PDGF β Receptor. Protein 1106 amino acid protein Weinberg Fig 5.10.
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Transcript of PDGF β Receptor. Protein 1106 amino acid protein Weinberg Fig 5.10.
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
• 1106 amino acid protein
• Receptor tyrosine kinase located in plasma membrane
• Five extracellular immunoglobulin-like motifs and an intracellular split tyrosine kinase domainWeinberg Fig 5.10
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 ETV6-PDGFβR 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/...
SourcesCross, 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.