Association For Molecular Pathology et al v. United States Patent and Trademark Office et al

Filing 170

DECLARATION of JOSEPH SCHLESSINGER. PH.D. in Support re: 61 MOTION for Summary Judgment., 152 MOTION for Summary Judgment.. Document filed by Myriad Genetics, Lorris Betz, Roger Boyer, Jack Brittain, Arnold B. Combe, Raymond Gesteland, James U. Jensen, John Kendall Morris, Thomas Parks, David W. Pershing, Michael K. Young. (Attachments: # 1 Exhibit 1, # 2 Exhibit 2 Part 1, # 3 Exhibit 2 Part 2)(Poissant, Brian)

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ockets.Justia.com

CURRICULUM VITAE NAME: BORN: Joseph Schlessinger, Ph.D.
March 26, 1945 Yale University School of Medicine Department of Pharmacology 333 Cedar Street, SHM-B95 P.O. Box 208066 New Haven, CT 06520-8066 [phone]

LABORATORY ASSIGNMENT:

EDUCATION:
1965 - 1968 1968 - 1969 1970 -1974 B.Sc. in Chemistry and Physics, Magna Cum Laude The Hebrew University, Jerusalem M.Sc. in Chemistry, Magna Cum Laude The Hebrew University, Jerusalem Ph.D. Thesis on "Study of Chemical and Biological Systems by Circular Polarization of Fluorescence," Department of Chemical Physics, The Weizmann Institute of Science, Rehovot, Israel

CAREER:
1974 - 1976 1977 - 1978 1978 - 1980 1980 - 1985 1985 - 1991 Postdoctoral Associate at the School of Applied and Engineering Physics and Department of Chemistry, Cornell University, Ithaca, NY Visiting Scientist at the Immunology Branch of the National Cancer Institute of the National Institutes of Health, Bethesda, MD Senior Scientist, Department of Chemical Immunology The Weizmann Institute of Science, Rehovot, Israel Associate Professor, Department of Chemical Immunology The Weizmann Institute of Science, Rehovot, Israel Professor, Department of Chemical Immunology The Ruth and Leonard Simon Professor of Cancer Research The Weizmann Institute of Science, Rehovot, Israel Research Director, Rorer Biotech. Inc., Rockville, MD. and King of Prussia, PA Founder, SUGEN, Inc. Professor and Chairman, Department of Pharmacology The Milton and Helen Kimmelman Chair NYU Medical Center Director of the Skirball Institute for Biomolecular Medicine NYU Medical Center Founder, Plexxikon Inc. Professor and Chairman, Department of Pharmacology The William H. Prusoff Professor and Chair Yale University School of Medicine Founder, Kolltan, Inc.
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1985 - 1990 1991 1990 - 2001

1998 - 2001 2001 2001 - Present

2008

PROFESSIONAL HONORS AND NAMED LECTURES:
1973 1980 1982 1983 1984 1986 1988 1993 1993 1993 1994 1994 1994 1994 1994 1995 1995 1995 1995 1995 1996 1997 1998 1999 1999 1999 1999 2000 2000 2000 2000 2000 2000 2000 2001 2001 2001 2002 2003 2003 2003 2004 2005 2005 2006 2006 2006 2006 2006 2006 2006 Michael Landau Prize for Ph.D. Thesis Sara Leedy Prize Elected to EMBO Hestrin Prize Levinson Prize Keynote Presidential Lecture of the Endocrine Society The Fourth Kroc Lecture, Joslin Center, Harvard Medical School The E.J. Cohn Lecture, Harvard Medical School The E. Fisher Lecture, University of Geneva The Lamport Lecture, University of Seattle, Washington The Harvey Lecture, Rockefeller University, New York The Deans lecture, Mount Sinai Medical School, New York Opening Keynote Lecture, American Society for Biochemistry and Molecular Biology, Washington, D.C. The Feigen Lecture, Stanford University Medical School The Randall Lecture, University of Pennsylvania Sigma-Tau Lecture, Rome Opening Keynote Lecture: HHMI Symposium on Signal Transduction Opening Keynote Lecture, Whitehead Institute Symposium The Ciba-Drew Award Antoine Lacassagne Prize The Lindner Lecture, Weizmann Institute The Burroughs Wellcome Lecture, Indiana University The Juan March Lecture, Madrid, Spain The Distinguished Service Award, Miami Nature Biotechnology The Bayer Lecture, University of California, Berkeley The Sixth Ray A. and Robert L. Kroc Lecture University of Massachusetts Medical School Honorary Member, The Japanese Biochemical Society Elected to Neurosciences Research Program, La Jolla, California The NIH Director's Lecture The Distinguished Speaker Program, University of Texas Health Science Center Elected to the National Academy of Science Sixteenth Annual Kenneth F. Naidorf Memorial Lecture, Columbia University The Taylor Prize The Severo Ochoa Lecture, Madrid, Spain Elected to the American Academy of Arts and Sciences The First Alton Meister Memorial Lecture, Weil Medical College of Cornell University The Fritz Lipmann Lecture, German Society for Biochemistry and Molecular Biology Honorary Doctor of Philosophy, Honoris Causa, University of Haifa Aventis Perspective Lecture, Frankfurt, Germany The Karl Beyer Lectures, University of Wisconsin, Madison The Asher Rothstein Lecture, The Hospital of Sick Children Research Institute, Toronto, Canada Elected to the European Academy of Sciences Elected to the Institute of Medicine of the National Academies Distinguished Lecture on Molecular Targets for Cancer Prevention, AACR, Baltimore, Maryland The 33rd Annual Calbiochem­UCSD Lectureship Series Dan David Prize The 13th John F. Enders Lecture, Harvard Medical School The 41st Annual Mager Lecture, Hebrew University Elected as a foreign member of the Russian Academy of Sciences Inaugural Pfizer Lecture, Ann Arbor, Michigan The Keith Porter Lecture, ASCB Annual Meeting, San Diego, California
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2008 2008 2008 2008 2009 2009

Elected as a foreign member of the Croatian Academy of Science NIH-WALS Lecture, Bethesda, Maryland. Helen Coley-Nauts Lecture, Moscow State University 24th Medical Scientist Lecture Series, UC Irvine Medal of Danica Hrvatska Order, Republic of Croatia Ef Racker Lecture in Biology and Medicine, Cornell University

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EDITORIAL BOARDS (Past and present):
EMBO Journal Cell Molecular Cell Genes and Development Molecular and Cellular Biology Molecular Biology of the Cell Journal of Biological Chemistry Cancer Research Journal of Cell Biology Growth Factors Protein Engineering Cell Growth & Differentiation Journal of Cell Physiology

