Tatton, Emma Louise; (2003) The role of Src kinases in cytokine induced signalling in haemopoietic cells. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Stimulation of haemopoietic cells with granulocyte-macrophage colony stimulating factor (GM-CSF) or interleukin 3 (IL-3) activates Src, JAK and STAT kinases and the MAPK and PI-3K pathways resulting in survival, proliferation and differentiation. The role of Src kinases in signalling pathways initiated by stimulation with the related cytokines GM-CSF and IL-3 and by stem cell factor (SCF), and the subsequent biological effects were examined using the inhibitor PPI, which was originally described as a selective inhibitor of Src tyrosine kinase family members. In this study, Src was shown to play a critical role in GM-CSF and IL-3 induced PI- 3K signalling and activation of it target proteins, Akt and p70 S6K, and in GM-CSF induced proliferation of myeloid derived cell lines and primary haemopoietic cells. There was no evidence to suggest that Src kinases are required for GM-CSF or IL-3 activation of MAPK or STAT5, or for protection from apoptosis due to cytokine withdrawal. In neutrophils, cell surface expression of the adhesion molecules CD11b and CD621 is altered in response to GM-CSF stimulation, resulting in increased tethering to, and migration through the endothelium. The GM-CSF induced increase of CD11b and decrease of CD621 on the surface of neutrophils was unaffected by incubation with PPI. PPI has been extensively used to demonstrate a requirement for Src kinases in SCF signalling. However, it was shown that PPI is also a potent inhibitor of the SCF receptor c-Kit, as it blocked SCF induced MAPK and Akt phosphorylation, and c-Kit autophosphorylation as well as c-Kit mediated proliferation and survival. These effects were observed in cells expressing wild type and constitutively active mutant c-Kit. These results demonstrate that Src kinases play a significant role in GM-CSF/IL-3 cell signalling, and may be beneficial in the treatment of malignant diseases associated with dysregulated c-Kit tyrosine kinase activity.

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