Download PDGF-β Receptor

PDGF-β Receptor
Chris Halloran
03.04.2004
Baker, http://www.bcm.tmc.edu/medicine/hema-onco/lectures/mds/sld017.htm.
PDGF-β Receptor Function
• Receptor Tyrosine
Kinase
• Activated by PDGF
ligand dimers.
Lodish et al. Fig. 20-21
PDGFR Ligands
http://www.licr.org/07_spot/PDGF.htm
http://bind.ca/tutorials/pdgfr_tut/pdgfr_breakdown.html
Cytological Effectors
• 13 phospho-Y residues
• Phosphatidylinositol 3’
kinase (PI3K) &
Phospholipase C-γ (PLCγ)
are key effectors
Tallquist, et al., PLOS Biology (2003), 288-99.
The Biology of PDGF-βR
• Activated after wounding ~ stimulates vascular growth
(angiogenesis)
• Erythroid & myeloid precursor cells (hematopoeitic stem
cells)
- Monocyte differentiation
- Macrophage activation
Cross & Reiter, Leukemia (2002), 1207-12.
Knockouts
• Mouse KO’s for
PDGF-A & B and
their receptors
• Disappointing results
for PDGF-βR KO’s…
PDGF-βR KO Phenotype
Misdeveloped Kidneys!
Perinatal Death!
Vascular Weaknesses & Cardiac Hypertrophy!
WHY???
Redundancy in the PDGFR
superfamily.
Hoch and Soriano, Development 120 (30), 4769-84.
PDGF-βR, the Oncogene
• Disease:
Chronic Myelomonocytic
Leukemia (CMML)
- myeloproliferative disorder
(MPD)
• Constitutive activation by chromosomal translocation
t(5;12)
- novel gene product TEL-PDGF-βR
- TEL: transcription factor
Sjöblom, et al., Oncogene (1999) 18, 7055-62.
http://www.infobiogen.fr/services/chromcancer/Genes/ETV6ID38.html
TEL
Why does this help PDGF-βR become oncogenic?
• Helix-turn-helix domain near N-terminus
- Self binds
- Important for angiogenesis & bone
marrow hematopoiesis
Chackrabarti, et al., Proc Natl Acad Sci 1999, 96 (13): 7467–72.
What happens in CMML?
• CMML is late onset (~70 yrs), male dominance,
median survival ~20 months
• General symptoms: fatigue, shortness of breath, enlarged
spleen and lymph glands, bruising, & abnormal bleeding
• Anemia & increase in monocytes and myelocytes
- Marrow rich in developing monocytes and myelocytes, however
http://www.leukemia-lymphoma.org/all_mat_toc.adp?item_id=69974&cat_id=1215
Treatment Options
• Tyrosine kinase inhibitor
(Gleevec—Phase II) plus
allogenic transplant (stem
cells) shown effective
• Topoisomerase I inhibitor
(Topotecan) ~allowing
p53 mediated apoptosis
• Monoclonal AB therapy
In Conclusion…
• PDGF-βR is an RTK.
• Its major effectors are PI3K and PLCγ.
• PDGF-βR is important for wound healing, blood cell
differentiation, & vascular development.
• PDGF-βR is often mutated in Chronic Myelomonocytic
Leukemia because of a translocation.
- PDGF-βR is an oncogene.
- CMML treatment is currently bleak but hope exists.