Download TGF-β receptor 1

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
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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

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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

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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
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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 factoroverproduction 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)