Transforming Growth Factor β Receptor Type II

Tina Morrishttp://en.wikipedia.org/wiki/TGF_beta_receptor_2

What is TGF-βR2?

• A transmembrane serine/threonine kinase• A tumor suppressor• Important in mammalian development • Required for growth inhibition in colon

The TGF-β Pathway

Just a Bit Simplified

Waite, K. A. & Eng, C. (2003)

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)

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-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

• 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

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)

Waite, K. A. & Eng, C. (2003)

The TGFβ Pathway Has Important Redundancies

TGFβR2 is mutated in manycancers of the gastrointestinal

tract

http://en.wikipedia.org/wiki/Small_intestine_cancer

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)

What Goes Wrong In Cancer?

Yang, H. et al (1999)

Cystein rich domain = binding site for Type 1 Receptor

Poly A Region = Microsatellite Instability

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

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)

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.