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Transforming Growth Factor β Receptor Type II

Transforming Growth Factor β Receptor Type II. Tina Morris. http://en.wikipedia.org/wiki/TGF_beta_receptor_2. What is TGF- β R2?. A transmembrane serine/threonine kinase A tumor suppressor Important in mammalian development Required for growth inhibition in colon. The TGF- β Pathway.

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Transforming Growth Factor β Receptor Type II

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  1. Transforming Growth Factor β Receptor Type II TinaMorris http://en.wikipedia.org/wiki/TGF_beta_receptor_2

  2. What is TGF-βR2? • A transmembrane serine/threonine kinase • A tumor suppressor • Important in mammalian development • Required for growth inhibition in colon

  3. The TGF-β Pathway Just a Bit Simplified Waite, K. A. & Eng, C. (2003)

  4. TGF-βR2 is important for mammalian development • Expressed during embryogenesis • Necessary for hematopoesis and vasculogenesis in the yolk sac. Oshima, M., Oshima, H., & Taketo, M. M. (1996)

  5. Different Ligands Do Different Jobs • Knockout of TGF-β1 • Wasting syndrome and Diffuse inflammation • ~50% die at E10 days due to hematopoetic and vasculogenetic defect in the yolk sac.

  6. Different Ligands Do Different Jobs • Knockout of TGF-β1 • Wasting syndrome and Diffuse inflammation • ~50% die at E10 days due to hematopoetic and vasculogenetic defect in the yolk sac. • Knockout of TGF-β2 • Embryos die at 13.5 days

  7. Different Ligands Do Different Jobs • Knockout of TGF-β1 • Wasting syndrome and Diffuse inflammation • ~50% die at E10 days due to hematopoetic and vasculogenetic defect in the yolk sac. • Knockout of TGF-β2 -- Embryos die at 13.5 days • Knockout of TGF-β3 • Abnormal lung development • Abnormal cleft palate

  8. To get around early embryonic defects, scientists made chimeric mice • Gene inactivated by introducing a truncation • All surviving chimeras had ≤5% mutant cells • Surviving chimeras indistinguishable from wild-type at birth • Showed wasting phenotype and severe weight-loss after two weeks Oshima, M., Oshima, H., & Taketo, M. M. (1996)

  9. The TGFβ Pathway Has Important Redundancies Waite, K. A. & Eng, C. (2003)

  10. TGFβR2 is mutated in manycancers of the gastrointestinal tract http://en.wikipedia.org/wiki/Small_intestine_cancer

  11. Where Does TGF-βR2 work in the intestine? • In differentiated cells of the small intestines TGF-βR2 Important Here Sancho, E., Batlle, E., & Clever, H. (2004)

  12. What Goes Wrong In Cancer? Cystein rich domain = binding site for Type 1 Receptor Poly A Region = Microsatellite Instability Yang, H. et al (1999)

  13. Microsatellite Instability • Causes mis-alignment during replication Lin, H. Y., Wang, X. F., Ng-Eaton, E., Weinberg, R. A., & Lodish, H.F. Expression Cloning. Cell 68, 775-785

  14. Immunoblot Analysis of SNU Gastric Cancer Cell Lines • Lane 1 and 2: Truncated mRNA, no protein • Lane 3: Control • Lane 4: Amplified DNA, over expression of protein Park, K. et al (1994)

  15. References: Oshima, M., Oshima, H., & Taketo, M. M. TGF-β Receptor Type II Deficiency Results in Defects of Yolk Sac Hematopoiesis and Vasculogenesis. Developmental Biology 179, 297-302. Pardali, K., & Moustakas, A. Actions of TGF-β as Tumor Suppressor and Pro-Metastatic Factor in Human Cancer. Biochemica et Biophysica Acta 1775, 21-62. Park, K., Kim, S., Yung-Jue, B., Park, J., Kim, N., Roberts, A. B., & Sporn, M. B. Genetic Changes in the Transforming Growth Factor β (TGF-β) Type II Receptor Gene in Human Gastric Cancer Cells: Correlation with Sensitivity to Growth Inhibition by TGF-β. Proc. Natl. Acad. Sci. USA91, 8772-8776. Sancho, E., Battle, E., & Clevers, H. Signaling Pathways in Intestinal Developmental and Cancer. Annu. Rev. Cell Dev. Biol. 20, 695-723. Sasaki, A. et al. Microsatellite Instability in Gastric Cancer Prone Families. Cancer Letters99, 169-175. Waite, K. A. & Eng, C. From Developmental Disorder to Heritable Cancer: It’s All in The BMP/TGF-β Family. Nature Reviews 4, 763-772. Yang, H., Kang, S. H., Kim, Y., Won, K., Bang, Y., & Kim, S. Truncation of the TGF-β Type II Receptor Gene Results in Insensitivity to TGF-β in Human Gastric Cancer Cells. Oncogene 18, 2213-2219.

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