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RET

RET. Proto-Oncogene of Multiple Endocrine Neoplasia type 2(MEN2). What is RET? . Codes for a RTK On chromosome 10 21 exons “Rearranged during Transfection”. Alberti et al., Journal of Cellular Physiology. 195: 168-186 (2003). RET protein function .

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RET

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  1. RET Proto-Oncogene of Multiple Endocrine Neoplasia type 2(MEN2)

  2. What is RET? • Codes for a RTK • On chromosome 10 • 21 exons • “Rearranged during Transfection” Alberti et al., Journal of Cellular Physiology. 195: 168-186 (2003)

  3. RET protein function • signaling to a variety of pathways, most notably the Ras signaling pathway and the phosphatidylinositol-3 kinase pathway. • The ultimate biological effects: • morphological changes in the cytoskeleton, cell scattering, proliferation, and differentiation. Alberti et al., Journal of Cellular Physiology. 195: 168-186 (2003)

  4. RET protein structure • N-terminal signal peptide • Cadherin domain • Cysteine rich region • TK domain • C-terminal; different isoforms for different functions Alberti et al., Journal of Cellular Physiology. 195: 168-186 (2003)

  5. Ligands: GDNF – glial derived neutrotrophic factor NTN – neurturin PSP – persephin Artemin Co-receptors GFRa 1, 2, 3 and 4 How is RET normally activated? Alberti et al., Journal of Cellular Physiology. 195: 168-186 (2003)

  6. Ligand Binding

  7. How is RET normally activated? • RTK signalling induced by ligand oligomerization • Tyrosine autophosphorylation • Ca+2-dependent extracellular cadherin domain Manie et al. http://tig.trends.com

  8. Ligand binding Manie et al. http://tig.trends.com

  9. RET activating pathways

  10. Normal RET functions • TK receptor for GDNF, NTN, PSP and Artemin • Expressed in • Neural crest • Urogenital precursor cells • Required for • Kidney morphogenesis • Neuron maturation • Spermatogonia maturation Alberti et al., Journal of Cellular Physiology. 195: 168-186 (2003)

  11. Knockout Mutation

  12. RET-null mice • Transgenic mice without functional RET or its co-receptors showed defective enteric growth and ureteric budding Manie et al. http://tig.trends.com

  13. Kidney morphogenesis Manie et al. http://tig.trends.com

  14. Recent Finding: RET apoptotic activity • RET to induce apoptosis in the absence of GDNF • Is ligand-independent • Molecular mechanisms unknown Manie et al. http://tig.trends.com

  15. Summary: Normal RET activation • Calcium-dependent ligand binding • Autophosphorylation of Tyrosine residues • Activation of proliferation pathways • Cell growth and differentiation

  16. Carcinomas Caused by RET mutations • Papillary Thyroid Carcinoma (PTC) • Medullary Thyroid Carcinomas (MTC) • Multiple Endocrine Neoplasia type 2 (MEN2) A,B • Famillilar Medullary Thyroid Carcinoma (FMTC) • Hirschsprung disease Manie et al. http://tig.trends.com

  17. Mutations Manie et al. http://tig.trends.com

  18. Carcinomas

  19. RET in PTC • Rearrangements of RET tyrosine kinase coding region with unrelated genes = PTC

  20. Medullary Thyroid Carcinomas (MTCs) • Facts • Thyroid C cells are derived from neural crest • 75% are sporadic • Remainding are inherited forms of MEN2 • Activating mutations of RET Alberti et al., Journal of Cellular Physiology. 195: 168-186 (2003)

  21. MEN2A • Mutations in cysteine-rich extracellular domain of RET • 80% of these mutations are exchange of a cysteine for arginine • Leaves unpaired cysteine residue, loss of intramolecular dissulfide bond, and an available intermolecular dissulfide bond with other mutant RET receptors. Alberti et al., Journal of Cellular Physiology. 195: 168-186 (2003)

  22. Disulfide bond interactions Alberti et al., Journal of Cellular Physiology. 195: 168-186 (2003)

  23. MEN2B • 95% are mutations in M918T (exon 16) • Usually paternal • 5% mutations in RET TK domain • Changes substrate binding, RET phosphorylation of proteins, and RET autophosphorylation Alberti et al., Journal of Cellular Physiology. 195: 168-186 (2003)

  24. MEN2 Treatment • Good prognosis with early detection • Thryoidectomy early • Removal of thyroid gland • RET oncoprotein inhibitors • ZD6474 • Pyrazolo-pyrimidine (PP2)

  25. ZD6474: Oral inhibitor • In vivo • Blocked phosphorylation of PTC3 and MEN2B oncoproteins • Blocked EGF receptor • Reverted some PTC cells http://cancerres.aacrjournals.org/cgi/content/full/62/24/7284

  26. PP2 • Blocked kinase activity of PTC1 oncoproteins • Prevented serium growth of PTC cells • Hopeful for MTC therapy http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12679489&dopt=Abstract

  27. Sources • Alberti et al., Journal of Cellular Physiology. 195: 168-186 (2003)  • Manie et al. http://tig.trends.com • http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12679489&dopt=Abstract • http://cancerres.aacrjournals.org/cgi/content/full/64/24/7284.com • http://www.ohiolink.edu/etd/send-pdf.cgi?osu970163275

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