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

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


1
Bone Morphogenetic Protein Receptor 1A (BMPR1A)
and Juvenile Polyposis SyndromeCara
DavidsonMarch 18, 2004
2
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)

3
Signaling Pathway for TGF-ß
Waite, Kristin and Chris Eng. From Developmental
Disorder to Heritable Cancer Its all in the
BMP/TGF-ß Family. Nature Reviews 4, 763-73
(2003).
4
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

5
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

6
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

7
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)

8
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

9
Knockout (cont)
Hebert, Jean et al. BMP Signaling Is Required
Locally to Pattern the Dorsal Telencephalic
Midline. Neuron. 2002351029-41.
10
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

11
The Network of Pathways
Waite, Kristin and Chris Eng. From Developmental
Disorder to Heritable Cancer Its all in the
BMP/TGF-ß Family. Nature Reviews 4, 763-73
(2003).
12
But the point is
  • BMPR1A acts as a tumor suppressor
  • When ligand bound and pathway on, proliferation
    is suppressed

13
Mutations in BMPR1A remove the pathways 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)

14
The Mutations
Green kinase domain
Waite and Eng, 2003.
15
Juvenile Polyposis (JP)
  • Inherited syndrome (autosomal dominant)
  • Gastrointestinal hamartomatous polyps
  • Fun vocab fact hamartomatousdeveloping from
    normal tissue
  • Effects 1 in 100,000 people

www.murrasaca.com/Juvenilepolyposis
16
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 (Cowdens)
  • Treatment regular examination, removal

http//aboutplastic.surgery.uiowa.edu/fjp.html
17
How did we connect BMPR1A to JP?
  • JP originally blamed on SMAD4 and PTEN only
  • But some JP sufferers dont have a mutation in
    these genes
  • Study of JP families showed frequent mutations in
    area near PTEN on chromosome 10
  • Sequence comparisons ? BMPR1A

18
Cancer Risks and JP
  • Increases individuals 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

19
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

20
Sources
  • Howe JR., et al. Germline mutations of the gene
    encoding bone morphogenetic protein receptor 1A
    in juvenile polyposis.Nature Genetics. 2001
    Jun28(2)184-7.
  • Waite, Kristin and Chris Eng. From Developmental
    Disorder to Heritable Cancer Its all in the
    BMP/TGF-ß Family. Nature Reviews. 2003 4
    763-73.
  • http//www.mtsinai.on.ca/familialcancer/Diseases/J
    P/default.htm
  • www.vh.org/pediatric/patient/cancercenter/juvenile
    polyposis/
  • Zhang, et al. Bone morphogenetic protein (BMP)
    induced apoptosis in human pulmonary vascular
    smooth muscle cells. Am J Physiol Lung Cell Mol
    Physiol. 2003 285L740-54.
  • 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 46243-53.
  • 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. 2002351029-41.
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