Transforming Growth Factor-Beta Receptor 2 TGF-β receptor 2 In gastric cancer.
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Transcript of Transforming Growth Factor-Beta Receptor 2 TGF-β receptor 2 In gastric cancer.
Gene Information
TGF-β receptor 2, also called, TGFβRII or TβRII is located at 3p22
Ventura et al., Genome Res. 14:1696-1703, 2004
7 exons
http://butler.cit.nih.gov/hembase/hembase.taf?_function=list&Chromosome=3&_UserReference=0666662AC360969CC75B2853
TGF-β receptor 2 is a receptor serine-threonine kinase
TGF-β
K. Pardali, A. Moustakas / Biochimica et Biophysica Acta 1775 (2007) 21–62 Fig. 1
TβRII binds to TβRI
This complex binds the ligand TGF- β
Han-Kwang Yan Oncogene (1999) 18, 2213 ± 2219 Fig. 4
kinase domain
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
http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NM_001024847.1&dopt=gb
K. Pardali, A. Moustakas / Biochimica et Biophysica Acta 1775 (2007) 21–62 Fig. 1
It trans-phosphorylates
TβRI which phosphorylates other
molecules
How does the pathway work?
First, meet the molecules
TGF-β
TGF-β receptor 2 and TGF-β receptor 1
Smads
Types:R-Smads
Co-Smad
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
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
Who are these again?
p21, p27 and p57 are in the p21 family of CDK inhibitors that bind directly to CDK complex
CDK
Cyclinp21
P15 is in the INK4 family of CDK inhibitors which replaces cyclin D in the
complexCDK
p15
c-Myc is an early response gene that
encodes a transcription factor turned on by
growth factors
And to follow the pathway
When TGF-β receptor 2 is active the pathway
inhibits the CDKs
CDKI
CDKs do not phosphorylate pRb so
the cell does not progress into S phase
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 PROLIFERATIONK. Pardali, A. Moustakas / Biochimica et Biophysica Acta 1775 (2007) 21–62 Fig. 2
The normal function of TGF-β complex is as a Tumor Suppressor
Oncogene or Tumor Suppressor?
TGF-β signaling inhibits proliferation
and induces apoptosis
Tumor Suppressor = Loss of Function
What happens when TGFβRII is knockout?
Day 9.5 yolk sac anemia
Day 10.5 Growth retardation
The embryos did not survive past day 13.5
TGFβRII required in early development
Oshima, Masanobu Developmental Biology 179, 297–302 (1996)
Chimeric mice had cerebral hemorrhages, extra fluid in the brain, and cranial abnormalities
Needed for vascular and blood cell development
www.gihealth.com/images/imgStomachCancer.gif
Mutations in TGF β-Receptor 2 can contribute to the development of stomach tumors
TGF-β Receptor 2 and gastric cancer
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
One piece of evidence supporting this hypothesis
Han-Kwang Yan Oncogene (1999) 18, 2213 ± 2219 Fig. 5
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
What happens to TβRII to cause inactivation?
Microsatellite instability
Addition or deletion of a single base pair in the microsatellite can cause a frame shift
mutation and inactivation of the kinase
Microsatellites are repeats of a single base pair or a few base pairs
attatgaagg aaaaaaaaaa gcctggtgag
Microsatellite in exon 3
R.-J.Guo et al. Carcinogenesis vol.19 no.9 pp.1539–1544, 1998
We know it is microsatellite instability because…
R.-J.Guo et al. Carcinogenesis vol.19 no.9 pp.1539–1544, 1998
Case ACase B
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
In Review
Transforming Growth Factor Beta Receptor 2 is a serine/threonine receptorkinase that activates the SMAD transcription factors
During normal development, its first role is in promoting development of thevascular system
It's normal function in the gastrointestinal system is to activate CKDI orinhibit c-Myc, thus arresting the cell cycle in G1
TβRII acts as a tumor suppressor and inactivation can cause gastric cancer
TβRII is inactivated by microsatellite instability which causes frame shift mutations