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

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)

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).

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

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

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

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)

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

Knockout (cont) Hebert, Jean et al. BMP Signaling Is Required Locally to Pattern the Dorsal Telencephalic Midline. Neuron. 2002;35:1029-41.

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

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).

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

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)

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

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

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

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

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

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

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.