Program Leader, Immunology Program
Professor, Department of Laboratory Medicine and Pathology
Director, Cancer Biology Training Grant

shimi002@umn.edu
612-626-6849 — office
612-626-6713 — lab
Preferred contact method: e-mail

Dr. Shimizu received his Ph.D. in Genetics in 1987 from the University of Wisconsin-Madison. He conducted postdoctoral training with Dr. Stephen Shaw at the National Cancer Institute/National Institutes of Health from 1987-1990. Following three years at the University of Michigan Medical School, Dr. Shimizu was recruited to the University of Minnesota Medical School in 1994.

Research Interests

Signal transduction and molecular mechanisms of cell adhesion and migration that regulate the immune response 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 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.

Selected Publications

Pribila JT, Itano AA, Mueller KL, Shimizu Y. The alpha1 beta1 and alpahE beta7 integrins define a subset of dendritic cells in peripheral lymph nodes with unique adhesive and antigen uptake properties. J Immunol. 2004;172:282-291.

Goda S, Quale AC, Woods ML, Felthauser A, Shimizu Y. Control of TCR-mediated activation of beta1 integrins by the ZAP-70 interdomain B region and the linker for activation of T cells adapter protein. J Immunol. 2004; 172:5379-5387.

Mueller KL, Daniels MA, Felthauser A, Kao C, Jameson SC, Shimizu Y. Cutting edge: LFA-1 integrin-dependent T cell adhesion is regulated by both Ag specificity and sensitivity. J Immunol. 2004; 173:2222-2226.

Finkelstein LD, Shimizu Y, Schwartzberg PL. Tec kinases regulate T cell receptor-mediated recruitment of signaling molecules and integrin-dependent cell adhesion. J Immunol. 2005;175:5923-5930.

Medeiros, R.B., Dickey, D.M., Chung, H., Quale, A.C., Nagarajan, L.R., Billadeau, D.B. and Shimizu, Y. Protein kinase D1 and the beta1 integrin cytoplasmic domain control beta1 integrin function via regulation of Rap1 activation. Immunity 2005;23:213-226.

Nolz JC, Gomez TS, Zhu P, Li S, Medeiros RB, Shimizu Y, Burkhardt JK, Freedman BD, Billadeau DD. WAVE2 regulates actin cytoskeletal reorganization and CRAC-mediated calcium entry during T cell activation. Curr Biol. 2006;16:24-34.

George TC, Fanning SL, Fitzgerald-Bocarsly P, Medeiros RB, Highfill S, Shimizu Y, Hall BE, Frost K, Basiji D, Ortyn WE, Morrissey PJ, Lynch DH. Quantitative measurement of nuclear translocation events using similarity analysis of multispectral cellular images obtained in flow. J Immunol Methods 2006;311:117-129.

Fostel LV, Dluzniewska J, Shimizu Y, Burbach BJ, Peterson EJ. ADAP is dispensable for natural killer cell development and function. Int Immunol. 2006;18:1305-1314.

Gomez TS, Kumar K, Medeiros RB, Shimizu Y, Leibson PJ, Billadeau, D.D. Formins regulate the actin-related protein 2/3 complex-independent polarization of the centrosome to the immunological synapse. Immunity 2007;26:177-190.

Fischer UB, Jacovetty EL, Medeiros RB, Goudy BD, Zell T, Swanson J.-B, Lorez E, Shimizu Y, Miller MJ, Khoruts A, Ingulli E. MHC class II deprivation impairs CD4 T cell motility and responsiveness to antigen-bearing dendritic cells in vivo. Proc Natl Acad Sci USA 2007;104:7181-7186.

Burbach BJ, Medeiros RB, Mueller KL, Shimizu Y. T cell receptor signaling to integrins. Immunol Rev. 2007;218:65-81.

Medeiros RB, Burbach BJ, Mueller KL, Srivastava R, Moon JJ, Highfill S, Peterson EJ, Shimizu Y. Regulation of NF-kappaB activation in T cells via association of the adapter proteins ADAP and CARMA1. Science 2007;316:754-758.

Nolz JC, Medeiros RB, Mitchell JS, Zhu P, Freedman BD, Shimizu Y, Billadeau DD. WAVE2 recruits vinculin and talin to generate high affinity integrin binding at the immunological synapse. Mol Cell Biol. 2007:27:5986-6000.

Mueller KL, Thomas MS, Burbach BJ, Peterson EJ, Shimizu Y. Adhesion and degranulation-promoting adapter protein (ADAP) positively regulates T cell sensitivity to antigen and T cell survival. J Immunol. 2007;179:3559-3569.

Martin AL, Schwartz MD, Jameson SC, Shimizu Y. Selective regulation of CD8 effector T cell migration by the p110gamma isoform of phosphatidylinositol 3-kinase (PI 3-K). J Immunol. 2008;180:2081-2088.