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Regulation of G-CSF receptor ubiquitination: Implications on granulopoieses and pathogenesis in myeloid disorders.
- Abstract
- Myelodysplastic syndromes (MDS) and severe congenital neutropenia (SCN) are myeloid disorders characterized by defective myeloid differentiation. We and others have identified mutations within the granulocyte colony-stimulation factor receptor (G-CSF-R), which es the mamor transducer of signals regulating granulopoiesis, in SCN or MDS patients prone to develop acute myeloid leukemia (AML). Many of the Phenotypic features conferred by these mutations can be explained by defects in negative regulation of G-CSF-R signaling. Modulation and, finally, termination of signaling is largely influenced by receptor routing from the plasma membrane, a process that is controlled by ubiquitination. Two ubiquitin ligases, SOCS3 and WSB-1/2, habe recently been shown to bind to the G-CSF-R and to modulate its signaling suggesting an important role of ubiquitination on G-CSF-R signaling. In addition, preliminary experiments in myelid progenitor cells suggest that the candidate targets for ubiquitination, i.e. conserved lysine residues in the cytoplasmic domain of the G-CSF-R, regulate the G-CSF response.
The aim of this projet ist to thoroughly investigate the mechanisms of G-CSF-R ubiqutination and to determine their impact on intracellular receptor routing and signaling functions. For this purpose, a series of lysine substitution as well as the sisease specific mutant G-CSF-R construckts will be generated. Tu study the individual contribution of SOCS3 and WSB-1/2 to receptor ubiquination, mutants which in addition lack SOCS3 recruitment site Y729 or the C-terminal WSB-binding domain will bei included. Introduction of these G-CSF-R mutants into myeloid progenitor cells form G-CSF-R deficient mice, myeloid 32D cells and HEK293 human embryonic kidney cells will elucidate the mechanisms regulating G-CSF-R ubiquitination and their impact on receptor routing and signaling pathways in al cellular context. This project will therefore provied insights in the mechanisms whereby receptor ubiquitination and their impact on receptor routing and signaling pathways in al cellular context. This project will therefore provide insights in the mechanisms whereby receptor ubiquitination modulates G-CSF-controlled granulopoiesis and will reveal the significance of their deregulation in myeloid disorders. This knowledge may contribute to the design of therapeutic modalities aimed at restoring the signaling network in human myeloid disorders, such as MDS and AML.
- Project Leader:
- Wölfler Albert
- Duration:
- 01.02.2006-31.01.2008
- Programme:
- Schrödinger-Stipendium
- Type of Research
- basic research
- MUG Research Units
- Division of Haematology
- Project partners
- Erasmus MC-Daniel den Hoed Cancer Center, Netherlands