BMP receptor1a Amit Patel

2005 Estimated US Cancer Deaths* ONS=Other nervous system. Source: American Cancer Society, 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

Causes of Colon Cancer Source: National Institute of Gastroenterology.

Juvenile Polyposis Source: Mount Sinai Hospital

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

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

BMPR1a is a BMP receptor Waite and Eng, Nature Reviews 4: (2003)

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

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

Heart -specific deletion of BMPR1a leads to cardiac anomalies

Juvenile Polyposis Source: Mount Sinai Hospital

What Goes Wrong in Juvenile Polyposis? Waite and Eng, Nature Reviews 4: (2003)

How Do These Mutations Lead to Cancer?

Used mice as a model organism

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

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

Wnt Expression WNT He et al, Nature Genetics 36: (2004)

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