Novel mechanisms for regulation of cell survival and migration by ceramide 1-phosphate
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Ceramide 1-phosphate is a bioactive sphingolipid that regulates important cell functions, including cell proliferation, apoptosis, migration or inflammation. Cell homeostasis is essential for the normal development of any organism and alteration of any of these pro¬cesses can lead to metabolic dysfunction or cause illnesses such as autoimmune diseases, chronic inflammation, neural degeneration, cardiovascular disorders, or cancer. The molecular mechanisms involved in the regulation of these cell responses by C1P have only begun to be understood. The aim of this Doctoral Thesis was to study the cellular signaling processes involved in C1P-stimulated cell proliferation and migration in immune cells, mainly macrophages. Concerning the regulation of cell proliferation, this Thesis has contributed to the elucidation of three major mechanisms by which C1P exerts its mitogenic actions: 1) Stimulation of vascular endothelial growth factor (VEGF) secretion, an action that involves activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. 2) Induction of translocation and activation of protein kinase C alpha (PKCα). 3) Activation of NADPH oxidase and the subsequent formation of reactive oxygen species (ROS). With regards to cell migration, we have demonstrated that C1P stimulates the release of macrophage chemoattractant protein-1 (MCP-1), which is essential for the induction of macrophage migration. In addition, we have shown that C1P-stimulated cell migration requires the interaction of C1P with a putative C1P receptor, and the subsequent activation of the PI3K/Akt, MAPK/Erk1-2, p38 and JNK signalling pathways. Finally, this Thesis also shows that C1P increases the expression of CD69 in spleenic mononuclear cells, and that it protects these cells from entering apoptosis. A major pathway involved in this action is the mitogen-activated protein kinase kinase (MEK)/ERK1-2/ NF-кB pathway.