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Member Information
Mark I. Greene, MD, PhD, FRCP
John Eckman Professor of Medical Science
Academic Scientist, Department of Pathology
Office Phone: 215-898-2847
Office Fax: 215-898-2401
Email: greene@reo.med.upenn.edu
Website(s):
Education: MD 1972; PhD 1977; FRCP 1976
Keywords: Receptors, Cancer, Structure
Research and/or Clinical Interests:
Receptor function, small molecules, centrosome and associated proteins
Summary:
Dr. Greene's research is concerned with defining the principles of receptor function. An area he has concentrated on for the last 19 years involves members of the erbB gene family. Greene's laboratory discovered that pl85c-neu could associate with EGFR to form a heteromeric assembly. This heteromeric complex possessed unique properties including increased kinase activity. The heterodimers had a higher affinity for EGF than homomeric forms of the EGFR receptor and were found to represent the major signaling receptor form. Heteromer formation was found to be preferred over homomeric assembly and the ectodomains were found essential in stabilizing the dimeric species.
Greene's laboratory developed an approach to down-modulate oncoproteins which when expressed were critical for abnormal growth. This simple approach developed in the neu system involved developing monoclonal antibodies specific for the ectodomain of pl85. The approach was to take advantage of the formation of kinase active homomeric (pl85-pl85) or heteromeric (pl85c-neu-EGFr) assemblies found on malignant cells and which were active in mediating the transformed phenotype. Normal receptor species which are not activated are in a kinase inactive configuration. Furthermore, down modulation of normal receptors is not associated with cell injury. The approach was so successful that it has led to an improved treatment for advanced breast cancer.
To develop this therapeutic modality Greene has pioneered an entirely new approach to reduce macromolecules such as antibodies to small synthetic forms. His laboratory was the first to develop organic synthetic antibody-like forms which retained biological activity. These small forms are designed with the aid of structural analysis, computer modeling and synthetic chemistry. The creation of small molecular forms modeled from the complementarity determining regions has now become widely practiced.
Representative Publications:
Kumagai, T., Davis, J.G., Horie, T., O'Rourke, D., and Greene, M.I. The role of distinct p185 extracellular subdomains for dimerization with the epidermal growth factor receptor and EGF mediated signaling, Proc. Natl. Acad. Sci ., 98:5526-5531, 2001.
Zhang, H.T., Kacharmina, J.E., Miyashiro, K., Greene, M.I., and Eberwine, J. Protein Quantification from Complex Protein Mixtures Using a Novel Proteomics Methodology with Single Cell Resolution, Proc. Natl. Acad. Sci ., 98:5497-5502, 2001.
Matsunaga, T., Davis, J.G., Greene, M.I. Adult rat otic placode-derived neurons and sensory epithelium express all four erbB receptors: A role in regulating vestibular ganglion neuron viability , DNA and Cell Biology , 20:307-319, 2001
Berezov, A., Zhang, H.T., Murali, R., Greene, M.I.: Disabling ErbB Receptors with Rationally Designed Exocyclic Mimetics of Antibodies: Structure-Function Analysis, Journal of Medicinal Chemistry , 44:2565-2574, 2001.
Wang, Q., Zhang, H., Guerrette, S., Mazurek, A., Wilson, T., Kajino, K., Fischel, R. and Greene, M.I.: Adenosine nucleotide modulated interaction between hMSH2 and BRCA1. Oncogene ., 20:4640-4649, 2001.
Wu, C., O'Rourke, D. M., Feng, G., Johnson, G.R., Wang, Q., and Greene, M.I. The Tyrosine Phosphatase SHP-2 is Required for Mediating Phosphatidylinositol 3-Kinase/Akt Activatyion by Growth Factors, Oncogene ., 20:6018-6025, 2001.
Murayama, E., Takagi, Y., Ohiro, T., Davis. J.G., Greene, M.I., and Nagasawa, H. Fish otolith contains a unique structural protein, otolin-1, European Journal of Biochemistry , 269: 688-696, 2002.
Cowan, D.A., Gay, D., Bieler, B. M., Zhao, H. Yoshino, A., Davis, J.G., Tomayko, M. M., Murali, R., Greene, M. I., and Marks, M. S. Characterization of mouse tGolgin-1 (golgin-245/trans golgi p230/256kD golgin) and its upregulation during oligodendrocyte development, ¨ DNA and Cell Biology , 21 (7): 505-517, 2002.
