Lecture 3: Receptor Protein Tyrosine Kinases and Their Signaling Pathways

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1 Lecture 3: Receptor Protein Tyrosine Kinases and Their Signaling Pathways

2 Edmond H. Fischer and Edwin G. Krebs 1992 Nobel Prize for their discoveries in the 1950s concerning reversible protein phosphorylation. Phosphorylase kinase, phosphorylase phosphatase, camp-dependent kinase,protein tyrosine phosphatase, MAP kinase kinase

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4 The Nobel Prize in Physiology or Medicine 1923 "for the discovery of insulin" Frederick Grant Banting University of Toronto John James Richard Macleod University of Toronto Insulin is a hormone produced in the pancreas. It was isolated in at the University of Toronto. The scientists involved in the research were Dr. Fredrick Banting, Charles Best (a medical student at the time of the discovery), Professor J. J. R. Macleod and Dr. James Collip. On June 3, 1934, Dr Frederick Banting the co-inventor of insulin was knighted for his medical discovery.

5 The Nobel Prize in Physiology or Medicine 1986 "for their discoveries of growth factors" Rita Levi-Montalcini Discovery of nerve growth factor (NGF) Stanley Cohen Discovery of epidermal growth factor (EGF)

6 The Nobel Prize in Physiology or Medicine 1989 "for their discovery of the cellular origin of retroviral oncogenes Michael Bishop and Harold Varmus identified a large family of genes which control the normal growth and division of cells. Disturbances in one or some of these so-called oncogenes (Gk ónco(s) bulk, mass) can lead to transformation of a normal cell into a tumor cell and result in cancer. They used an oncogenic retrovirus to identify the growth-controlling oncogenes in normal cells. In 1976 they published the remarkable conclusion that the oncogene in the virus did not represent a true viral gene but instead was a normal cellular gene, which the virus had acquired during replication in the host cell and thereafter carried along.

7 Discovery of Oncogene Rouse Sarcoma virus 1911 Tumor virology 1970 V-Src V-abl pp6o src encoded by Rous Sarcoma virus, which causes sarcoma in chickens nonreceptor tyrosine kinase encoded by Abelson murine leukemia virus Oncogene 1976

8 Discovery of Protein Tyrosine Phosphorylation Two-dimensional Analysis of phosphoamino acids Tony Hunter, 1979 HUNTER AND SEFTON: Transforming gene product of Rous sarcoma virus phosphorylates tyrosine, Proc. Nati. Acad. Sci. 1980

9 Ullrich A. Shine J, Chirgwin J, Pictet R, Tischer E, Rutter W J & Goodman H M. Rat insulin genes: construction of plasmids containing the coding sequences. Science 196: : Ullrich A, Coussens L, Hayflick J S, Dull T J, Gray A, Tam A W, Lee J, Yarden Y, Libermann T A, Schlessinger J, Downward J, Mayes E L V, Whittle N, Waterfield M D & Seeburg P H. Human epidermal growth factor receptor cdna sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 309:418-25, 1984; and Ullrich A, Bell J R, Chen E Y, Herrera R, Petruzzelli L M, Dull T J, Gray A, Coussens L, Liao Y-C, Tsubokawa M, Mason A, Seeburg P H, Grunfeld C, Rosen O M & Ramachandran J. Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature 313:756-61, [Dept. Biochem. and Biophys. and Dept. Med.. Metab. Sect., VA Med. Or., University of California. San Francisco, CA; Depts. Mol. Biol. and Protein Biochem., Genentech, South San Francisco, CA: Dept. Chem Immunol.. Weizmann Inst. Sci., Rehovot. Israel; Protein Chem. Lab., Imperial Cancer Res. Fund, London, England; and Dept. Mol. Biol. and Virol.. Memorial Sloan Kettering Cancer Ctr., New York, NY]

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22 (I) A soluble PDGF dimer cross-links two PDGF receptors (PDGFR) leading to activation of the cytoplasmic PTK. (II) FGF binds to FGF receptors (FGFR) monovalently. Oligomerization of FGF molecules by means of multimeric interactions with membrane-attached heparin sulfate proteoglycan receptor (HSPR) induces FGFR dimerization and tyrosine kinase activation. (III) Transmembrane (TM) Ephrins (also GPI-linked Ephrins) expressed on the cell surface of a cell bind to EPH receptors (EphR) expressed on the cell surface of neighboring cells. Binding is followed by receptor dimerization and protein tyrosine kinase activation.

23 glial-derived neurotrophic factor (GDNF). (IV) GDNF induces dimerization of the GPI-linked GDNF receptor (GDNFR). Ligand-occupied GDNFRs form a complex with the receptor tyrosine kinase Ret. GDNF-induced dimerization of GDNFR/Ret complex leads to PTK activation. (V) Both soluble or surface-attached collagen fibers bind to DDR1 and DDR2 leading to tyrosine kinase activation. Integrities of the Gly-X-Y repeat and carbohydrates attached to collagen are essential for DDR receptor activation.

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27 Drosophila In 1901, at Harvard University, Charles Woodworth brought the fruit fly Drosophila melanogaster into their labs for experimental use. Thomas Morgan is considered to be one of the most influential men in experimental biology during the early twentieth century and his work with the Drosophila was extensive. He was one of the first in the field to realize the potential of mapping the chromosomes of Drosophila melanogaster and all known mutants. He would later expand his findings to a comparative study of other species. With careful and painstaking observation he and other "Drosophilists" were able to control for mutations and cross breed for new phenotypes. Through many years of work like this standards of these flies have become quite uniform and are still used in research today.

28 The Nobel Prize in Physiology or Medicine 2002 "for their discoveries concerning 'genetic regulation of organ development and programmed cell death'" Bob Horvitz was a post-doc with Brenner in Cambridge in the mid-1970s and John Sulstron held a junior staff position at Cambridge under Brenner. Sydney Brenner realized, in the early 1960s, that fundamental questions regarding cell differentiation and organ development were hard to tackle in higher animals. Therefore, a genetically amenable and multicellular model organism simpler than mammals, was required. The ideal solution proved to be the nematode Caenorhabditis elegans. This worm, approximately 1 mm long, has a short generation time and is transparent, which made it possible to follow cell division directly under the microscope. Brenner provided the basis in a publication from 1974, in which he broke new ground by demonstrating that specific gene mutations could be induced in the genome of C. elegans by the chemical compound EMS (ethyl methane sulphonate).

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30 Drosophila eye development Each small eye consists of 8 photoreceptor cells. Development of receptor cell 7 requires the product of two genes, sevenless (sev) and bride-ofsevenless (boss). sos (son-of-sevenless); drk (downstream of receptor tyrosine kinase) C. elegans vulval development let (lethal mutants); sem (sex muscle mutants) lin (lineage mutants) Mammalian growth factor signaling Grb2 (growth factor receptor binding protein 2); ras and raf (oncogenes); MAPK (initially microtubule associated protein kinase, then changed to mean mitogen activated kinase); ERK (exracellular signal regulated kinase); MEK (MAP kinase-erk kinase); SRE (serum response element); SRF(serum response factor)

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33 Grb2: growth factor receptor binding protein 2

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