transforming growth factor β receptor type ii tina morris
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Transforming Growth Factor β Receptor Type II
Tina Morrishttp://en.wikipedia.org/wiki/TGF_beta_receptor_2
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What is TGF-βR2?
• A transmembrane serine/threonine kinase• A tumor suppressor• Important in mammalian development • Required for growth inhibition in colon
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The TGF-β Pathway
Just a Bit Simplified
Waite, K. A. & Eng, C. (2003)
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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)
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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.
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• 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
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• 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
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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)
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Waite, K. A. & Eng, C. (2003)
The TGFβ Pathway Has Important Redundancies
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TGFβR2 is mutated in manycancers of the gastrointestinal
tract
http://en.wikipedia.org/wiki/Small_intestine_cancer
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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)
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What Goes Wrong In Cancer?
Yang, H. et al (1999)
Cystein rich domain = binding site for Type 1 Receptor
Poly A Region = Microsatellite Instability
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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
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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)
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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.