Download - PDGF- β Receptor
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PDGF-β Receptor
Chris Halloran
03.04.2004
Baker, http://www.bcm.tmc.edu/medicine/hema-onco/lectures/mds/sld017.htm.
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PDGF-β Receptor Function
• Receptor Tyrosine Kinase
• Activated by PDGF ligand dimers.
Lodish et al. Fig. 20-21
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PDGFR Ligands
http://www.licr.org/07_spot/PDGF.htm
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http://bind.ca/tutorials/pdgfr_tut/pdgfr_breakdown.html
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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.
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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.
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Knockouts
• Mouse KO’s for PDGF-A & B and their receptors
• Disappointing results
for PDGF-βR KO’s…
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PDGF-βR KO Phenotype
Misdeveloped Kidneys!
WHY???Redundancy in the PDGFR
superfamily.
Perinatal Death!
Vascular Weaknesses & Cardiac Hypertrophy!
Hoch and Soriano, Development 120 (30), 4769-84.
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PDGF-βR, the Oncogene
• Disease:Chronic MyelomonocyticLeukemia (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
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TEL
• 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.
Why does this help PDGF-βR become oncogenic?
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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
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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
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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.
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