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Member Information
Gary Koretzky, MD, PhD
Professor, Pathology and Laboratory Medicine
University of Pennsylvania School of Medicine
Investigator and Director, Signal Transduction Program
Abramson Family Cancer Research Institute
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Website(s): http://www.uphs.upenn.edu/abramson/koretzky.html
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Keywords: Immunology, adapter proteins, T cells, SLP-76, diacylglycerol kinase zeta, PRAM-1
Research and/or Clinical Interests:
A major area of investigation for the Koretzky laboratory is understanding how signal transduction pathways in hematopoietic cells are integrated.
Summary:
A major area of investigation for the Koretzky laboratory is understanding how signal transduction pathways in hematopoietic cells are integrated. To this end, our laboratory has identified and characterized three novel adapter proteins (molecules which function by mediating intermolecular interactions). To date we have made the greatest progress examining the biology of SH2 domain containing leukocyte phosphoprotein of 76 kD (SLP-76).
Initial work in our laboratory demonstrated that overexpression of SLP-76 in a T cell line enhances efficiency of signaling via the T cell antigen receptor. Subsequent studies making use of SLP-76 deficient animals documented the critical role that this adapter protein plays in T cell development, as SLP-76 null animals have a complete block in thymocyte progression. More recent data from the laboratory have provided information about the structural features of SLP-76 most critical for its function using biochemical, molecular and genetic approaches.
In addition to a profound T cell defect, SLP-76 deficient animals also have platelet signaling abnormalities which we have been pursued both ex vivo and in vivo. Most recently we found that there are also vascular abnormalities in SLP-76 deficient animals suggesting that this protein plays a key role in endothelial cell biology. Our progress with SLP-76 has been enhanced by collaborative relationships with a number of laboratories at the University of Pennsylvania .
A second adapter protein whose study in our laboratory has also provided new insights into the biology of lymphocyte activation is adhesion and degranulation promoting adapter protein (ADAP). The cDNA for ADAP was originally cloned in our laboratory as the product of a protein which associates with SLP-76 following TCR engagement. Genetic and biochemical studies suggest that this protein plays a role coupling the T cell antigen receptor with "inside out" signaling to various integrin family members. To our knowledge, this is the first example of an adapter protein which couples cell surface receptor signaling with integrins.
One approach we employed to investigate the biology of ADAP involved identifying molecules which have homology to this adapter. We recently reported the cloning of the cDNA for PRAM-1, a myeloid specific adapter protein which shares structural similarity with ADAP. Biochemical studies suggest that this protein may have functions which overlap with those of ADAP. Mice deficient for PRAM-1 have just been generated and should provide insight into the role this protein plays in activation of cells of the myeloid lineage .
In addition to studies of adapter proteins, our laboratory is interested also in the regulation of signal transduction by enzymes which we speculate function to terminate immune cell response. To this end we have recently targeted diacylglycerol kinase zeta, a putative regulator of the Ras/MAP kinase and PKC signaling pathways. Preliminary evidence suggests that DGK-zeta deficient animals manifest enhanced T cell responsiveness, presumably due to uncontrolled activation of Ras signaling following T cell receptor engagement. We hope that these animals will prove to be an important tool as we investigate the biology of lymphoproliferative and autoimmune events.
Representative Publications:
Zhong, X.P., Hainey, E.A., Olenchock, B., Zhao, H., Topham, M.K., and Koretzky, G.A. Regulation of T cell receptor induced activation of the Ras-MAPK pathway by DGK?, J. Biol. Chem. 277:31089-31098, 2002.
Leo, L., Di Paola, J., Judd, B.A., Koretzky, G.A. and Lentz, S.R. Role of the adapter protein SLP-76 in GPVI-dependent platelet procoagulant responses to collagen. Blood, 100:2839-44, 2002.
Kovacs, B., Maus, M.V., Riley, J.L., Derimanov, G.S., Koretzky, G.A, June, C.H. and Finkel, T.H. Human CD8+ T-cells do not require the polarization of lipid rafts for activation and proliferation. Proc. Nat. Acad. Sci. USA, 99:15006-11, 2002.
Jordan, M.S., Singer A.L. and Koretzky, G.A. Adaptors as central mediators of signal transduction in immune cells. Nat. Immunol. 4:110-6, 2003.
Koretzky, G.A. T cell activation I: proximal events, Immunol. Rev. 191:5-6, 2003.
Maltzman, J.S. and Koretzky, G.A. Azathioprine: old drug, new actions, J. Clin. Invest. 111:1122-24, 2003.
Koretzky, G.A. T cell activation II. Signal integration, Immunol Rev. 192:5-6, 2003.
Abtahian, F., Guerriero, A., Sebzda, E, Lu, M-M., Zhou, R., Mocsai A., Meyers, E.E., Huang, B., Jackson, D., Ferrari, V.A., Tybulewicz, V., Lowell, C.A., Lepore, J.J., Koretzky, G.A. and Kahn, M.L. Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science, 299:247-251, 2003.
Koretzky, G.A., Abtahian, F., Derimanov, G.S., Dmowski, S.A., Guerriero, A., Jordan , M.S., Maltzman, J.S., Olenchock, B.A., Singer, A.L., Wu, J.N., Zhong, X.P. Regulation of hematopoietic cell development and activation by adapter proteins. Immunol. Res. 27:357-66, 2003.
Zhong, XP., Hainey, E.A., Jordan , M.S., Nichols, K.E., Olenchock, B.A., Shen, H, and Koretzky , GA. Enhanced T cell responses due to diacylglycerol kinase ? deficiency. Nat. Immunol. [Epub ahead of print] 2003.
Singer, AL, Bunnell, SC, Obstfeld, AE, Jordan, MS, Wu, JN, Myung, PS, Samelson, LE, Koretzky, GA. Roles of SLP-76 proline-rich domains in SLP-76 subcellular localization and T cell function. (submitted).
Zhong, X.-P., Hainey, E.A., Maltzman, J. and Koretzky, G.A. Transcriptional regulation of SLP-76: activation of SLP-76 transcription by the Ets transcription factors. (submitted).
Newbrough , S.A. , Mocsai, A., Clemens, R.A., Wu, J.N., Silverman, M.A., Singer, A.L., Lowell , C.A. , and Koretzky, G.A. SLP-76 regulates Fc? Receptor and Integrin Signaling in Neutrophils. (submitted).
Nichols, K.E., Haines, K., Myung, P.S., Dmowski, S., Meyers, E., Jumaa, H., Shedlock, D.J., Shen, H., and Koretzky G.A. Macrophage activation and Fc?-receptor signaling do not require expression of the SLP-76 and SLP-65 adaptors. (submitted)
Wu, JN, Gheith, S, Liu, Q-H, Freedman, BD, and Koretzky , GA , Peterson, EJ. Thymocyte selection requires ADAP. (in preparation).
