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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.

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PDGF- β Receptor

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  1. PDGF-β Receptor Chris Halloran 03.04.2004 Baker, http://www.bcm.tmc.edu/medicine/hema-onco/lectures/mds/sld017.htm.

  2. PDGF-β Receptor Function • Receptor Tyrosine Kinase • Activated by PDGF ligand dimers. Lodish et al. Fig. 20-21

  3. PDGFR Ligands http://www.licr.org/07_spot/PDGF.htm

  4. http://bind.ca/tutorials/pdgfr_tut/pdgfr_breakdown.html

  5. 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.

  6. Activated after wounding ~ stimulates vascular growth (angiogenesis) Erythroid & myeloid precursor cells (hematopoeitic stem cells) - Monocyte differentiation - Macrophage activation The Biology of PDGF-βR Cross & Reiter, Leukemia (2002), 1207-12.

  7. Knockouts • Mouse KO’s for PDGF-A & B and their receptors • Disappointing results • for PDGF-βR KO’s…

  8. PDGF-βR KO Phenotype Perinatal Death! Vascular Weaknesses & Cardiac Hypertrophy! Misdeveloped Kidneys! WHY??? Redundancy in the PDGFR superfamily. Hoch and Soriano, Development 120 (30), 4769-84.

  9. 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

  10. 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.

  11. 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

  12. 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

  13. 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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