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PUBLICATIONS:
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. A.Y. Meyer and J. Schlessinger. Three chromophore compounds. I. Reductive transformations of the 3,5diaryl-2cyclohexen-1-ones. Israel J. Chem. 8, 671 (1970). A.Y. Meyer, J. Schlessinger and E.D. Bergmann. Composes a trois chromophores. II. Analyze geometriques des cyclohexanones flexibles. Chim. Phys. 68, (1971). A.Y. Meyer and J. Schlessinger. Three chromophore compounds. III. Stereochemical studies of 3,5disubstituted cyclohexanones. Tetrahedron 27, 2191 (1971). J. Schlessinger and I.Z. Steinberg. Circular polarization of fluorescence of probes bound to chymotrypsin. Change in asymmetric environment upon electronic excitation. Proc. Natl. Acad. Sci. USA 69, 769 (1972). A. Gafni, J. Schlessinger and I.Z. Steinberg. Fluorescence and optical activity of acridine dyes bound to poly-A and DNA. Israel J. Chem. 11, 423 (1973). J. Schlessinger and A. Levitzki. Molecular basis of negative cooperativity in rabbit muscle glyceraldehyde-3phosphate dehydrogenase. J. Mol. Biol. 82, 547 (1974). J. Schlessinger, I.Z. Steinberg and I. Pecht. Antibody-hapten interactions: Circular and linear polarization of the fluorescence of dansyl bound to anti-dansyl antibodies. J. Mol. Biol. 87, 725 (1974). I.Z. Steinberg, J. Schlessinger and A. Gafni. Application of circular polarization of luminescence to the study of peptides, polypeptides and proteins. In: Peptides, Polypeptides and Proteins, eds. E.R. Blout, F.A. Bovey, M. Goodman and N. Lotan (John Wiley & Sons, Inc., 1974) pp. 351-369. J. Schlessinger and A. Warshel. Calculation of CD and CPL spectra as a tool for evaluation of the conformational differences between ground and excited states of chiral molecules. Chem. Phys. Lett. 28, 380 (1974). J. Schlessinger, A. Gafni and I.Z. Steinberg. Optical rotary power in the ground state and electronically excited state of diketopiperazines containing aromatic side-chains. J. Am. Chem. Soc. 96, 7396 (1974). A. Levitzki and J. Schlessinger. Cooperative ligand binding in a dimerizing system. Biochemistry 13, 5214 (1974). D. Givol, I. Pecht, J. Hochman, J. Schlessinger and I.Z. Steinberg. Conformational changes in the Fab and Fc of the antibody as a consequence of antigen binding. In: Progress in Immunology II, Vol. 1, eds. Brent and Holbrow (North-Holland Publ. Co., 1974) pp. 39-48. J. Schlessinger, I.Z. Steinberg and A. Levitzki. A comparative study of NAD+ binding sites in dehydrogenases by circular polarization of fluorescence. J. Mol. Biol. 91, 523-528 (1975). J. Schlessinger, R.S. Roche and I.Z. Steinberg. A study of subtilisin types Novo and Carlsberg by circular polarization of fluorescence. Biochemistry 14, 255-262 (1975). A. Grinvald, J. Schlessinger, I. Pecht and I.Z. Steinberg. Homogeneity and variability in the structure of azurin molecules studied by fluorescence decay and circular polarization. Biochemistry 14, 1921 (1975). A. Gafni, H. Hardt, J. Schlessinger and I.Z. Steinberg. Circular polarization of chlorophyll in solution and in native structure. Biophys. Biochem. Acta 387, 256-264 (1975). J. Schlessinger, I.Z. Steinberg, D. Givol, J. Hochman and I. Pecht. Antigen induced conformational changes in antibodies and their Fab fragments studied by circular polarization of fluorescence. Proc. Natl. Acad. Sci. USA 72, 2775-2779 (1975). J. Schlessinger, I.Z. Steinberg, D. Givol and J. Hochman. Subunit interaction in antibodies and antibody fragments studied by circular polarization of fluorescence. FEBS Lett. 52, 231-235 (1975). J.-C. Jaton, H. Huser, D.G. Braun, D. Givol, I. Pecht, and J. Schlessinger. Conformational changes induced in a homogeneous anti-type III pneumoccocal antibody by oligoaccharides of increasing size. Biochemistry 14, 5312-5325 (1975). A. Gafni, J. Schlessinger and I.Z. Steinberg. Variation of the linear polarization across the emission band of nicotinamide 1,N°-ethenoadenid dinucleotide bound to dehydrogenases. J. Am. Chem. Soc. 101, 463-467 (1979). J.-C. Jaton, H. Huser, W.F. Riesen, J. Schlessinger and D. Givol. The binding of complement by complexes formed between a rabbit antibody and oligosaccharides of increasing size. J. Immunol. 116, 1363-1366 (1976). W.F. Riesen, J. Schlessinger and J.-C. Jaton. Binding of phosphorylcholin to an IgM Waldenstrom studied by fluorescence spectroscopy and circular dichroism. Biochemistry 15, 3391-3395 (1976). J. Schlessinger, D.E. Koppel, D. Axelrod, K. Jacobson, W.W. Webb and E.L. Elson. Lateral transport on cell membranes. The mobility of Concanavalin A receptors on myoblasts. Proc. Natl. Acad. Sci. USA 73, 24092413 (1976). 5

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E.L. Elson, J. Schlessinger, D.E. Koppel, D. Axelrod and W.W. Webb. Measurement of lateral transport on cell surfaces. In: Membranes and Neoplasia: New Approaches and Strategies. (Alan R. Liss. Inc., N.Y. 1976) pp. 137-147. D. Axelrod, D.E. Koppel, J. Schlessinger, E.L. Elson and W.W. Webb. Mobility measurements by analysis of fluorescence photobleaching recovery kinetics. Biophys. J. 16, 1055-1069 (1976). J. Schlessinger, D. Axelrod, D.E. Koppel, E.L. Elson and W.W. Webb. Lateral transport of proteins and lipid probe on myoblast plasma membrane. Science 195, 307-309 (1977). D.E. Koppel, D. Axelrod, J. Schlessinger, E.L. Elson and W.W. Webb. Dynamics of fluorescence marker as a probe of mobility. Biophys. J. 16, 1315-1329 (1976). D. Axelrod, P. Ravdin, D.E. Koppel, J. Schlessinger, W.W. Webb, E.L. Elson and T.R. Podleski. Lateral motion of fluorescent-labeled acetyocholine receptors in membrane of developing muscle fibers. Proc. Natl. Acad. Sci. USA 73, 4594-4598 (1976). J. Schlessinger, H. Metzger, W.W. Webb and E.L. Elson. The lateral motion and valence of Fc receptors on rat peritoneal mast cells. Nature 264, 550-552 (1976). H. Metzger, E.L. Elson, C. Isersky, M. Mendoza, S. Newman, G. Rossi and J. Schlessinger. Valence, mobility and membrane integration of the cell surface receptor for immunoglobulin. Proc. IX Int. Congr. Allergology, Buenos Aires (Oct. 1977). J. Schlessinger, E.L. Elson, W.W. Webb, I. Yahara, U. Rutishauser and G.M. Edelman. Receptor diffusion on cell surface after modulation by locally bound Con A. Proc. Natl. Acad. Sci. USA 74, 1100-1114 (1977). J. Schlessinger, L.S. Barak, G.G. Hames, K.M. Yamada, I. Pastan, W.W. Webb and E.L. Elson. Mobility and distribution of a cell surface glycoprotein and its interaction with other membrane components. Proc. Natl. Acad. Sci. USA 74, 2909-2913 (1977). D. Wolf, J. Schlessinger, E.L. Elson, W.W. Webb, R. Blumenthal and P. Henkart Diffusion and patching of macromolecules on planar lipid bilayer membranes. Biochemistry 16, 3476-3483 (1977). E.L. Elson and J. Schlessinger. Long range motions on cell surfaces. In: The Neurosciences: Fourth Study Program. eds. F.O. Schmidt and F. Worden, Cambridge, Ma.: (The MIT Press) pp. 691-701 (1979). J. Schlessinger and I.Z. Steinberg. Heterogeneity of protein fluorescence as revealed by CPL spectroscopy. Biophys. J. 19, 80-82 (1977). Y. Shechter, J. Schlessinger, S. Jacobs, K.S. Chang and P. Cuatrecasas. Fluorescent labeling of hormone receptors on viable cells: The preparation and properties of highly fluorescent derivatives of epidermal growth factor and insulin. Proc. Natl. Acad. Sci. USA 75, 2135-2139 (1978). J. Schlessinger, Y. Shechter, M.C. Willingham and I. Pastan. Direct visualization of the binding aggregation and internalization of insulin and epidermal growth factor on living fibroblastic cells. Proc. Natl. Acad. Sci. USA 75, 2659-2663 (1978). J. Schlessinger, Y. Shechter, P. Cuatrecasas and I. Pastan. Quantitative determination of the lateral diffusion coefficients of the hormone receptor complexes of insulin and epidermal growth factor on the plasma membrane of cultured fibroblasts. Proc. Natl. Acad. Sci. USA 75, 5353-5357 (1978). F.R. Maxfield, J. Schlessinger, Y. Shechter, I. Pastan and M.C. Willingham. Insulin, epidermal growth factor and macroglobulin rapidly collect in the same patches on the surface of cultured fibroblasts and are internalized together. Cell 14, 805-810 (1978). J. Schlessinger. Receptor aggregation as a mechanism for transmembrane signaling: Models for hormone action. In: Physical Chemical Aspects of Cell Surface Events in Cellular Regulation (eds. R. Blumenthal and C. Delisi, Elsevier North Holland, Amsterdam) pp. 89-111 (1979). Y. Shechter, L. Hernandez, J. Schlessinger and P. Cuatrecasas. Epidermal growth factor: Local aggregation of hormone receptor complexes is required for activation. Nature 278, 835 (1979). S.W. deLaat, P.T. Van der Saag, E.L. Elson and J. Schlessinger. Lateral mobility or membrane lipids and proteins during the cell cycle of neuroblastoma cells. Proc. Natl. Acad. Sci. USA 77, 1526-1528 (1980). S.W. deLaat, P.T. Van der Saag, E.L. Elson and J. Schlessinger. Lateral mobility of membrane components in differentiating neuroblastoma cells. Biochim. Biophys. Acta 558, 247-250 (1979). P. Dragsten, P. Henkart, R. Blumenthal, J. Weinstein and J. Schlessinger. Lateral diffusion of surface immunoglobulin, Thy-1 antigen, and A lipid probe in lymphocyte plasma membrane. Proc. Natl. Acad. Sci. USA 76, 5163-5167 (1979). J. Schlessinger and E.L. Elson. Fluorescence methods for studying membrane dynamics. In: Biophysics methods of Exp. Physics. eds. E. Ehrenstein and H. Lecar, Academic Press, N.Y., 20, 197-226 (1982). J. Schlessinger and Y. Shechter. Possible role for receptor motion in the mechanism of action of insulin and epidermal growth factor. In: Hormonal Control of Epithelial Transport. INSERM 85, 55-62 (1979). 6

