What is BMPR1A?

1. Bone Morphogenetic Protein Receptor 1A (BMPR1A) and Juvenile Polyposis SyndromeCara DavidsonMarch 18, 2004

2. Whatis 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, 763-73 (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;35:1029-41.

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, 763-73 (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 www.murrasaca.com/Juvenilepolyposis

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 http://aboutplastic.surgery.uiowa.edu/fjp.html

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. 2001 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: 763-73. • http://www.mtsinai.on.ca/familialcancer/Diseases/JP/default.htm • www.vh.org/pediatric/patient/cancercenter/juvenilepolyposis/ • 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:L740-54. • Suzuki, et al. A truncated BMP receptor affects dorsal-ventral patterning in early Xenopus embryos. Proc Natl Acad Sci USA. 1994 Oct; 91(22):10255-9. • 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; 46:243-53. • http://aboutplastic.surgery.uiowa.edu/fjp.html • www.murrasca.com.Juvenilepolyposis • Hebert, Jean et al. BMP Signaling Is Required Locally to Pattern the Dorsal Telencephalic Midline. Neuron. 2002;35:1029-41.