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TGF- β receptor 1

TGF- β receptor 1

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TGF- β receptor 1

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  1. TGF-β receptor 1 Anshul Badhwar

  2. Transforming Growth Factorβ - receptor type I / ALK5 • Serine/Threonine kinase receptor.

  3. Transforming Growth Factorβ - receptor type I • Serine/Threonine kinase receptor. • Involved in both tumor suppression and promotion.

  4. Transforming Growth Factorβ - receptor type I • Serine/Threonine kinase receptor. • Involved in both tumor suppression and promotion. • Normal role in tissue regeneration, cell differentiation, embryonic development, growth inhibition and cell migration.

  5. TGF- β Signal Transduction Pasche et. al

  6. Knocking out the TGF- β Receptor Larsson et. al 2001

  7. Knocking out the TGF- β Receptor • Genotyping by PCR will produce a 350bp if TGF- β Receptor gene has been knocked out. • If exon 3 has not been knocked out a 150bp band will show up.

  8. TGF- β Knockout Mice • TGF- β-/- • Embryonic Lethal at Day 10.5 • Abnormal Vascular Development • Reduced Fibronectin Production (in vitro) • Insensitive to TGF- β growth inhibition. (in vitro) • Unresponsive to anti-migratory signals of TGF- β(in vitro) • TGF- β+/- • Development and phenotype same as wildtype

  9. Insensitivity to Growth Suppresion • T3M4 Human Pancreatic Cell lines showed no response to TGF-Beta growth suppression • Interestingly enough, sequencing analysis indicated that T3M4 cells do not harbor mutations in the TGFβ GRI or Smad4 genes.

  10. Transfection of TGF-β receptor • Suprisingly enough cells became responsive to TGF- β and underwent growth inhibition similar to wild type.

  11. Connection to Human Cancers • In Vivo many human pancreatic cancers express low levels of the TGF-beta receptor. • 5% of all pancreatic tumors have the TGF-beta receptor mutated in some form. • In Vitro many human pancreatic are often resistant to growth inhibition by the TGF-beta. • TGF-βRI (ALK5) expression is decreased in a prostate, pancreatic and colon cancer cells.

  12. Pancreatic Cancer • Pancreatic cancer incredibly hard to treat • Symptoms show up very late • 99% fatality rate when diagnosed

  13. References • Baldwin, R. L., Friess, H., Yokoyama, M., Lopez, M. E., Kobrin, M. S., Büchler, M. W. and Korc, M., Attenuated ALK5 receptor expression in human pancreatic cancer: correlation with resistance to growth inhibition. Int. J. Cancer , 67, 283-288 (1996). • Larrsson J., Goumans M.J., Sjostrand L.J., Rooijen M.A., Ward D., Leveen P., Xu X., Dijke P., Mummery C., Karlsson S., Abnormal angiogenesis but intact hematopoietic potential in TGF- β type I receptor-deficient mice, EMBO, 20, 1663-1673 (2001). • Steiner, M. S. and Barrack, E. R., Transforming growth factor- overproduction in prostate cancer: effects on growth in vivo and in vitro. Mol. Endocrinol. , 6, 15-25 (1992). • Wagner M.,Kleeff J, Lopez M.E., Bockman I., Massaqué J., Korc M., Transfection of the type I TGF- β receptor restores TGF- β responsiveness in pancreatic cancer. Int. J. Cancer , 78, 255-260 (1998)