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T.R. Podleski, J. Greenberg, J. Schlessinger and K.M. Yamada. Fibronectin delays the fusion of L6 myoblasts. Exp. Cell. Res. 122, 317-326 (1979). J. Schlessinger and E.L. Elson. Quantitative methods for studying the mobility and distribution of receptors on viable cells. In: Receptors and Recognition. eds. P. Cuatrecasas and M.F. Greaves, Chapman and Hall, London 9, 158-170 (1980). F.R. Maxfield, M.C. Willingham, J. Schlessinger, P.J.A. Davies and I. Pastan. In: Hormones and Cell Cultures. Cold Spring Harbor Conferences on Cell Proliferation 6, 159-167 (1979). A. Levi, Y. Shechter, E.J. Neufeld and J. Schlessinger. Mobility, clustering and transport of nerve growth factor in embryonal sensory cells and in a sympathetic cell line. Proc. Natl. Acad. Sci. USA 77, 3465-3473 (1980). J. Schlessinger, A. Levi, I. Yuli, M. Gabbay and Y. Shechter. Common and distinct aspects in the regulation of action of specific growth factors. In: Control Mechanism in Animal Cells. (eds. L. Jimenez de Asua, R. Levi- Montalcini, R. Shields and S. Iacobelli. Raven Press, N.Y.) pp. 27-34 (1980). J. Schlessinger, E. Van Obberghen and G.R. Kahn. Insulin and antibodies against insulin receptors cap on the membrane of cultured human lymphocytes. Nature 286, 729-731 (1980). J. Schlessinger. The mechanism and role of hormone-induced clustering of membrane receptors. Trends in Biochem. Sci. 5, 210-214 (1980). Y. Yarden, M. Gabbay and J. Schlessinger. Primary amines do not prevent the endocytosis of epidermal growth factor into 3T3 fibroblasts. Biophys. Biochem. Acta 674, 188-203 (1981). J. Schlessinger. Dynamics of hormone receptors on cell membrane. Ann. N.Y. Acad. Sci. 366, 274-284 (1981). J. Schlessinger and B. Geiger. Epidermal growth factor induces redistribution of actin and -Actinin in human epidermal carcinoma cells. Exp. Cell. Res. 134, 273-279 (1981). D. Tramontano, A. Avivi, F.S. Ambesi-Impiombato, L. Barak, B. Geiger and J. Schlessinger. Thyrotropin induces changes in the morphology and the organization of microfilament structure in cultured thyroid cells. Exp. Cell. Res. 137, 269-275 (1982). A.B. Schreiber, I. Lax, Y. Yarden, Z. Eshhar and J. Schlessinger. Monoclonal antibodies against the receptor for epidermal growth factor induce early and delayed effects of epidermal growth factor. Proc. Natl. Acad. Sci. USA 78, 7535-7539 (1981). A.B. Schreiber, Y. Yarden, Z. Eshhar and J. Schlessinger. A non-mitogenic analogue of epidermal growth factor, enhances the phosphorylation of endogenous membrane proteins. Biochim. Biophys. Res. Commun. 101, 517-523 (1981). J. Schlessinger, Y. Yarden, L. Barak, I. Lax, M. Gabbay and B. Geiger. Epidermal growth factor: New facts concerning its mode of action. Hormone and Cell Regulation 5, 197-207 (1981). eds. J.E. Dumont and J. Nunez, Elsevier/North Holland, Biomedical Press. A. Avivi, D. Tramontano, F.S. Ambesi-Impiombato and J. Schlessinger. Direct visualization of membrane clustering and endocytosis of thyrotropin into cultured thyroid cells. Mol. Cell Endocrin. 25, 55-71 (1982). A. Avivi, D. Tramontano, F.S. Ambesi-Impiombato and J. Schlessinger. cAMP modulates thyrotropinreceptor clustering and thyrotropin-activity in cultured thyroid cells. Science 214, 1237-1239 (1981). R. Zidovetzki, Y. Yarden, J. Schlessinger and T. Jovin. Rotational diffusion of epidermal growth factor complexed to its surface receptor reflects the rapid microaggregation and endocytosis of occupied receptors. Proc. Natl. Acad. Sci. USA 78, 6981-6985 (1981). I. Vlodavsky, A. Levi, I. Lax, Z. Fuks and J. Schlessinger. Induction of cell attachment and morphological differentiation in a pheochromocytoma cell line and embryonal sensory cells by the extracellular matrix. Dev. Biol. 93, 285-300 (1982). J. Schlessinger, A.B. Schreiber, I. Lax, Y. Yashu-Gan, T.A. Libermann, G.M. Hillman, A. Levi and Y. Yarden. Molecular steps in the action and regulation of epidermal growth factor: A cellular mitogen. In: Membranes in Growth and Development. Prog. in Clin. and Biol. Res. eds. L. Bolis and J.F. Hoffman. Alan R. Liss, Inc., N.Y. 91, 359-429 (1982). Y. Yarden, A.B. Schreiber and J. Schlessinger. A non-mitogenic analogue of epidermal growth factor induces various early responses mediated by epidermal growth factor. J. Cell Biol. 92, 687-693 (1982). G.M. Hillman and J. Schlessinger. The lateral diffusion of epidermal growth factor complexes to its surface receptors does not account for the thermal sensitivity of patch formation, and endocytosis. Biochemistry 21, 1667-1672 (1982). W.H. Moolenaar, Y. Yarden, S.W. deLaat and J. Schlessinger. Epidermal growth factor-induced Na+ influx in human fibroblasts is electrically silent. J. Biol. Chem. 257, 8502-8506 (1982). 7

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A. Avivi, J. Schlessinger, M. Shemesh and B. Geiger. The interaction of cultured thyroid cells of early bovine embryos with TSH and thyroglobulin. Endocrinology 111, 589-598 (1982). B. Geiger, Z. Avnur and J. Schlessinger. Restricted mobility of membrane constituents in cell-substrate focal contacts of chicken fibroblasts. J. Cell Biol. 93, 495-500 (1982). T.E. Kreis, B. Geiger and J. Schlessinger. The mobility of microinjected fluorescently labeled actin within specific domains of living chicken gizzard cells. Cell 29, 835-845 (1982). J. Schlessinger, A.B. Schreiber, A. Levi, I. Lax, T. Libermann and Y. Yarden. Regulation of cell proliferation by epidermal growth factor. Critical reviews in Biochemistry (CRC), 14, 93-112 (1983). J. Schlessinger, A.B. Schreiber, T.A. Libermann, I. Lax, A. Avivi and Y. Yarden. Polypeptide hormone induced receptor clustering and internalization. In: Cell Membranes: Methods and Reviews. eds. E.L. Elson,W. Frazier and L. Glaser. Plenum Publishing Corp., N.Y., 1, 117-144 (1983). A.B. Schreiber, T. Libermann, I. Lax, Y. Yarden and J. Schlessinger. Biological role of EGF-receptor clustering: Investigation with monoclonal anti-EGF-receptor antibodies. J. Biol. Chem. 258, 846-853 (1983). J. Schlessinger. The lateral and rotational diffusion of the EGF-receptor complex: Relationship to receptor mediated endocytosis. Biopolymers 22, 347-353 (1983). A.B. Schreiber, J. Schlessinger and M. Edidin. Interaction between major histocompatibility complex antigens and epidermal growth factor receptor on human cells. J. Cell Biol. 84, 725-731 (1984). J. Hapgood, T.A. Libermann, A.B. Schreiber, I. Lax, Y. Yarden, Z. Naor and J. Schlessinger. Monoclonal antibodies against EGF-receptor induce prolactin synthesis incultured rat pituitary cells. Proc. Natl. Acad. Sci. USA 80, 645-650 (1983). T. Sherson, T.E. Kreis, J. Schlessinger, U.Z. Littauer, G.G. Borisy and B. Geiger. Dynamic interactions of fluorescently labeled microtubule associated proteins in living cells. J. Cell Biol. 99, 425-434 (1984). A. Komoriya, M. Hortsch, C. Meyers, M. Smith, H. Kanety and J. Schlessinger Biologically active fragments of epidermal growth factor: Localization of a major binding region. Proc. Natl. Acad. Sci. USA 81, 13511355 (1984). J. Schlessinger. Mobilities of cell membrane proteins: How are they modulated by the cytoskeleton. Trends in Neuro. Sci. 6, 360-363 (1983). T.A. Libermann, N. Razon, A.D. Bartal, Y. Yarden, J. Schlessinger and M. Soreq Expression of epidermal growth factor receptors in human brain tumors. Cancer Res. 44, 753-760 (1984). Y. Yarden and J. Schlessinger. Phosphoamino acid specificity of the EGF-receptor kinase system in normal mitogenically responsive human cells. Cell Biol. Int. Report 7, 533-534 (1983). M. Hortsch, J. Schlessinger, E. Gootwine and C.G. Webb. Appearance of a functional EGF-receptor kinase during Rodent Embryogenesis. EMBO J. 2, 1937-1941 (1983). C.Ho. Gooi, J. Schlessinger, I. Lax, Y. Yarden, T.A. Libermann and T. Feizi Monoclonal antibody reactive with the human epidermal growth factor receptor recognizes the blood-group A antigen. Bioscience Reports 3, 1045-1052 (1984). M. Burmeister, A. Avivi, J. Schlessinger and M. Soreq. Production of EGF-containing polypeptides in Xenopus oocytes microinjected with submaxillary gland mRNA. EMBO J. 3, 1499-1505 (1984). H. Meiri, I. Zeitoun, H.H. Grunhagen, V. Lev-Ram, A. Eshhar and J. Schlessinger. Monoclonal antibodies associated with sodium channel block nerve impulse and stain nodes of Ranvier. Brain Res. 310, 168-173 (1984). I. Lax, M. Bar-Eli, Y. Yarden, T.A. Libermann and J. Schlessinger. Antibodies to two defined regions of pp60src interact specifically with the EGF-receptor kinase system. Proc. Natl. Acad. Sci. USA 81, 59115915 (1984). S. Spiegel, J. Schlessinger and P.H. Fishman. Incorporation of fluorescent ganglosides into human fibroblasts: Mobility, fate and interaction with fibronectin. J. Cell Biol. 99, 699-704 (1984). J. Downward, Y. Yarden, E. Mayes, G. Scrace, N. Totty, P. Stockwell, A. Ullrich, J. Schlessinger and M.D. Waterfield. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature 307, 521-526 (1984). J. Schlessinger, I. Lax, Y. Yarden, H. Kanety and T.A. Libermann. Monoclonal antibodies against the membrane receptor for epidermal growth factor: A versatile tool for structural and mechanistic studies. In: Receptors and Recognition Volume on "Antibodies to Receptors: Probes for Receptor, Structure and Function. "Chapman and Hall, London, ed. M. Greaves. 17, 279-303 (1984). J. Schlessinger, I. Lax, S. Gill, R. Kris, T.A. Libermann, M. Bar-Eli, I. Harari and Y. Yarden. The membrane receptor for EGF: Structural and functional studies In: Mechanisms of Receptor Regulation, a 8

