TGF-β receptor 1

Anshul Badhwar

Transforming Growth Factor β - receptor type I / ALK5 Serine/Threonine kinase receptor.

Transforming Growth Factor β - receptor type I Serine/Threonine kinase receptor. Involved in both tumor suppression and

promotion.

Transforming Growth Factor β - 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.

TGF- β Signal Transduction

Pasche et. al

Knocking out the TGF- β Receptor

Larsson et. al 2001

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.

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

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.

Transfection of TGF-β receptor

Suprisingly enough cells became responsive to TGF- β and underwent growth inhibition similar to wild type.

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.

Pancreatic Cancer

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

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)