PDGF- β Receptor

14
PDGF-β Receptor Chris Halloran 03.04.2004 Baker, http://www.bcm.tmc.edu/medicine/hema-onco/lectures/mds

description

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. - PowerPoint PPT Presentation

Transcript of PDGF- β Receptor

Page 1: PDGF- β Receptor

PDGF-β Receptor

Chris Halloran

03.04.2004

Baker, http://www.bcm.tmc.edu/medicine/hema-onco/lectures/mds/sld017.htm.

Page 2: PDGF- β Receptor

PDGF-β Receptor Function

• Receptor Tyrosine Kinase

• Activated by PDGF ligand dimers.

Lodish et al. Fig. 20-21

Page 3: PDGF- β Receptor

PDGFR Ligands

http://www.licr.org/07_spot/PDGF.htm

Page 4: PDGF- β Receptor

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

Page 5: PDGF- β Receptor

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.

Page 6: PDGF- β Receptor

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.

Page 7: PDGF- β Receptor

Knockouts

• Mouse KO’s for PDGF-A & B and their receptors

• Disappointing results

for PDGF-βR KO’s…

Page 8: PDGF- β Receptor

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.

Page 9: PDGF- β Receptor

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

Page 10: PDGF- β Receptor

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?

Page 11: PDGF- β Receptor

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

Page 12: PDGF- β Receptor

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

Page 13: PDGF- β Receptor

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.

Page 14: PDGF- β Receptor