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volume in the Smith Kline and French Laboratories Research Symposia. eds. S.T. Crooke and G. Poste. Plenum Press, N.Y. (1984). Y. Yarden, I. Harari and J. Schlessinger. Purification of an active EGF-receptor kinase with monoclonal antireceptor antibodies. J. Biol. Chem. 260, 315-319 (1985). A. Ullrich, L. Coussens, J.S. Hayflick, T.J. Dull, A. Gray, J. Schlessinger, J. Downward, E.L.V. Mayes, N. Whittle, M.D. Waterfield and P.H. Seeburg. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A-431 epidermoid carcinoma cells. Nature 309, 418-425 (1984). R. Kris, A. Avivi, M. Bar-Eli, P. Carmi, J. Schlessinger and A. Raz. The expression of Ki-ras oncogene in tumor cell variants exhibiting different metastatic capabilities. Inter. J. Cancer 35, 227-230 (1985). T.A. Libermann, H.R. Nussbaum, N. Razon, R. Kris, I. Lax, M. Soreq, N. Whittle, M.D. Waterfield, A. Ullrich and J. Schlessinger. Amplification, enhanced expression and possible rearrangement of the EGFreceptor gene in primary human brain tumors of glial origin. Nature 313, 144-147 (1985). H.C. Gooi, E.F. Hounsell, I. Lax, R.M. Kris, T.A. Libermann, J. Schlessinger, J.D. Sato, T. Kawamoto, J. Mendelsohn and T. Feizi. Bioscience Reports 5, 83-94 (1985). R. Kris, I. Lax, M. Gullick, M.D. Waterfield, A. Ullrich, M. Fridkin and J. Schlessinger. Antibodies against a synthetic peptide as a probe for the kinase activity of the avian EGF-receptor and V-erb-B proteins. Cell 40, 619-625 (1985). Y. Yarden and J. Schlessinger. EGF-receptor self phosphorylation is mediated by an intermolecular allosteric process. Growth Factors in Biology and Medicine. Pitman Publishing Ltd. London. 116, 23-45 (1985). B. Geiger, Z. Avnur, T.E. Kreis, and J. Schlessinger. The dynamics of cytoskeletol organization in areas of cell contact in "Cell and Muscle mortality", ed. Jerry W. Shaw, Plenum Press New York and London. 5, 195228 (1984). T.E. Kreis, Z. Avnur, J. Schlessinger and B. Geiger. The dynamic properties of membrane-cytoskeleton interaction in cell substrate focal contacts of cultured fibroblasts. Proc. of Cold Spring Harbor Symposia (1984). R.M. Kris, T.A. Libermann, A. Avivi and J. Schlessinger. Growth factors, growth factor receptors and oncogenes. Biotechnology 3, 135-140 (1985). Lax, R. Kris, I. Sasson, A. Ullrich, M.J. Hayman, H. Beug and J. Schlessinger. Activation of C-erb-B in avian leukosis virus-induced erythroblastosis leads to the expression of a truncated EGF-receptor kinase. EMBO J. 4, 3179-3182 (1985). E. Livneh, L. Glazer, D. Segal, J. Schlessinger and B.-Z. Shilo. The Drosphila EGF-receptor gene homolog: Conversion of both hormone binding and kinase domains. Cell 40, 599-607 (1985). J. Schlessinger. Purification and functional analysis of EGF-receptor with immunological probes in "Monoclonal antibodies 84: Biological and clinical applications" Kurtis, Milano, Ed. A. Pinchera, G. Doria, F. Dammacco, A. Bargellesi, pp. 313-329 (1984). T.A. Libermann, H.R. Nussbaum, N. Razon, R. Kris, I. Lax, H. Soreq, N. Whittle, M.D. Waterfield, A. Ullrich and J. Schlessinger. Amplification and overexpression of the EGF-receptor gene in primary human glioblastomas. In "Growth Factors: Structure and Function: C.R. Hopkins and C.R. Hughes. The Company of Biologists, Ltd., J. Cell Sci. Suppl. 3, 161-173 (1985). L. Coussens, T.L. Yang-Feng, Y.-C. Liao, E. Chen, A. Gray, J. McGrath, P.H. Seeburg, T.A. Libermann, J. Schlessinger, U. Francke, A. Levinson and A. Ullrich. Tyrosine-kinase receptor with extensive homology to EGF-receptor shares chromosomal location with neu oncogene. Science 230, 1132-1139 (1985). P.J. Parker, J. Downward, H.S. Earp, W. Gullick, P. Seeburg, A. Ullrich, R. Kris, J. Schlessinger, and M.D. Waterfield. Structure and function of the EGF receptor and its interaction with protein kinases A and C. In: Cancer Cells 3: Growth Factors and Transformation, Cold Spring Harbor Laboratory, New York, 353-358. (1985). W.J. Guillick, J. Downward, P.J. Parker, N. Whittle, R. Kris, J. Schlessinger, A. Ullrich, and M.D. Waterfield. The structure and function of the epirdermal growth factor receptor studied by using antisynthetic peptide antibodies. Proceedings of the Royal Society of London 226, 127-134. (1985). A. Ullrich, A.W. Tam, M.D. Waterfield, Y. Yarden, T.A. Libermann, and J. Schlessinger. Structural features of epidermal growth factor precursor and receptor domains and their possible significance. In: Leukemia: Recent Advances in Biology and Treatment, Alan R. Liss, Inc., 277-292. (1985). K. Miller, J. Beardmore, H. Kanety, J. Schlessinger and C.R. Hopkins. Localization of the epidermal growth factor (EGF) receptor within the endosome of EGF-stimulated epidermoid carcinoma (A-431) cells. J. Cell Biol. 102, 500-509 (1986).

