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PDGF β Receptor Protein • 1106 amino acid protein Weinberg Fig 5.10 Protein • 1106 amino acid protein • Receptor tyrosine kinase located in plasma membrane Weinberg Fig 5.10 Protein Weinberg Fig 5.10 • 1106 amino acid protein • Receptor tyrosine kinase located in plasma membrane • Five extracellular immunoglobulin-like motifs and an intracellular split tyrosine kinase domain PDGF Receptor Family • Family contains α and β subunits that can homodimerize or heterodimerize Hoch and Soriano. (2003) Development. 130: 4769-4787. 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 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 Receptor Activation • Receptor dimerization with ligand binding www.che.ncsu.edu/haughlab/PDGFR.jpg Receptor Activation • Receptor dimerization with ligand binding • Activation of tyrosine kinase domains www.che.ncsu.edu/haughlab/PDGFR.jpg 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 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 Signaling Pathways • Receptor activation initiates multiple signaling pathways • Many signaling pathways influence cell proliferation Hoch and Soriano. (2003) Development. 130: 4769-4787. Normal Cellular Role • Promotes mesenchymal cell migration • Involved in wound healing and vascular repair www.scienceboard.net/.../cyto_figure1_2002.gif 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 Developmental Roles: Vasculature Support Cells Hoch and Soriano. (2003) Development. 130: 4769-4787. 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 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 Cancer: Myeloproliferative Disorders • Acute Myelogenous Leukemia (AML) – translocation of CEV14 gene and PDGFβR www.leukemia-web.org/images/cells.jpg Cancer: Myeloproliferative Disorders • Chronic Myeloid Leukemia (CML) – translocation between chromosomes 12 and 5 creating an ETV6PDGFβR fusion gene http://www.pathguy.com/lectures/cml.jpg Metastatic Medulloblastomas • Tumor of primitive precursors of neurons in cerebellum • 85% overexpress PDGF β receptor Gilbertson and Clifford. (2003) Nature Genetics. 35: 197-198 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.jpg content.answers.com/main/content/wp/en/thumb/... 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.
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