1. PDGF β Receptor

2. Protein 1106 amino acid protein Weinberg Fig 5.10

3. Protein 1106 amino acid protein Receptor tyrosine kinase located in plasma membrane Weinberg Fig 5.10

4. Protein 1106 amino acid protein Receptor tyrosine kinase located in plasma membrane Five extracellular immunoglobulin-like motifs and an intracellular split tyrosine kinase domain Weinberg Fig 5.10

5. PDGF Receptor Family Family contains α and β subunits that can homodimerize or heterodimerize Hoch and Soriano. (2003) Development. 130: 4769-4787.

6. PDGF Receptor Family Family contains α and β subunits that can homodimerize or heterodimerize Receptor associates with different PDGF ligands that also dimerize Hoch and Soriano. (2003) Development. 130: 4769-4787.

7. PDGF Receptor Family Family contains α and β subunits that can homodimerize or heterodimerize Receptor associates with different PDGF ligands that also dimerize PDGFβ receptor has highest affinity for PDGF BB ligand Hoch and Soriano. (2003) Development. 130: 4769-4787.

8. Receptor Activation Receptor dimerization with ligand binding www.che.ncsu.edu/haughlab/PDGFR.jpg

9. Receptor Activation Receptor dimerization with ligand binding Activation of tyrosine kinase domains www.che.ncsu.edu/haughlab/PDGFR.jpg

10. Receptor Activation Receptor dimerization with ligand binding Activation of tyrosine kinase domains Autophosphorylation of tyrosine residues in cytoplasmic domains www.che.ncsu.edu/haughlab/PDGFR.jpg

11. Receptor Activation Receptor dimerization with ligand binding Activation of tyrosine kinase domains Autophosphorylation of tyrosine residues in cytoplasmic domains Creation of docking sites at phosphorylated tyrosine residues for proteins and adaptors that initiate signal transduction www.che.ncsu.edu/haughlab/PDGFR.jpg

12. Signaling Pathways Receptor activation initiates multiple signaling pathways Many signaling pathways influence cell proliferation Hoch and Soriano. (2003) Development. 130: 4769-4787.

13. Normal Cellular Role Promotes mesenchymal cell migration Involved in wound healing and vascular repair www.scienceboard.net/.../cyto_figure1_2002.gif

14. Knock Out Mice PDGFB and PDGFβR show same phenotype in knockout mice Embryonic lethal due to extensive hemorrhaging Kuo et al. (1997). Genes and Development. 22: 2996-3006.

15. Developmental Roles: Vasculature Support Cells Hoch and Soriano. (2003) Development. 130: 4769-4787.

16. Gene Fusion Occurs in acute myelogenous leukemia and chronic myeloid leukemia Translocation of PDGFβR gene with the gene for other proteins that are prone to dimerize Creates a constitutively dimerized receptor

17. PDGFβ Receptor Regulates Blood Cell Proliferation and Differentiation Myeloproliferative disorders – large numbers of abnormal red blood cells, white blood cells, or platelets grow and spread in the bone marrow and the peripheral blood Eosinophilia – too many eosinophils (type of white blood cell) are found in bone marrow, blood, and tissue

18. Cancer: Myeloproliferative Disorders Acute Myelogenous Leukemia (AML) – translocation of CEV14 gene and PDGFβR www.leukemia-web.org/images/cells.jpg

19. Cancer: Myeloproliferative Disorders Chronic Myeloid Leukemia (CML) – translocation between chromosomes 12 and 5 creating an ETV6- PDGFβR fusion gene http://www.pathguy.com/lectures/cml.jpg

20. Metastatic Medulloblastomas Tumor of primitive precursors of neurons in cerebellum 85% overexpress PDGF β receptor Gilbertson and Clifford. (2003) Nature Genetics. 35: 197-198

21. Gleevec Imatinib mesylate Inhibitor of kinase activity of PDGFβR and other protein tyrosine kinases Occupies ATP binding site FDA approved for treatment of chronic myeloid leukemia medicineworld.org/.../9-2006/gleevec-89121.jpgcontent.answers.com/main/content/wp/en/thumb/...

22. Sources Cross, N.C.P. and A. Reiter. (2002). Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Leukemia. 16, 1207-1212. Gilbertson, Richard J. and Steven C. Clifford. (2003). PDGFRB is overexpressed in metastatic medulloblastoma. Nature Genetics. 35, 197-198. Hoch, Renee V. and Philippe Soriano. (2003). Roles of PDGF in animal development. Development. 130, 4769-4784. Irusta, Pablo M. and Daniel DiMaio. (1998). A single amino acid substitution in a WW-like domain of diverse members of the PDGF receptor subfamily of tyrosine kinases causes constitutive receptor activation. EMBO Journal. 17, 6912–6923. Weinberg, Robert A. The Biology of Cancer. New York: Garland Science, 2007.