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111. E.G. Bremer, J. Schlessinger and S. Itiroh Hakamori. Ganglioside-mediated modulation of cell growth: Specific effects of GM3 on tyrosine phosphorylation of the epidermal growth factor receptor. J. Biol. Chem. 261, 2434-2440 (1986). 112. R. Zidovezki, Y. Yarden, J. Schlessinger and T.M. Jovin. Micro-aggregation of hormone-occupied epidermal growth factor receptors on plasma membrane preparations. EMBO J. 5, 247-250 (1986). 113. E. Livneh, M. Benveniste, R. Prywes, S. Felder, Z. Kam and J. Schlessinger. Large deletions in the cytoplasmic kinase domain of EGF-receptor do not affect its lateral mobility. J. Cell Biol. 103, 327-331 (1986). 114. E. Livneh, R. Prywes, O. Kashles, N. Reiss, I. Sasson, Y. Mory, A. Ullrich and J. Schlessinger. Reconstitution of the human EGF-receptor and its deletion mutants in cultured hamster cells. J. Biol. Chem. 261, 12490-12497 (1986). 115. R. Prywes, E. Livneh, A. Ullrich and J. Schlessinger. Mutations in the cytoplasmic domain of EGF-receptor affect EGF-binding and receptor internalization. EMBO J. 5, 2179-2190 (1986). 116. H. Reidel, T.J. Dull, J. Schlessinger and A. Ullrich. A chimeric receptor allows insulin to stimulate tyrosine kinase activity of epidermal growth factor receptor. Nature 324, 68-70 (1986). 117. N. Reiss, H. Kanety and J. Schlessinger. Five enzymes of the glycolytic pathway serve as substrates for purified EGF-receptor kinase. Biochem. J. 239, 691-697 (1986). 118. J. Schlessinger. Regulation of cell growth by the EGF-receptor in "Oncongenes and growth control" eds. Kahn, P. and Graf., T. Springer-Verlag, Heidelberg, 116. 77-84 (1986). 119. J. Schlessinger. Allosteric regulation of the EGF-receptor kinase. J. Cell Biol. 103, 2067-2072 (1986). 120. Y. Yarden and J. Schlessinger. Self-phosphorylation of EGF-receptor: Evidence for a model of intermolecular allosteric activation. Biochemistry 26, 1434-1442 (1987). 121. Y. Yarden and J. Schlessinger. Epidermal growth factor induces rapid, reversible aggregation of the purified EGF-receptor. Biochemistry 26, 1443-1451 (1987). 122. J.L. Carpentier, A.R. Rees, M. Gregoriou, R. Kris and J. Schlessinger. Subcellular distribution of external and internal domains of EGF-receptor in A-431 cells. Exp. Cell Res. 166, 312-326 (1986). 123. E. Chen, L. Coussens, Y.C. Liao, D. Smith, T.L. Yang-Feng, J. McGrath, C. Van Beversen, I. Verma, T. Libermann, J. Schlessinger, A. Francke, A. Levinson and A. Ullrich. Structural features of growth factor receptors with oncogenic potential. Biochem. Soc. Symp. 52, 65-82 (1986). 124. M. Popliker, A. Shatz, A. Avivi, A Ullrich, J. Schlessinger and C. Webb. Onset of endogenous synthesis of epidermal growth factor in neonatal mice. Develop. Biol. 119, 38-44 (1987). 125. A. Ullrich, H. Riedel, Y. Yarden, L. Coussens, A. Gray, T. Dull, J. Schlessinger, M.D. Waterfield, and P.J. Parker. Protein Kinases in cellular signal transduction: Tyrosine kinase growth factor receptors and protein kinase C. Cold Spring Harbor Symposia on Quantitative Biology. 51, 713-724. (1986). 126. H. Riedel, Y. Yarden, L. Coussens, L. Lee, A. Gray, T. Dull, J. Schlessinger, A. Ullrich. Structural and functional analysis of cell surface receptors with tyrosine kinase activity. In: Cell Cylce and Oncogenes, Tanner, W. and Gallwitz, D., Springer Verlag, Heidelberg, 157-171. 127. H. Reidel, J. Schlessinger and A. Ullrich. A chimeric ligand binding v-erb-B/EGF-receptor retains transforming potential. Science 236, 197-200 (1987). 128. O. Bernard, B. Fazekas de St. Groth, A. Ullrich, W. Greene and J. Schlessinger Specific interleukin-2 binding to an oncogenic hybrid interleukin 2-epidermal growth factor receptor molecule. Proc. Natl. Acad. Sci. USA 84, 2125-2129 (1987). 129. T.A. Libermann, R. Friesel, M. Jaye, R.M. Lyall, B. Westermark, W. Drohan, A. Schmidt, T. Maciag and J. Schlessinger. An angiogenic growth factor is expressed in human glioma cells. EMBO J. 6., 1627-1632 (1987). 130. M. Tal, C.R. King, M.H. Kraus, A. Ullrich, J. Schlessinger and D. Givol. The human HER2 (neu) promoter: evidence for multiple mechanisms for transcriptional initiation. Mol. Cell Biol. 7, 2597-2601 (1987). 131. E. Livneh, N. Reiss, E. Berent, A. Ullrich and J. Schlessinger. An insertional mutant of EGF-receptor allows dissection of diverse receptor functions. EMBO J. 6, 2669-2676 (1987). 132. R.M. Kris, R. Hazan, J. Villines, T. Moody and J. Schlessinger. Identification of the bombesin-receptor on murine and human cells by cross-linking experiments. J. Biol. Chem. 262, 11215-11220 (1987). 133. M. Bajaj, M.D. Waterfield, J. Schlessinger, W.R. Taylor, and T. Blundel. On the tertiary structure of the extracellular domains of the epidermal growth factor and insulin receptors. Biochem. Biophys. Acta 916, 220-226 (1987). 134. Y. Yarden, W.J. Kuang, T. Yang-Feng, L. Coussens, S. Munemitsu, T.J. 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135. A.M. Honegger, T.J. Dull, S. Felder, E. Van-Obberghen, F. Bellot, D. Szapary, A. Schmidt, A. Ullrich and J. Schlessinger. Point mutation in the ATP binding site of EGF-receptor abolishes protein tyrosine-kinase activity and alters normal receptor cellular routing. Cell 51, 199-209 (1987). 136. A.M. Honegger, D. Szapary, A. Schmidt, E. Van-Obberghen, T.J. Dull, S.L. Massoglia, A. Ullrich and J. Schlessinger. A mutant EGF-receptor with defective tyrosine-kinase is unable to stimulate proto-oncogene expression and DNA synthesis. Mol. Cell Biol. 7, 4568-4571 (1987). 137. R.M. Hudziak, J. Schlessinger and A. Ullrich. Increased expression of the putative growth factor receptor p185HER2 causes transformation and tumorigenesis of NIH-3T3 cells. Proc. Natl. Acad. Sci. USA 6, 33413351 (1987). 138. P.P. DiFiore, J.H. Pierce, T.P. Fleming, R. Hazan, A. Ullrich, C.R. King, J. Schlessinger and S.A. Aaronson. Overexpression of the human EGF-receptor confers an EGF-dependent transformed phenotype to NIH-3T3 cells. Cell 51, 1063-1070 (1987). 139. J.H. Pierce, M. Ruggiero, T.P. Fleming, P.P. DiFiore, J.S. Greenberger, J. Schlessinger, G. Rovera and S.A. Aaronson. Signal transduction through the EGF-receptor transfected into interleukin-3 dependent hematopoietic cells. Science 239, 628-631 (1988). 140. I. Lax, W.H. Burgess, F. Bellot, A. Ullrich, J. Schlessinger and D. Givol. Localization of a major receptor binding domain for epidermal growth factory by affinity labeling. Mol. Cell Biol. 8, 1831-1834 (1988). 141. E. Livneh, T.J. Dull, R. Prywes, A. Ullrich and J. Schlessinger. Release of phorbol ester-induced mitogenic block by mutation at Thr654 of EGF-receptor. Mol. Cell Biol. 8, 2302-2308 (1988) 142. M. Nister, T.A. Libermann, C. Betsholtz, M. Pettersson, L. Claesson-Welsh, C.H. Heldin, J. Schlessinger and B. Westermark. Expression of messenger RNAs for platelet-derived growth factor and transforming growth factor- and their receptors in human malignant glioma cell lines. Cancer Research 48, 3910-3918 (1988). 143. M. Tal, M. Wetzler, Z. Josepberg, A. Deutch, M. Gutman, D. Assaf, A.Ullrich, Y. Shiloh, D. Givol and J. Schlessinger. Sporadic amplification of the HER2/neu proto-oncogene in adenocarcinoma of various tissues. Cancer Research (1988) 48, 1517-1520 (1988). 144. W.H. Moolenaar, A.J. Bierman, B.C. Tilly, I. Verlaan, A.M. Honegger, A. Ullrich and J. Schlessinger. A point mutation at the ATP binding site of the EGF-receptor abolishes signal transduction. EMBO J. 7, 707710 (1988). 145. C. Cochet, O. Kashles, E.M. Chambaz, I. Borrello, C.R. King and J. Schlessinger. Demonstration of EGFinduced receptor dimerization in living cells using a chemical covalent cross-linking agent. J. Biol. Chem. 263, 3290-3295 (1988). 146. H. Riedel, S. Massoglia, J. Schlessinger and A. Ullrich. Ligand activation of overexpressed EGF-receptor transforms NIH-3T3 cells. Proc. Natl. Acad. Sci. USA 85, 1477-1481 (1988). 147. M. Jaye, R.M. Lyall, R. Mudd, J. Schlessinger and N. Sarver. Expression of acidic fibroblast growth factor cDNA confers growth advantage and tumorigenesis to Swiss 3T3 cells. EMBO J. 7, 963-969 (1988). 148. T. Moody, R. Kris, M. Berg, G. Fiskum, C.O. Linden and J. Schlessinger. Characterization of receptors for Bombesin/GRP in human and murine cells. Methods Enzymol. (1988). 149. C.R. King, I. Borrello, F. Bellot, P. Comoglio and J. Schlessinger. EGF binding to its receptor triggers a rapid tyrosine phosphorylation of the erbB-2 protein in the mammary tumor cell line (SK-BR-3). EMBO J. 7, 1647-1651 (1988). 150. M. Benveniste, E. Livneh, J. Schlessinger and Z. Kam. Overexpression of epidermal growth factor in NIH3T3 transfected cells slows its lateral diffusion and rate of endocytosis. J. Cell Biol. 106, 1903-1909 (1988). 151. J. Schlessinger. Epidermal growth factor receptor as a multifunctional allosteric protein. Biochemistry 27, 3119-3123 (1988). 152. I. Lax, A. Johnson, R. Howk, J. Sap, F. Bellot, M. Winkler, A. Ullrich, B. Vennstrom, J. Schlessinger and D. Givol. Chicken EGF-receptor: cDNA cloning expression and differential binding of EGF and TGFa. Mol. Cell Biol. 8, 1970-1978 (1988). 153. A.M. Honegger, T.J. Dull, F. Bellot, E. Van-Obberghen, D. Szapary, A.Schmidt, A. Ullrich and J. Schlessinger. Biological activities of EGF-receptor mutants with individually altered autophosphorylation sites. EMBO J. 7, 3045-3052 (1988). 154. A.M. Honegger, F. Bellot, R. Kris, D. Szapary, E. Van-Obberghen, A.Komoriya, T.J. Dull, A. Ullrich and J. Schlessinger. Kinetic parameters of the tyrosine kinase activity of EGF-receptor mutants with individually altered autophosphorylation sites. EMBO J. 7, 3053-3060 (1988). 155. M. Ruta, R. Howk, G. Ricca, W. Drohan, M. Zabelshanky, G. Laureys, D. Barton, U. Francke, J. Schlessinger and D. Givol. A novel protein tyrosine kinase gene whose expression is modulated during endothelial cell differentiation. Oncogene 3, 9-15 (1988). 11

