ervasti, J.M. 2011. b-actin specifically controls cell growth, migration, and the G-actin pool. Mol. Biol. Cell 22:4047-4058.
  • Burbach, B.J., Srivastava, R., Ingram, M.A., Mitchell, J.S. and Shimizu, Y. 2011. The pleckstrin homology domain in the SKAP55 adapter protein defines the ability of the adapter protein ADAP to regulate integrin function and NF-kB activation. J. Immunol. 186:6227-6237.
  • DeNucci, C.C. and Shimizu, Y. 2011. b1 integrin is critical for the maintenance of Listeria monocytogenes-specific CD4 T cells in the bone marrow but not long-term immunological memory. J. Immunol. 186:4019-4026.
  • DeNucci, C.C., Pagan, A.J., Mitchell, J.S. and Shimizu, Y. 2010. Control of a4b7 integrin expression and T cell homing by the b1 integrin subunit. J. Immunol. 184:2458-2467.
  • Srivastava, R., Burbach, B.J. and Shimizu, Y. 2010. NF-kB activation in T cells requires discrete control of IkB kinase a/b (IKKa/b) phosphorylation and IKKg ubiquitination by the ADAP adapter protein. J. Biol. Chem. 285:11100-11105.
  • DeNucci, C.C., Mitchell, J.S. and Shimizu, Y. 2009. Integrin function in T cell homing to lymphoid and non-lymphoid sites: getting there and staying there.Crit. Rev. Immunol. 29:87-109.
  • Burbach, B.J., Srivastava, R., Medeiros, R.B., O'Gorman, W.E., Peterson, E.J. and Shimizu, Y. 2008. Distinct regulation of integrin-dependent T cell conjugate formation and NF-kB activation by the adapter protein ADAP. J. Immunol. 2008; 181:4840-4851.
  • Nolz, J.C., Nacusi, L.P., Segovis, C.M., Medeiros, R.B., Mitchell, J.S., Shimizu, Y. and Billadeau, D.D 2008. The WAVE2 complex regulates T cell receptor signaling to integrins via Abl- and CrkL-C3G-mediated activated of Rap1. J. Cell Biol. 182:1231-1244.
  • Thomas, M.S., Mitchell, J.S., DeNucci, C.C., Martin, A.L. and Shimizu, Y. 2008. The p110gamma isoform of phosphatidylinositol 3-kinase regulates migration of effector CD4 T lymphocytes into peripheral inflammatory sites. J. Leukoc. Biol. 84:814-823.
  • Martin, A.L., Schwartz, M.D., Jameson, S.C. and Shimizu, Y. 2008. Selective regulation of CD8 effector T cell migration by the p110gamma isoform of phosphatidylinositol 3-kinase (PI 3-K). J. Immunol.180:2081-2088.
  • Mueller, K.L., Thomas, M.S., Burbach, B.J., Peterson, E.J. and Shimizu, Y. 2007. Adhesion and degranulation-promoting adapter protein (ADAP) positively regulates T cell sensitivity to antigen and T cell survival. J. Immunol. 179:3559-3569.
  • Nolz, J.C., Medeiros, R.B., Mitchell, J.S., Zhu, P., Freedman, B.D., Shimizu, Y. and Billadeau, D.D. 2007. WAVE2 recruits vinculin and talin to generate high affinity integrin binding at the immunological synapse.  Mol. Cell. Biol. 27:5986-6000.
  • Burbach, B.J., Medeiros, R.B., Mueller, K.L. and Shimizu, Y. 2007. T cell receptor signaling to integrins. Immunol. Rev. 218:65-81.
  • Fischer, U.B., Jacovetty, E.L., Medeiros, R.B., Goudy, B.D., Zell, T., Swanson, J.-B., Lorez, E., Shimizu, Y., Miller, M.J., Khoruts, A. and Ingulli, E. 2007. MHC class II deprivation impairs CD4 T cell motility and responsiveness to antigen-bearing dendritic cells in vivo.  Proc. Natl. Acad. Sci. USA 104:7181-7186.
