1. BMP receptor1a Amit Patel

2. 2005 Estimated US Cancer Deaths* ONS=Other nervous system. Source: American Cancer Society, 2005. Men 295,280 Women 275,000 27%Lung & bronchus 15%Breast 10%Colon & rectum 6%Ovary 6%Pancreas 4%Leukemia 3%Non-Hodgkin lymphoma 3%Uterine corpus 2%Multiple myeloma 2%Brain/ONS 22% All other sites Lung and bronchus31% Prostate10% Colon & rectum 10% Pancreas5% Leukemia4% Esophagus4% Liver and intrahepatic3% bile duct Non-Hodgkin 3% Lymphoma Urinary bladder3% Kidney3% All other sites 24% Colon Cancer is an Important Cause of Cancer Deaths in the US

3. Causes of Colon Cancer Source: National Institute of Gastroenterology.

4. Juvenile Polyposis Source: Mount Sinai Hospital

5. Which Gene Causes JP? A heterogeneous disease – 15%-20% of mutations occur on SMAD4 – 25-40% of mutations occur on BMPR1a – Remaining causes are unknown

6. The BMP/TGF-ß Family Waite and Eng, Nature Reviews 4:763-773 (2003)

7. BMPR1a is a BMP receptor Waite and Eng, Nature Reviews 4:763-773 (2003)

8. Loss of BMPR1a leads to embryonic lethality Mishina et al, Genes & Development 9:3027-3027 (1995)

9. BMPR1a signaling is important in many cell fates decisions in embryonic & postembryonic development! Wild Type Mutant Mishina et al, Genes & Development 9:3027-3027 (1995) E 7.0 E 8.5

10. Heart -specific deletion of BMPR1a leads to cardiac anomalies

11. Juvenile Polyposis Source: Mount Sinai Hospital

12. What Goes Wrong in Juvenile Polyposis? Waite and Eng, Nature Reviews 4:763-773 (2003)

13. How Do These Mutations Lead to Cancer?

14. Used mice as a model organism

15. How Do These Mutations Lead to Cancer? BMPR1a is expressed in all but the proliferating cells He et al, Nature Genetics 36: 1117-1121 (2004)

16. How Do These Mutations Lead to Cancer? -Inactivating BMPR1a in developing colon triggered the formation of polyps He et al, Nature Genetics 36: 1117-1121 (2004)

17. Wnt Expression WNT He et al, Nature Genetics 36: 1117-1121 (2004)

18. Inactivating BMPR1a in developing colon triggered the formation of polyps Crosnier et al, Nature Genetics 7: 349-359 (2006)