156. R. Seger, Y. Yarden, O. Kashles, D. Goldblat, J. Schlessinger and S. Shaltiel. The epidermal growth factor as a substrate for a kinase-splitting membranal proteinase. J. Biol. Chem. 263, 3496-3500 (1988). 157. O. Kashles, D. Szapary, F. Bellot, A. Ullrich, J. Schlessinger and A. Schmidt. Ligand-induced stimulation of EGF-receptor mutants with altered transmembrane regions. Proc. Natl. Acad. Sci. USA 85, 9567-9571 (1988). 158. E. Aboud-Pirak, E. Hurwitz, M.E. Pirak, F. Bellot, J. Schlessinger and M. Sela. Efficacy of antibodies to epidermal growth factor receptor against KB carcinoma in vitro and in nude mice. J. Natl. Cancer Inst. 80, 1605-1611 (1988). 159. K. Khazaie, T. Dull, T. Graf, J. Schlessinger, A. Ullrich, B. Vennstrom. Truncation of the human EGF receptor leads to differential transforming potentials in primary avian fibroblasts and erythroblasts. EMBO J. 7, 3061-3971 (1988). 160. J. Schlessinger. Signal transduction by allosteric receptor oligomerization. Trends in Biochem. Sci. 13, 443447 (1988). 161. J. Schlessinger, A. Ullrich, A.M. Honegger and W. Moolenaar. Signal transduction by epidermal growth factor. Cold Spring Harbor Symposia on Quantitative Biology. Molecular Biology of Signal Transduction 53, 515-521 (1988). 162. A.M. Honegger, R. Kris, A. Ullrich and J. Schlessinger. Evidence that authophosphorylation of solubilized EGF-receptors is mediated by intermolecular cross-phosphorylation. Proc. Natl. Acad. Sci. USA 86, 925-929 (1989). 163. J. Lee, T.J. Dull, I. Lax, J. Schlessinger and A. Ullrich. HER2 cytoplasmic domain generates normal mitogenic and transforming signals in a chimeric receptor. EMBO J. 8, 176-178 (1989). 164. I. Lax, F. Bellot, R. Howk, A. Ullrich, D. Givol and J. Schlessinger. Functional analysis of the ligand binding site of EGf-receptor utilizing chimeric human/chicken receptor molecules. EMBO J. 8, 421-427 (1989). 165. C.R. King, I. Borrello, L. Porter, P. Comoglio and J. Schlessinger. Ligand-independent self-phosphorylation of EGF receptor and the erbB-2/neu proto-onconge is induced by hypersosmotic shock. Oncogene 4, 13-18 (1989) . 166. J. Lammers, A. Gray, J. Schlessinger and A. Ullrich. Differential signalling potential of insulin-and IGF-1 receptor cytoplasmic domains. EMBO J. 8, 1369-1375 (1989). 167. J.-C. Scimeca, R. Ballotti, F. Alengrin, A.-M. Honegger, A. Ullrich, J. Schlessinger and E. Van Obberghen. Metabolic effects induced by EGF in cells expressing EGF receptor mutants. J. Biol. Chem. 264, 6831-6835 (1989). 168. H. Riedel, S.L. Massaglia, J. Schlessinger and A. Ullrich. Cytoplasmic domain defines biological signal specificity of a chimeric insulin-EGF-receptor. EMBO J. 8, 2942-2954 (1989). 169. I. Lax, F. Bellot, A.M. Honegger, A. Schmidt, A. Ullrich, D. Givol and J. Schlessinger. Domain deletion in the extracellular portion of the EGF-receptor reduces ligand binding and impairs cell surface expression. Cell Regulation 1, 173-188 (1990). 170. E. Aboud-Pirak, E. Hurwitz, F. Bellot, J. Schlessinger, and M. Sela. Inhibition of human tumor growth in nude mice elicited by monoclonal anti EGF-receptor antibodies conjugated with Doxorubicin. Proc. Nat. Acad. Sci. USA 86, 3778- (1989). 171. B.L. Margolis, I. Lax, R. Kris, M. Dombalagian, A.M. Honegger, R. Howk, D. Givol, A. Ullrich and j. Schlessinger. All autophosphorylation sites of EGF receptor and HER2/neu are located in their carboxyterminal tails: identification of a novel site in EGF receptor. J. Biol. Chem. 264, 10667-10671 (1989). 172. R. Balloti, R. Lammers, J.-C. Scimeca, T. Dull, J. Schlessinger, A. Ullrich, and E. Van Obberghen. Intermolecualr transphosphorylation between insulin receptors and EGF-insulin receptor chimerae. EMBO J. 8, 3303-3309 (1989). 173. R.M. Lyall, A. Zilberstein, A. Gazit, C. Gilon, A. Levitzki and J. Schlessinger. Tyrphostins inhibit EGFreceptor tyrosine kinase activity in living cells and EGF-stimulated cell proliferation. J. Biol. Chem. 264, 14503-14509 (1989). 174. B. Margolis, S.-G. Rhee, S. Felder, R. Lyall, A. Levitzki, A. Ullrich, A. Zilberstein, and J. Schlessinger. EGF-induced tyrosine phosphorylation of phospholipase C-II: a potential mechanism for EGF-receptor signalling. Cell 57, 1101-1107 (1989). 175. M. Benveniste, J. Schlessinger and Z. Kam. Characterization of internalization and endosome formation of EGF in transfected NIH-3T3 cells by computerized image-intensified three-dimensional fluorescence microscopy. J. Cell. Biol. 109, 2105-2115 (1989). 176. F. Bellot, W. Moolenaar, R. Kirs, B. Mirakhur, I. Verlaan, A. Ullrich, J. Schlessinger, and S. Felder. High Affinity epidermal growth factor binding is specifically reduced by a monoclonal antibody, and appears necessary for early responses. J. Cell. Biol. 110, 491-502 (1989). 12

