ZAFIA ANKLESARIA Role of BMPR1A in Juvenile Polyposis Syndrome Biology 169

THE DISCOVERIES BEGIN….

What is juvenile polyposis syndrome?  Autosomal dominant inherited syndrome with variable penetrance  Presence of juvenile polyps in the gastrointestinal tract  Increased intestinal crypt formation and increased intestinal stem cell number.  Congenital defects such as pulmonary valve stenosis  Gastrointestinal cancer predisposition with a malignant potential

Symptoms include…  Severe recurrent diarrhea  Rectal bleeding  Intussusception  Anemia  Prolapse  Abdominal pain

Where and When  1/ /  Malignancy potential of 65%  Extra intestinal cancers are not common  Age of diagnosis years  Clinical similarity to other polyposis syndromes - Cowdens syndrome - Peutz-Jeghers syndrome - Bannayan-Riley-Ruvalcaba syndrome

And of course … HOW  Mutations in SMAD4  23%  Mutations in BMPR1A  25 % The other 50% have UNKNOWN mutations

My focus : BMPR1A  Bone Morphogenic Protein Receptor Type IA  Serine Threonine Kinase Receptor  Receptor for the Bone Morphogenic Protein ligand  Phosphorylates downstream SMADS  Signaling controls duplication of intestinal stem cells and restricts crypt number  Tumor Suppressor gene ( surprised ?)

PATHWAY P BMP BPMPR2 BMPR1A SMAD4 P P P RSMAD DNA binding &  Down regulation of growth Transcription & Apoptosis Nuclear membrane Cell membrane

PATHWAY  BMP ligand binds to the type I – type II receptor complex  Receptors oligomerize and BMPR2 phosphorylates and activates BMPR1A  BMPR1A phosphorylates R SMADS  R SMADS hetero- oligomerize with Co SMAD (SMAD4)  Complex migrates to the nucleus  Transcribe genes that down regulate growth and promotes apoptosis

Therefore…. Normal BMP signaling reduces cell Proliferation….so BMPR1A is a TUMOR SUPPRESSOR When a tumor suppressor gets mutated we get tumors

Mutations BMPR1A mutations cause :  Formation of juvenile polyps in the GI tract due to excess intestinal stem cells and crypt formation  The polyps cause the diagnostic symptoms of the syndrome  Predisposition to cancers of the GI tract, due to loss of tumor suppression properties

The GENE  Receptor for ligands of the TGF-β super-family  11 exons encoding : Signal peptide Extracellular ligand binding domain Transmembrane domain Kinase domain ATP binding domain  Most mutations are missense but a few are truncating  Most mutations occur in the kinase domain

Other players in the pathway…  Noggin – A BMP antagonist  PTEN - BMP signaling enhances PTEN activity PTEN is a major Tumor Suppressor

Other players… P BMP BPMPR2 BMPR1A PTEN NOG R-SMAD SMAD4 Cell membrane Nuclear membrane

P BMP BPMPR2 BMPR1A PTEN NOG R-SMAD SMAD4 Cell membrane Nuclear membrane

ROLE OF BMPR1A  Critical role in endodermal morphogenesis and ectodermal patterning : - homozygous mutant mouse fails to gastrulate - mosaic embryos have a convolution of the ectoderm, distorted anterior end, and form no heart  Important role in intestinal growth control: - conditional inactivation in the intestine of mice leads to the formation of juvenile polyps - conditional misexpression of noggin in the intestine leads to ectopic crypt formation and large polyps

Therefore…. BMPR1A is :  A regulator of morphogenesis  congenital defects  A suppressor of crypt formation and regulates intestinal growth  Intestinal Polyps  A tumor suppressor, regulator of PTEN  Predisposition to cancers

TREATMENTS  Routine colonoscopy  Endoscopic polypectomy to reduce bleeding and intestinal obstruction  Colectomy may be necessary  Regular screening for cancers

Now we know… (quite a bit)

References Batts, L. E., et al. "Bmp Signaling is Required for Intestinal Growth and Morphogenesis." Developmental dynamics : an official publication of the American Association of Anatomists (2006) Chow, E., and F. Macrae. "A Review of Juvenile Polyposis Syndrome." Journal of gastroenterology and hepatology (2005): Haramis, A. P., et al. "De Novo Crypt Formation and Juvenile Polyposis on BMP Inhibition in Mouse Intestine." Science (2004): Sayed, M. G., et al. "Germline SMAD4 Or BMPR1A Mutations and Phenotype of Juvenile Polyposis." Annals of Surgical Oncology : The Official Journal of the Society of Surgical Oncology 9.9 (2002): Tian, Q., et al. "Bridging the BMP and Wnt Pathways by PI3 kinase/Akt and zeta." Cell.Cycle 4.2 (2005):