Routing dynamics of the colony-stimulating factor 3 receptor and implications for intracellular signaling

Hematopoiesis is the tightly regulated formation of all blood cell types from hematopoietic stem cells, which in adults takes place in the bone marrow. The bone marrow of an average healthy adult produces approximately 10(11)-10(12) peripheral blood cells a day. This process largely depends on hematopoietic growth factors. The granulocyte colony-stimulating factor (CSF)-3 is a member of the cytokine class I superfamily of growth factors that plays an important role in granulopoiesis by stimulating proliferation, survival and differentiation of myeloid progenitor cells. CSF3 deficient mice develop severe neutropenia. Neutrophils are the most abundant white blood cells in man and are rapidly elevated in case of a bacterial infection. CSF3 is administered to neutropenia patients in order to increase peripheral neutrophil levels, thereby reducing the risk of bacterial infection. CSF3 is also commonly used for the mobilization of hematopoietic stem cells into peripheral blood, to facilitate their harvest for the purpose of transplantation. The biological activities of CSF3 are mediated by its binding to the granulocyte colony-stimulating factor receptor (CSF3R), which results in the activation of multiple intracellular signaling pathways such as the janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. Experiments reported in this thesis have specifically dealt with the mechanisms that regulate intracellular trafficking of the CSF3R and the implications on signaling. There are several negative regulatory pathways responsible for switching-off CSF3R signaling. CSF3R internalization and lysosomal routing is one of the major negative feedback mechanisms described and involves SOCS3 dependent ubiquitination of CSF3R juxtamembrane lysine (K)632.

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