1. Transforming Growth Factor-Beta Receptor 2 TGF-β receptor 2
In gastric cancer

2. Gene Information
TGF-β receptor 2, also called, TGFβRII or TβRII is located at 3p22
7 exons
P is the smaller arm of a chromosome
Ventura et al., Genome Res. 14: , 2004

3. TGF-β receptor 2 is a receptor serine-threonine kinase
TβRII binds to TβRI
This complex binds the ligand TGF- β
kinase domain
Han-Kwang Yan Oncogene (1999) 18, 2213 ± 2219 Fig. 4
K. Pardali, A. Moustakas / Biochimica et Biophysica Acta 1775 (2007) 21–62 Fig. 1

4. Where is it found and what does it do?
TGF-β receptor 2 is a receptor kinase: it is found in the plasma membrane
TGF-β
It trans-phosphorylates TβRI which phosphorylates other molecules
K. Pardali, A. Moustakas / Biochimica et Biophysica Acta 1775 (2007) 21–62 Fig. 1

5. How does the pathway work?
First, meet the molecules
Smads
Types:
R-Smads
Co-Smad
TGF-β
TGF-β receptor 2 and TGF-β receptor 1

6. How does the pathway work?
To turn ON:
1) TGF-β binds to TβRII & TβRI complex
2) TβRII trans-phosphorylates TβRI
3) TβRI phosphorylates R-Smads
4) R-Smads move to nucleus and bind with Co-Smads
5) Complex binds to DNA and regulates transcription 1 2 3 4 5
K. Pardali, A. Moustakas / Biochimica et Biophysica Acta 1775 (2007) 21–62 Fig. 1

7. So then what? We run into some old friends again
TGF-β/Smad signaling induces directly transcription of p21, p27, p57, p15
And also represses transcription of
c-Myc
K. Pardali, A. Moustakas / Biochimica et Biophysica Acta 1775 (2007) 21–62 Fig. 2

8. Who are these again?
p21, p27 and p57 are in the p21 family of CDK inhibitors that bind directly to CDK complex
P15 is in the INK4 family of CDK inhibitors which replaces cyclin D in the complex
CDK
p15
CDK
Cyclin
p21
c-Myc is an early response gene that encodes a transcription factor turned on by growth factors

9. And to follow the pathway
CDKI
When TGF-β receptor 2 is active the pathway inhibits the CDKs
CDKs do not phosphorylate pRb so the cell does not progress into S phase

10. And the point is…?
When TGF-β is turned on it either inhibits c-Myc or turns on CDK inhibitors which stop the cell in early G1
= NO PROLIFERATION
K. Pardali, A. Moustakas / Biochimica et Biophysica Acta 1775 (2007) 21–62 Fig. 2

11. Tumor Suppressor = Loss of Function
Oncogene or Tumor Suppressor?
The normal function of TGF-β complex is as a Tumor Suppressor
TGF-β signaling inhibits proliferation
and induces apoptosis
Tumor Suppressor = Loss of Function

12. Scientists explored what role TGF-βRII plays in normal development

13. What happens when TGFβRII is knockout?
TGFβRII required in early development
Day 9.5
yolk sac anemia
Day 10.5
Growth retardation
The embryos did not survive past day 13.5
Chimeric mice had cerebral hemorrhages, extra fluid in the brain, and cranial abnormalities
Needed for vascular and blood cell development
Oshima, Masanobu Developmental Biology 179, 297–302 (1996)

14. TGF-β Receptor 2 and gastric cancer
Mutations in TGF β-Receptor 2 can contribute to the development of stomach tumors

15. How cancer arises
Loss of function of TGF-β receptor 2 causes continuous proliferation
Because even if there is the ligand (TGF-β) the pathway is not activated and the cell cycle is not stopped

16. One piece of evidence supporting this hypothesis
The gastric cancer cell line SNU-5 was transfected with TGF-β, TGF-β RI, and TGF-β RII
Recovery of normal function was found when TGF-β RII was added
Han-Kwang Yan Oncogene (1999) 18, 2213 ± 2219 Fig. 5

17. Microsatellite in exon 3
What happens to TβRII to cause inactivation?
Microsatellite instability
Microsatellites are repeats of a single base pair or a few base pairs
attatgaagg aaaaaaaaaa gcctggtgag
Microsatellite in exon 3
Addition or deletion of a single base pair in the microsatellite can cause a frame shift mutation and inactivation of the kinase
R.-J.Guo et al. Carcinogenesis vol.19 no.9 pp.1539–1544, 1998

18. We know it is microsatellite instability because…
Case B
Case A
Wild Type
Wild Type has 10 adenines
In Case A there was a single deletion
In Case B there were two and three deletions
In Case C there was an addition of adenine and guanine
R.-J.Guo et al. Carcinogenesis vol.19 no.9 pp.1539–1544, 1998

19. In Review
TβRII acts as a tumor suppressor and inactivation can cause gastric cancer
TβRII is inactivated by microsatellite instability which causes frame shift mutations
Transforming Growth Factor Beta Receptor 2 is a serine/threonine receptor kinase that activates the SMAD transcription factors
During normal development, its first role is in promoting development of the vascular system It's normal function in the gastrointestinal system is to activate CKDI or inhibit c-Myc, thus arresting the cell cycle in G1