The role of calcium-binding proteins MRP8 and MRP14 during cellular dynamics in phagocytes.

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Phagocytic functions like adherence, migration and phagocytosis depend on major rearrangements of the cytoskeleton. These processes are controlled by receptor-mediated calcium signaling and protein phosphorylation cascades. However, the molecular links coordinating the interplay of different cytoskeletal compartments and membrane receptors are not well defined. In previous work we have shown that two members of the S100-family, MRP8 (myeloid related protein 8) and MRP14 play a relevant role in the regulation of cellular dynamics in phagocytes. We have demonstrated that these major calcium-binding proteins in neutrophils and monocytes can act as linker proteins between different cytoskeletal structures depending on the intracellular calcium concentration and the degree of MRP14 phosphorylation. We will now focus on the relevance of these interactions for the inflammatory activation of phagocytes. Based on preliminary results we will further analyse MRP-dependent mechanisms of cellular dynamics in monocytes regarding GTPase activities, Syk-/ Src-signalling, and their consequences for cytoskeletal dynamics, polarization and migration. We will use a combination of genetically modified cell lines, biochemical and biophysical approaches and life cell imaging techniques in vitro and in vivo to identify new pathways of innate immune activation.