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


• Receptor tyrosine kinase located in plasma membrane

Weinberg Fig 5.10

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.



• Receptor associates with different PDGF ligands that also dimerize

Hoch and Soriano. (2003) Development. 130: 4769-

4787.



• Receptor associates with different PDGF ligands that also dimerize

• PDGFβ receptor has highest affinity for PDGF BB ligand


Receptor Activation

• Receptor dimerization with ligand binding

www.che.ncsu.edu/haughlab/PDGFR.jpg

Receptor Activation


• Activation of tyrosine kinase domains


Receptor Activation



• Autophosphorylation of tyrosine residues in cytoplasmic domains


Receptor Activation



• Autophosphorylation of tyrosine residues in cytoplasmic domains

• Creation of docking sites at phosphorylated tyrosine residues for proteins and adaptors that initiate signal transduction


Signaling Pathways

• Receptor activation initiates multiple signaling pathways

• Many signaling pathways influence cell proliferation


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


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.

Documents

PDGF β Receptor. Protein 1106 amino acid protein Weinberg Fig 5.10