| The fps/fes (Fujinami poultry sarcoma/feline sarcoma; hereafter referred to as fps) and fer (fes-related) proto-oncogenes are the only two members of a distinct subfamily of cytoplasmic nonreceptor protein tyrosine kinases (PTK). The distinguishing feature of Fps and Fer kinases is a unique N-terminal region consisting of an N-terminal Fps/Fer-Cdc42-interacting protein 4 (CIP4) homology (FCH) domain, which might have cytoskeletal binding properties, followed by a region containing three predicted coiled-coil (CC) motifs, that modulate homotypic oligomerizatoin of Fps and Fer monomers. Fps expression is limited, however it is detected in cell types that arise from all three germinal layers, including hematopoietic, endothelial, epithelial, chondrocytic, and neuronal cells. In contrast, Fer has been detected in every cell type examined. Relatively little was known about the physiologic functions of fps at the start of my thesis. My main objective was to determine the biochemical and biological functions of Fps in the development and function of hematopoietic cells, through the use of mouse models. Work presented in this thesis demonstrates that Fps and Fer play redundant roles in regulating myelopoiesis and lymphoid homeostasis in vivo. Fps also appears to play a regulatory role in the innate immune response. Bone marrow (BM)-derived macrophages from mice expressing catalytically inactive Fps displayed a reduction in granulocyte macrophage-colony stimulating factor (GM-CSF)-induced tyrosine phosphorylation of the signal transducers and activators of transcription (STAT) 3 and STAT5A, and lipopolysaccharide (LPS)-induced tyrosine phosphorylation of extracellular signal regulated kinase (Erk) 1/2. This suggests that Fps plays a nonredundant role in Janus kinase (Jak)/STAT and mitogen-activated protein kinase (MAPK) signalling pathways. Fps and Fer were also shown to be present in platelets and to be activated downstream from the glycoprotein (GP) VI collagen receptor and protease-activated receptor (PAR) 4. Platelets from mice expressing catalytically inactive Fps and/or Fer exhibited aggregation defects, which might be due to defective inside-out signalling to the fibrinogen integrin. The data presented in this thesis is consistent with in vitro studies demonstrating that Fps is involved in cytokine receptor signalling and regulating myelopoiesis, and also provides evidence for novel roles of Fps in hemostasis and innate immunity. |