Berezov, A., Chen, J., Liu, Q., Zhang, H., Murali, R., and Greene, M.I. Disabling Receptor Ensembles with Rationally Designed Interface Peptidomimetics, The Journal of Biological Chemistry , 277:28330-28339, 2002.
Horie, T., Shen, Yuan, Kajino, K., Gaubin, M., Bonomi, G., Mani, J.-C., Berezov, A., Piatier-Tonneau, D., Guardiola, J.,Hillard, B., Rostami, A., Greene, M. I., and Murali, R. Study of disabling T-cell activation and inhibiting T-cell mediated immunopathology reveals a possible inverse agonist activity of CD4 peptidommimetics, Experimental and Molecular Pathology, 73:93-103, 2002.
Cheng, X., Kinosaki, M., Murali, R., and Greene, M.I. The TNF Receptor Superfamily: Role in Immune Inflammation and Bone Formation, Immunologic Research: 27: 1-8, 2003.
Kumagai, T., Katsumata, M., Hasegawa, A., Funakoshi, T., Kawase, I. And Greene, M.I. Role of extracellular subdomains of p185c-neu and the epidermal growth factor receptor (EGFR) in ligand-independent association and ligand-induced transactivation. PNAS, in press 2003.
Zhang, H.T., Richter, M., and Greene, M.I. Therapeutic monoclonal antibodies for the erbB family of receptor tyrosine kinases. Cancer Biology and Therapy 1, 90-96, 2003.
Murali, R., Liu, Q., Cheng, X., Berezov, A., Richter, M., Furuuchi, K., Greene, M.I., and Zhang, H. Antibody like peptidomimetics as large scale immunodetection probes. Immunological Reviews, in press, 2003.
Cheng, X., Kinosaki, M., Murali, R. and Greene, M. I. The TNF receptor superfamily: role in immune inflammation and bone formation. Imm. Res., in press, 2003.
Saragovi, U., Fitzpatrick, D., Raktabuhr, A., Nakanishi, H., Kahn, M. and Greene, M.I.: Design and synthesis of a mimetic from an antibody complementarity-determining region. Science, 253:792-795, 1991.
Chen, S, Chrusciel, R.A., Nakanishi, H, Raktabutr, A., Johnson, M.E., Sato, A., Weiner, D., Hoxie, J., Saragovi U., Greene M.I. and Kahn, M.: Design and synthesis of a CD4 b-turn mimetic that inhibits human immunodeficiency virus viral envelope glycoprotein gp120 binding and infection of human lymphocytes. Proc. Natl. Acad. Sci. ( USA ), 89:5872-5876, 1992.
Zhang, X., Piatier-Tonneau, D., Auffray, C., Murali, R., Mahapatra, A.,Zhang, F., Maier, C.C., Saragovi, H.U. and Greene, M.I.: Synthetic CD4 excocyclic peptides antagonize CD4 holoreceptor binding and T cell activation. Nature (Biotechnology), 14:472-475, 1996.
Sim, B-C., Zerva, L., Greene, M.I. and Gascoigne, N.R.J.: Control of MHC restriction by TCR VaCDR1 and CDR2. Science, 273:963-966, 1996.
Zhang, X., Gaubin, M., Briant, L., Srikantan, V., Murali, R., Saragovi, H.U., Weiner, D., Devaux, C., Piatier-Tonneau, D. and Greene, M.I.: Synthetic CD4 exocyclics inhibit binding of human immunodeficiency virus type 1 envelope to CD4 and virus replication in T lymphocytes. Nature (Biotechnology), 15:150-154, 1997.
Takasaki , W., Kajino, Y., Kajino, K., Murali, R. and Greene, M.I.: Structure-based design and characterization of exocyclic peptidomimetics that inhibit TNFa binding to its receptor. Nature (Biotechnology), 15:1266-1270, 1997.
Briant, L., Signoret, N., Gaubin, M., Robert-Hebmann, V., Zhang, X., Murali, R., Greene, M., Piatier-Tonneau, D. and Devaux, C.: Transduction of Activation Signal That Follows HIV-1 Binding to CD4 and CD4 Dimerization Involves the Immunoglobulin CDR3-like Region in Domain 1 of CD4. Journal of, Biological Chemistry, 272(31): 19441-19450, 1997.
Maier, C.C., Bhandoola, A., Borden, W., Yui, K., Hayakawa, K. and Greene, M.I.: Unique molecular surface features of in vivo tolerized T cells. Proc. of the Nat'l Acad. of Sci. ( USA ), 95,4499-4503, 1998.