177. J. R. Downing, B.L. Margolis, A. Zilberstein, R.A. Ashmun, A. Ullrich, C.J. Sherr, and J. Schlessinger. Phospholipase C: A substrate for PDGF receptor kinase, is not phosphorylated on tyrosine during the mitogenic response to CSF-1. EMBO J. 8, 3345-3350 (1989). 178. M. Ruta, W. Burgess, D. Givol, J. Epstein, N. Neiger, J. Kaplow, G. Crumley, C. Dionne, M. Jaye, and J. Schlessinger. The receptor for acidic fibroblast growth factor is related to flg tyrosine kinase. Proc. Natl. Acad, Sci. USA. 86 8722-8726 (1989). 179. B. Margolis, F. Bellot, A.M. Honegger, A. Ullrich, J. Schlessinger, and A. Zilberstein. Tyrosine kinase activity is essential for the association of phospholipase C- with the epidermal growth factor receptor. Mol. Cell. Biol. 10, 435-441 (1989). 180. S. Paik, R. Hazan, J. Schlessinger, B. Fisher, E.R. Fisher, R.E. Sass, C. Redmond, J.M. You, S. Kennedy, M.E. Lippman, and C.R. King. Overexpression of erbB-2 protein in breast cancer: Association with increased mortality rates among low risk patient groups. J. Clin. Oncology 8, 103-112 (1990). 181. L. Naldini, D. Cirillo, T.M. Moody, P. Comoglio, J. Schlessinger, and R. Kris. Solubilization of the receptor for the neuropeptide gastrin-releasing peptide (Bombesin) with functional ligand binding properties. Biochemistry 29, 5153-5160 (1990). 182. B.W. Ennis, E.M. Valverius, S.E. Bates, M.E. Lippman, F. Vellot, R. Kris, J. Schlessinger, H. Masui, A. Goldenberg, J. Mendelsohn, and R. B. Dickson. Anti-EGF receptor antibodies inhibit the autocrine stimulated growth of MDA-468 human breast cancer cells. Mol. Endocrinol. 3, 1830-1838 (1990). 183. R. Hazan, B. Margolis, M. Dombalagian, A. Ullrich, A. Zilberstein, and J. Schlessinger. Identification of autophosphorylation sites of HER2/neu. Cell Growth and Diff. 1, 3-7 (1990). 184. A.M. Honegger, A. Schmidt, A. Ullrich and J. Schlessinger. Evidence for EGF-induced intermolecular autophosphorylation of EGF-receptor in living cells. Mol. Cell. Biol. 10, 4035-4044 (1990). 185. W.H. Burgess, C.A. Dionne, J. Kaplow, R. Mudd, R. Friesel, A. Zilberstein, J. Schlessinger and M. Jaye. Characterization of cDNA cloning of a major substrate for HBGF-1 (acidic-FGF) activated tyrosine kinase: phospholipase C-. Mol. Cell. Biol. 10, 4770-4777 (1990). 186. A.M. Honegger, A. Schmidt, A. Ullrich, and J. Schlessinger. Separate endocytic pathways of kinase defective and active EGF-receptor mutants expressed in same cells. J. Cell Biol. 110, 1541-1548 (1990). 187. H.J. Goldberg, M.M. Viegas, B.L. Margolis, J. Schlessinger and K.L. Skorecki. The tyrosine activity of the EGF-receptor is necessary for phospholipase A-2 activation. Biochem. J. 267, 461-465 (1990). 188. 188. C.-Y. J. Hsu, M. Mohammadi, M. Nathan, A.M. Honegger, A. Ullrich, J. Schlessinger and D.R. Hurwitz. Generation of cytoplasmic domain of EGF-receptor with intrinsic protein tyrosine kinase activity. Cell Growth and Diff. 1, 191-200 (1990). 189. R. Lammers, E. Van Obberghen, J. Schlessinger and A. Ullrich. Transphosphorylation as a possible mechanism of insulin and EGF-receptor activation. J. Biol. Chem, 265, 16886-16890 (1990). 190. C.F.M. Verheijden, I. Verlaan, J. Schlessinger and W.H. Moolenaar. EGF-induced phosphoinositide hydrolysis in permeablized 3T3 cells: lack of guanoside triphosphate dependence and inhibition by tyrosinecontaining peptides. Mol. Biol. Cell 1, 615-620 (1990). 191. S. Felder, K. Miller, A. Ullrich, J. Schlessinger and C.R. Hopkins. Kinase activity controls the sorting of EGF-receptor within the multivesicular body. Cell 61, 623-634 (1990). 192. S. Massoglia, A. Gray, T.J. Dull, S. Munemitsu, H.J. Kung, J. Schlessinger and A. Ullrich. Epidermal growth factor receptor cytoplasmic domain mutations trigger ligand-independent transformation. Mol. Cell Biol. 10, 3048-3055 (1990). 193. B. Margolis, A. Zilberstein, C. Franks, S. Felder, S. Kremer, A. Ullrich, S.G. Rhee, K. Skrorecki and J. Schlessinger. Effect of phospholipase C- overexpression on PDGF-induced second messengers and Mitogenesis. Science 248, 607-610 (1990). 194. C. Dionne, G. Crumley, F. Bellot, J. Kaplow, M. Ruta, G. Searfosi, W. Burgess, M. Jaye and J. Schlessinger. Cloning and expression of two distinct high affinity receptors cross-reacting with acidic and basic fibroblast growth factors. EMBO J. 9, 2685-2692 (1990). 195. A. Ullrich and J. Schlessinger. Signal transduction by receptors with protein tyrosine activity. Cell 61, 203212 (1990). 196. J. Sap, P. D'Eustachio, D. Givol, and J. Schlessinger. Cloning and expression of a widely expressed receptor tyrosine phosphatase. Proc. Natl. Acad. of Sci. USA, 87, 6112-6116 (1990). 197. R. Kaplan, B. Morse, K. Huebner, C. Croce, R. Howk, M. Ravera, G. Ricca, M. Jaye, and J. Schlessinger. Cloning of three novel human tyrosine phosphatases reveals the existence of a multigenese family of receptor-linked protein tyrosine phosphatases expressed in brain. Proc. Natl. Acad. Sci. USA, 87, 7000-7004 (1990). 13

198. B. Margolis, N. Li, A. Koch, M. Mohamaddi, D. Hurwitz, A. Zilberstein, A. Ullrich, T. Pawson and J. Schlessinger. The tyrosine phosphorylated carboxyterminus of the EGF-receptor is a binding site for GAP and PLC-. EMBO J., 9, 4375-4380 (1990). 199. H. App, R. Hazan, A. Zilberstein, A. Ullrich, J. Schlessinger and U. Rapp. EGF stimulates association with c-raf and its kinase activity in living cells. Mol. Cell Biol., 11, 913-919 (1991). 200. O. Kashles, Y. Yarden, A. Ullrich and J. Schlessinger. A dominant negative mutation supresses the function of normal EGF-receptors by heterodimerization. Mol. Cell Biol., 11, 1454-1463 (1991). 201. J. den Hertog, J. Schlessinger, S.W. deLaat and W. Kruiger. Neuronal differentiation of transfected murine F19 embryonal carcinoma cells expressing human EGF-receptors. Cell Growth and Diff., 2, 155-164 (1991). 202. Lax, R. Fischer, C. Ng, J. Segre, A. Ullrich, D. Givol and J. Schlessinger. 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221. R. Schumacher, L. Mesthof, J. Schlessinger, D. Brandenbung and A. Ullrich. Insulin and IGF-1 binding sites are located in distinct region of their cognate receptors. J. Biol. Chem. 266, 19288-19295 (1991). 222. W. Li, N. Hack, B. Margolis, A. Ullrich, K. Skorecki and J. Schlessinger. Carboxy-terminal truncations of EGF-receptor affect diverse EGF-induced cellular responses. Mol. Biol. Cell 2, 641-649 (1991). 223. M. Mohammadi, A.M. Honegger, F. Bellot, W. Li, D. Rotin, R. Fischer, F. Bellot, C.A. Dionne, M. Jaye, M. Rubinstein and J. Schlessinger. A tyrosine phosphorylated carboxy-terminal peptide of FGF-recptor (flg) is a binding site for the SH2 domain of phospholipase C-. Mol. Cell Biol., 11, 5068-5078 (1991). 224. B. Schechter, R. Arnon, M. Wilcheck, J. Schlessinger, E. Hurwitz, E. Aboud-Pirak and M. Sela. Indirect immunotargeting of CIS-PIT to human epidermoid carcinoma KB using the avidin-biotin system. Int. J. Cancer 48, 167-172 (1991). 225. N. Hack, B. Margolis, A. Ullrich, K. Skorecki and J. Schlessinger. Distinct structural specificities for functional coupling of the epidermal factor receptor to calcium-signalling versus phospholipase A2 responses. Biochem. J. 275, 563-567 (1991). 226. S. Tartare, R. Balloti, R. Lammers, C. Fillowx, A. Chauval, J. Schlessinger, A. Ullrich and E. Van Obberghen. Activation of Insulin-EGF-chimera regulates EGF-receptor binding affinity. J. Cell Biol. 116, 627-633 (1991). 227. A. Ullrich, A. Gray, S. Munemitsu, J. Schlessinger and S. Massoglia. Epidermal growth factor receptor autophosphorylation is not required for normal mitogenic or transforming signal generation: in "Biological signal transduction, Nato ASI series, vol. H52, Springer-Verlag, Heidelberg (1991). 228. G. Crumley, F. Bellot, J.M. Kaplow, J. Schlessinger, M. Jaye and C. A. Dionne. High-affinity binding and activation of a truncated FGF receptor by both aFGF and bFGF. Oncogene 6, 2255-2262, (1991). 229. J. Oval, R. Hershberg, B. Gansbacher, E. Gilboa, J. Schlessinger and R. Taetle. Expression of functional epidermal growth factor receptors in a human hematopoietic cell line. Cancer Res. 51, 150-156, (1991). 230. C.A. Dionne, M. Jaye and J. Schlessinger. FGF receptors as targets for drug development. in "The clinical pharmacology of biotechnology products." M.M. Reidenberg, ed. Elsevier Science Publishers, pp. 49-56 (1991). 231. C.A. Dionne, W.S. Modi, G. Crumley, H. Seuanez, S.J. O'Brien, J. Schlessinger and M. Jaye. BEK, a receptor for multiple members of the FGF family, maps to human chromosome. l0q 25.3-q26. Cytogen Cell Gene. 60, 34-36 (1992). 232. C.D. Renard, M. McLean-Bolton, S.G. Rhee, B. Margolis, A. Zilberstein, J. Schlessinger and A.P. Thomas. Modified kinetics of PDGF-induced Ca+2 increase in NIH-3T3 cells overexpressing phospholipase-C1. Biochem. J. 281, 775-784 (1992). 233. K. Seedorf, B. Millauer, G. Kostra, J. Schlessinger and A. Ullrich. Differential effects of carboxy-terminal sequence deletions of platelet-derived growth factor receptor signaling activities and interactions with cellular substrates. Mol. Cell Biol. 12, 4347-4356 (1992). 234. D. Rotin, B. Margolis, M. Mohammadi, R.J. Daly, G. Daum, N. Li, E.H. Fischer, W.H. Burgess, A. Ullrich and J. Schlessinger. SH2 domain prevent tyrosine dephosphorylation of the EGF-receptor: identification of Tyr992 as the high-affinity binding site for the SH2 domains of phospolipase C. EMBO J. 11, 559-567 (1992). 235. P. Hu, B. Margolis, E. Skolnik, A. Ullrich and J. Schlessinger. Binding of EGF and PDGF-Receptors by PI-3 kinase associated p85 correlates with stimulation of PI-3 kinases. Mol. Cell Biol. 12, 981-990 (1992). 236. S. Felder, J. Lavin, A. Ullrich and J. Schlessinger. Kinetics of binding, endocythosis and EGF-receptor mutants. J. Cell Biol. 117, 203-210 (1992). 237. T. Spivak-Kroizman, D. Rotin, D. Pinchasi, A. Ullrich, J. Schlessinger and I. Lax. Heterodimerization of cerbB2 with different EGF-receptor mutants elicits stimulatory or inhibitory responses. J. Biol. Chem. 267, 8056-8063 (1992). 238. B. Margolis, P. Hu, S. Katzav, W. Li, J.M. Oliver, A. Ullrich, A. Weiss and J. Schlessinger. Tyrosine phosphorylation of vav proto-oncogene product containing SH2 domain and transcription factor motifs. Nature 356, 71-74 (1992). 239. V.V.N. Gopal Rao, C. Löffler, J. Sap, J. Schlessinger and I. Hansmann. The gene for receptor linked protein tyrosine phosphatase (R-PTP) is assigned to human chromosome 20p12-pter by in situ hybridization (ISH and FISH). Genomics 13, 906-907 (1992). 240. L.A. Cannizzaro, E. Skolnik, B. Margolis, C.M. Croce, J. Schlessinger and K. Huebner. The human gene encoding PI3-kinase associated P85 is at chromosome region 5g12-13. Cancer Res. 51, 3818-3820 (1992). 241. R. Herbst, M.S. Shearman, A. Obermeir, J. Schlessinger and A. Ullrich. Differential Effects of W mutations on p145c-kit tyrosine kinase activity and substrate interaction. J. Biol. Chem. 267, 13210-13216 (1992). 15

