ZAFIA ANKLESARIA

Role of BMPR1A in JuvenilePolyposis 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

1/100000 -1/160000

Malignancy potential of 65%

Extra intestinal cancers are not common

Age of diagnosis 26.1 + 15.6 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

PP

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)

ReferencesBatts, 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 20.11 (2005): 1634-40.

Haramis, A. P., et al. "De Novo Crypt Formation and Juvenile Polyposis on BMP Inhibition in Mouse Intestine." Science 303.5664 (2004): 1684-6.

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): 901-6.

Tian, Q., et al. "Bridging the BMP and Wnt Pathways by PI3 kinase/Akt and 14-3-3zeta." Cell.Cycle 4.2 (2005): 215-6.