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

Scientists explored what role TGF-βRII plays in normal development

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