242. M. Jaye, J. Schlessinger and C.A. Dionne. Fibroblast growth factor receptor tyrosine kinases: molecular analysis and signal transduction. Biochem. Biophys. Acta. 1135, 185-199 (1992). 243. J.M. Baker, M.G. Myers Jr., S.E. Shoelson, D.J. Chin, X.J. Sun, M. Miralpeix, P. Hu, B. Margolis, E. Skolnik, J. Schlessinger and M.F. White. Phosphatidylinositol 3-kinase is activated by association with IRS1 during insulin stimulation. EMBO J. 11, 3469-3479 (1992). 244. M.G. Myers Jr., J.M. Backer, X.J. Sun, S.E. Shoelson, P. Hu, J. Schlessinger, M. Yoakim, B. Schaffhausen and M.F. White. IRS-1 activates the phosphatidylinositol 3'-kinase by associating with src homology 2 domains of p85. Proc. Natl. Acad. Sci. USA., 89, 10350-10354 (1992). 245. D. Rotin, A.M. Honegger, B. Margolis, A. Ullrich and J. Schlessinger. Presence of SH2 domain of phospholipase C enhances substrate phosphorylation by increasing the affinity toward the EGF-receptor. J. Biol. Chem. 267, 9678-9683 (1992). 246. E.J. Lowenstein, R.J. Daly, A.G. Batzer, W. Li, B. Margolis, R. Lammers, A. Ullrich, E.Y. Skolnik, D. BarSagi and J. Schlessinger. The SH2 and SH3 domain containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell 70, 431-442 (1992). 247. B. Jallal, J. Schlessinger and A. Ullrich. Tyrosine phosphatase inhibition permits analysis of signal transduction complexes in p185HER2/neu-overexpressing human tumor cells. J. Biol. Chem. 267, 43574363 (1992). 248. H.A. Drabkin, M.J. Mendez, P.H. Rabbitts, T. Varkony, J. Bergh, J. Schlessinger, P. Erickson and R.M. Gemmill. Characterization of the submicroscopic deletion in the small-cell lung carcinoma (SCLC) cell line U2020. Genes, Chromosomes & Cancer 5, 67-74 (1992). 249. M. Mohammadi, C.A. Dionne, W. Li, N. Li, T. Spivak, A.M. Honegger, M. Jaye, and J. Schlessinger. Point mutation in FGF-receptor eliminates phosphatidylinositol hydrolysis without affecting mitogenesis. Nature 358, 681-684 (1992). 250. W. Li, G.G. Deanin, B. Margolis, J. Schlessinger and J.M. Oliver. FceR1-Mediated tyrosine phosphorylation of multiple proteins, including phospholipase C1 and the receptor 2 complex, in RBL-2H3 rat basophilic leukemia cells. Mol. Cell. Biol. 12, 3176-3182 (1992). 251. W. Li, P. Hu, E.Y. Skolnik, A. Ullrich and J. Schlessinger. The SH2 and SH3 domains-containing nck protein is oncogenic and a common target for phosphorylation by different surface receptors. Mol. Cell. Biol. 12, 5824-5833 (1992) . 252. J. Schlessinger and A. Ullrich. Growth factor signaling by receptor tyrosine kinases. Neuron 9, 383-391 (1992). 253. B. Margolis, O. Silvennoinen, F. Comoglio, C. Roonprapunt, E. Skolnik, A. Ullrich and J. Schlessinger. High-efficiency expression/cloning of epidermal growth factor-receptor-binding proteins with Src homology 2 domains. Proc. Natl. Acad. Sci. USA 89, 8894-8898 (1992). 254. M. Rozakis-Adcock, J. McGlade, G. Mbamalu, G. Pelicci, R. Daly, W. Li, A. Batzer, S. Thomas, J. Brugge, P.G. Pelicci, J. Schlessinger, and T. Pawson. Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the ras pathway by tyrosine kinases. Nature 360, 689-692 (1992). 255. J. Schlessinger, M. Mohammadi, B. Margolis, and A. Ullrich. Role of SH2 containing proteins in cellular signaling by receptor tyrosine kinases. Cold Spring Harbor, Symposium on Quantitative Biology. The Cell Surface 57, 67-74 (1992). 256. C.E. Futter, S. Felder, J. Schlessinger, A. Ullrich and C.R. Hopkins. Annexin I is phosphorylated in the multivesicular body during the processing of the epidermal growth factor receptor. J. Cell Biol. 120, 77-83 (1993). 257. D. Kohda, M. Odaka, I. Lax, H. Kawasaki, K. Suzuki, A. Ullrich, J. Schlessinger and F. Inagaki. A 40-kDa epidermal growth factor/transforming growth factor -binding domain produced by limited proteolysis of the extracellular domain of the epidermal growth factor receptor. J. Biol. Chem. 268, 1976-1981 (1993). 258. S.E. Shoelson, M. Sivaraja, K.P. Williams, P. Hu, J. Schlessinger and M.A. Weiss. Specific phosphopeptide binding regulates a conformational change in the PI-3-kinase SH2 domain associated with enzyme activation. EMBO J. 12, 795-802 (1993). 259. S. Felder, M. Zhou, P. Hu, J. Ureña, A. Ullrich, M. Chaudhury, M. White, S.E. Shoelson and J. Schlessinger. SH2 domains exhibit high-affinity binding to tyrosine phosphorylated peptides yet also exhibit rapid dissociation and exchange. Mol. Cell. Biol. 13, 1449-1455 (1993). 260. G. Barnea, O. Silvennoienen, B. Shaanan, A.M. Honegger, P.D. Canoll, P. D'Eustachio, B.Morse, J.B. Levy, S. LaForgia, K. Huebner, J.M. Musacchio, J. Sap and J. Schlessinger. Identification of a Carbonic anhydraselike domain in the extracellular region of RPTP defines a new subfamily of receptor tyrosine phosphatases. Mol. Cell. Biol. 13, 1497-1506 (1993). 16

261. A. Obermeier, H. Halfter, K.-H. Wiesmüller, G. Jung, J. Schlessinger and A. Ullrich. Tyrosine 785 is a major determinant of Trk - substrate interaction. EMBO J. 12, 933-941 (1993). 262. J. P. Olivier, T. Raabe, M. Henkemeyer, B. Dickson, G. Mbamalu, B. Margolis, J. Schlessinger, E. Hafen and T. Pawson. A Drosphila SH2-SH3 adaptor protein implicated in coupling the Sevenless tyrosine kinase to an activator of Ras guanine nucleotide exchange, Sos. Cell 73, 179-191 (1993). 263. P. Hu, B. Margolis and J. Schlessinger. Vav: a potential link between tyrosine kinases and ras-like GTPases in hematopoietic cell signaling. Bio Essays 15, 179-186 (1993). 264. D. Kohda, H. Hatanaka, M. Odaka, V. Mandiyan, A. Ullrich J. Schlessinger and F. Inagaki. Solution structure of the SH3 domain of phospholipase C. Cell 72, 953-960 (1993). 265. Y.P. Jiang, H. Wang, P.D'Eustachio, J.M. Musacchio, J. Schlessinger an