1. Bone Morphogenetic Protein Receptor 1A (BMPR1A) and Juvenile Polyposis Syndrome Cara Davidson March 18, 2004

2. What is BMPR1A? A receptor serine-threonine kinase
Located on plasma membrane
Part of the TGF-ß receptor superfamily
Large family of cell-surface receptors with pathways that regulate many processes (ex. cellular proliferation, adhesion, differentiation, development, wound repair)

3. Signaling Pathway for TGF-ß
Waite, Kristin and Chris Eng. From Developmental Disorder to Heritable Cancer: It’s all in the BMP/TGF-ß Family.
Nature Reviews 4, (2003).

4. What does BMP pathway do?
BMP, a cytokine is the ligand
Binds to type II receptor which…
Binds, phosphorylates, activates type I receptor (BMPR1A) which…
Phosphorylates, activates R-SMAD which…
Associates with Co-SMAD (SMAD4)
The SMAD complex moves to the nucleus and induces transcription of target genes

5. History of BMP pathway Discovered in 1965 by Urist
He injected demineralized bone matrix under skin of adult rodents  new bone
Protein named Bone Morphogenetic Protein
Later discovered to have much wider array of effects

6. What does pathway do normally?
Early embryonic development
Dorso-ventral axis development
For vertebrates (Xenopus) BMP leads to ventral fate
For invertebrates (Drosophila) BMP leads to dorsal fate
Implicated in bone/cartilage/feather development in chicken embryos
Bone development in mice
Neural development in mice embryos

7. More normal function Proliferation
Adding BMP (the ligand) to smooth muscle cells inhibits proliferation and growth
Adding BMP to pulmonary vascular cells induced apoptosis (tumor suppressor)

8. Knockout Mice that are -/- for BMP1A die at gastrulation
Must be important for basic development
Hebert et al. (2002) made mouse KO for BMP1A only in telencephalon region of brain
Result = abnormal choroid plexus (too much proliferation)
Choroid plexus- site of production of CS fluid, important in blood-brain barrier

9. Knockout (cont)
Hebert, Jean et al. BMP Signaling Is Required Locally to Pattern the Dorsal Telencephalic Midline. Neuron. 2002;35:

10. Knockout BMP1B
But mice that are KO for the very closely related BMP1B are viable!
Only problem is shortened bones in axial skeleton
More research needed to find out why

11. The Network of Pathways
Waite, Kristin and Chris Eng. From Developmental Disorder to Heritable Cancer: It’s all in the BMP/TGF-ß Family.
Nature Reviews 4, (2003).

12. But the point is… BMPR1A acts as a tumor suppressor
When ligand bound and pathway on, proliferation is suppressed

13. Mutations in BMPR1A remove the pathway’s tumor suppression
Several different mutations in protein can cause cancer
Nonsense mutations are most harmful, especially those that effect the Ser-Thr kinase domain
Mutation is recessive, need LOH to get cancer (like Rb)

14. The Mutations
Green = kinase domain
Waite and Eng, 2003.

15. Juvenile Polyposis (JP)
Inherited syndrome (autosomal dominant)
Gastrointestinal hamartomatous polyps
Fun vocab fact: hamartomatous=developing from normal tissue
Effects 1 in 100,000 people

16. Juvenile Polyposis (cont.)
Usually early onset (before 20) but can show up at any age
5-500 polyps, mostly in colon and rectum
Difficult to diagnose because of similar disorders (Cowden’s)
Treatment: regular examination, removal

17. How did we connect BMPR1A to JP?
JP originally blamed on SMAD4 and PTEN only
But some JP sufferers don’t have a mutation in these genes
Study of JP families showed frequent mutations in area near PTEN on chromosome 10
Sequence comparisons  BMPR1A

18. Cancer Risks and JP
Increases individual’s risk of getting colon cancer by 10 times (50% vs 5%)
Also increases chance of getting cancer of stomach, pancreas, upper GI tract
So far, little evidence that the specific BMPR1A mutation is significant in sporadic colon cancer, but pathway is believed to be important

19. The Real Picture probably more complicated
BMPR1A mutation not the only one connected with JP (also SMAD4)
Some individuals with JP show other symptoms
Cardiac and pulmonary malformations
Digital clubbing
Hypertension
The whole pathway needs to be investigated further

20. Sources
Howe JR., et al. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis.Nature Genetics Jun;28(2):184-7.
Waite, Kristin and Chris Eng. From Developmental Disorder to Heritable Cancer: It’s all in the BMP/TGF-ß Family. Nature Reviews. 2003; 4:
Zhang, et al. Bone morphogenetic protein (BMP) induced apoptosis in human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2003; 285:L
Suzuki, et al. A truncated BMP receptor affects dorsal-ventral patterning in early Xenopus embryos. Proc Natl Acad Sci USA Oct; 91(22):
Ashique, et al. Signalling via type IA and type IB BMPR regulates intramembranous bone formation, chondrogenesis, and feather formation in the chicken embryo. Int J Dev Biol. 2003; 46:
Hebert, Jean et al. BMP Signaling Is Required Locally to Pattern the Dorsal Telencephalic Midline. Neuron. 2002;35: