Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download PDGF receptor β and leukemia
Document related concepts
List of types of proteins wikipedia , lookup
Western blot wikipedia , lookup
Protein purification wikipedia , lookup
Bimolecular fluorescence complementation wikipedia , lookup
Nuclear magnetic resonance spectroscopy of proteins wikipedia , lookup
Protein domain wikipedia , lookup
Protein–protein interaction wikipedia , lookup
Transcript
PDGF receptor β and leukemia Caleb Parker Overview What is PDGFRB? What role does PDGFRB play in the cell? What is CMML? What is Tel/PDGFRB? What is the connection between CMML and Tel/PDGFRB? What are the potential therapies for CMML? What is PDGF? Platelet-derived growth factor Acts as ligand for α- and βreceptors PDGF PDGFR Heldin CH, Otsman A, Ronnstrand L. Signal transduction via Platelet-derived growth factor receptors. Biochem Biophys Acta 1998; 1378: F79-113 What is PDGFRB? Receptor tyrosine kinase Heldin CH, Otsman A, Ronnstrand L. Signal transduction via Platelet-derived growth factor receptors. Biochem Biophys Acta 1998; 1378: F79-113 Downstream molecules PI3 Kinase PLC-γ Grb2/Sos1 Src Fer Stat SHP-2 GAP Cellular roles of PDGFRB Heldin CH, Otsman A, Ronnstrand L. Signal transduction via Platelet-derived growth factor receptors. Biochem Biophys Acta 1998; 1378: F79-113 Important areas of expression Normally expressed in endothelial cells and fibroblasts Role in wound healing Expressed on Myeloid and Erythroid precursors in bone marrow Expressed by mature monocytes, megakaryocytes, and osteoblasts PDGFRB KO Mice Die at or around birth Numerous hematological defects Kidney malformation Hoch Renee V, Soriano Philippe, Roles of PDGF in Animal development. Development 2003 130:4769:4784 Chronic Myelomonocytic Leukemia Persistent, elevated monocyte count (monocytosis) Hypercellular bone marrow Progression into Acute Myeloid leukemia PDGFRB and CMML In late 1980s, a chromosome translocation t(5;12)(q31q33;p12) was associated with patients with CMML Translocation results in a fusion protein Other unique translocations have been discovered PDGFRB has many partner genes The Tel/PDGFRB is most common Phenotypic differences not discerned Np Cross, A Reiter. Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Nature 2002; 16: 1207-1212 What is Tel? Member of ETS family of transcription factors Two key domains: Helix-Loop-Helix (HLH) domain DNA binding domain Carroll M, Tomasson MH, Barker GF, Golub TR, and Gilliland DG (1996) The TEL/platelet-derived growth factor beta receptor (PDGF beta R) fusion in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGF beta Leukemia R kinase-dependent signaling pathways. Proc Natl Acad Sci USA 1996; 93: 14845–14850. Fusion protein Tel/PDGFRB HLH Wilbanks AM, Mahajan S, Frank DA, Druker BJ, Gilliland DG, Carroll M. TEL/PDGFbetaR fusion protein activates STAT1 and STAT5: a common mechanism for transformation by tyrosine kinase fusion proteins. Exp Hematol 2000; 28: 584–593. What causes transformation? Transformation is dependent on Tel HLH domain and PDGFRB kinase activity HLH is shown to mediate dimerization Consistent with model that T/P dimerizes via HLH domain and leads to consituitve activation Possible Therapies Transformation is dependent on functional PDGFRB domain Imantib inhibits phosphorylation of PDGFRB Transformation is dependent on oligomerization of Tel/PDGFRB May be able to interfere with ability to oligomerize Summary PDGFRB is a RTK involved in the maintenance of the hematopoetic system CMML is a type of leukemia marked by monocytosis A fusion protein, Tel/PDGFRB, is associated with CMML Therapies for CMML are developed based on the knowledge of how Tel/PDGFRB transforms a cell Resources Betscholtz christer, Role of Platelet-derived Growth factor in mouse development. Int. J. Dev. Biol. 1995 39:817-825 Carroll M, Tomasson MH, Barker GF, Golub TR, and Gilliland DG (1996) The TEL/plateletderived growth factor beta receptor (PDGF beta R) fusion in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGF beta Leukemia R kinase-dependent signaling pathways. Proc Natl Acad Sci USA 1996; 93: 14845–14850. Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 1994; 77: 307–316. Hoch Renee V, Soriano Philippe, Roles of PDGF in Animal development. Development 2003 130:4769:4784 http://www.leukemia-lymphoma.org/all_page.adp?item_id=557237 Np Cross, A Reiter. Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Nature 2002; 16: 1207-1212 Wilbanks AM, Mahajan S, Frank DA, Druker BJ, Gilliland DG, Carroll M. TEL/PDGFbetaR fusion protein activates STAT1 and STAT5: a common mechanism for transformation by tyrosine kinase fusion proteins. Exp Hematol 2000; 28: 584–593.