  • Gomez, T.S., Kumar, K., Medeiros, R.B., Shimizu, Y., Leibson, P.J. and Billadeau, D.D. 2007. Formins regulate the actin-related protein 2/3 complex-independent polarization of the centrosome to the immunological synapse.  Immunity 26:177-190.
  • Medeiros, R.B., Burbach, B.J., Mueller, K.L., Srivastava, R., Moon, J.J., Highfill, S., Peterson, E.J. and Shimizu, Y. 2007. Regulation of NF-kappaB activation in T cells via association of the adapter proteins ADAP and CARMA1. Science 316:754-758.
  • George, T.C., Fanning, S.L., Fitzgerald-Bocarsly, P., Medeiros, R.B., Highfill, S., Shimizu, Y., Hall, B.E., Frost, K., Basiji, D., Ortyn, W.E., Morrissey, P.J. and Lynch, D.H. 2006. Quantitative measurement of nuclear translocation events using similarity analysis of multispectral cellular images obtained in flow. J. Immunol. Methods; 311:117-129.
  • Nolz, J.C., Gomez, T.S., Zhu, P., Li, S., Medeiros, R.B., Shimizu, Y., Burkhardt, J.K., Freedman, B.D. and Billadeau, D.D. 2006. WAVE2 regulates actin cytoskeletal reorganization and CRAC-mediated calcium entry during T cell activation. Curr. Biol. 16:24-34.
  • Finkelstein, L.D., Shimizu, Y. and Schwartzberg, P.L. 2005. Tec kinases regulate T cell receptor-mediated recruitment of signaling molecules and integrin-dependent cell adhesion. J. Immunol. 175:5923-5930.
  • Rosenthal-Allieri, M.A., Ticchioni, M., Breittmayer, J.P., Shimizu, Y. and Bernard, A. 2005. Influence of beta1 integrin intracytoplasmic domains in the regulation of VLA-4-mediated adhesion of human T cells to VCAM-1 under flow conditions. J. Immunol. 175:1214-1223.
  • Medeiros, R.B., Dickey, D.M., Chung, H., Quale, A.C., Nagarajan, L.R., Billadeau, D.B. and Shimizu, Y. 2005. Protein kinase D1 and the beta1 integrin cytoplasmic domain control beta1 integrin function via regulation of Rap1 activation. Immunity 23:213-226.
  • Pribila, J.T., Itano, A.A., Mueller, K.L. and Shimizu, Y. 2004. The alpha1beta1 and alphaEbeta7 integrins define a subset of dendritic cells in peripheral lymph nodes with unique adhesive and antigen uptake properties. J. Immunol. 172:282-291.
  • Mueller, K.L., Daniels, M.A., Felthauser, A., Kao, C., Jameson, S.C. and Shimizu, Y. 2004. Cutting edge: LFA-1 integrin-dependent T cell adhesion is regulated by both Ag specificity and sensitivity. J. Immunol. 173:2222-2226.
  • Kellermann, S.-A., Dell, C.L., Hunt, S.W., III and Shimizu, Y. 2002. Genetic analysis of integrin activation in T lymphocytes. Immunol. Rev. 186:172-188.
  • Woods, M.L., Kivens, W.J., Adelsman, M.A., Qiu, Y., August, A. and Shimizu, Y. 2001. A novel function for the Tec family tyrosine kinase Itk in activation of beta1 integrins by the T cell receptor. EMBO J. 20:1232-1244.
  • Woods, M.L. and Shimizu, Y. 2001. Signaling networks regulating beta1 integrin-mediated adhesion of T lymphocytes to the extracellular matrix. J. Leukoc. Biol. 69:874-880.
  • Ottoson, N.C., Pribila, J.T., Chan, A.S.H. and Shimizu, Y. 2001. Cutting edge: T cell migration regulated by CXCR4 chemokine receptor signaling to ZAP-70 tyrosine kinase. J. Immunol. 167:1857-1861.
  • Peterson, E.J., Woods, M.L., Dmowski, S.A., Derimanov, G. Jordan, M.S., Wu, J.N., Myung, P.S., Liu, Q.-H., Pribila, J.T., Freedman, B.S., Shimizu, Y. and Koretzky, G.A. 2001. Coupling of the TCR to integrin activation by SLAP-130/Fyb. Science 293:2263-2265.