1. Transforming Growth Factor β Receptor Type II Tina Morris 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. 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 Different Ligands Do Different Jobs

7. 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 Different Ligands Do Different Jobs

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

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

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

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

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

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. USA 91, 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 Letters 99, 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.