Chemotaxis, or directed cell migration is essential for host defense, embryonic development, axon guidance, and tumor invasion. Chemotactic cells such as blood neutrophils and neutrophil-like, differentiated HL60 cells respond to a gradient of chemoattractant, e.g., fMet-Leu-Phe (fMLP), by adopting polarized morphology (polarization) and crawling up the gradient (directional sensing). How chemotactic cells initiate polarization and orient their polarity precisely toward spatial cues remains unclear. ‘Global inhibitors’ have been postulated to restrict cells from polarizing in random directions, but only permit the direction pointing to spatial cues. we found that moesin, a cross-linker between plasma membrane and actin cytoskeleton, acted as a global inhibitor for neutrophil chemotaxis, which turned-off both ‘frontness’ and ‘backness’ signals (responsible for pseudopod and uropod formation, respectively), and ensured cell's pseudopod correctly orienting toward the source of attractant in a gradient. Removal of moesin not only enhanced small Rho GTPases, Rac, Rho and Cdc42 activities, but also induced cell protrusion in wrong directions, thus abolished cell’s directional sensing. Myosin phosphatase, on the other hand initiated cell migration by breaking down the global inhibition provided by moesin. In order to kill invading bacteria, neutrophils must interpret spatial cues, migrate, and reach target sites. In addition to mechanisms that promote chemotaxis, there are inhibitory mechanisms ensure chemotactic cells to reach correct destinations where they perform bactericidal functions for phagocytes and antigen identification for homing lymphocytes. To date, little is known about the regulatory mechanisms that inhibit cell migration. We show that two mitogen-activated protein kinases played opposing roles in neutrophil trafficking. The extracellular signal-regulated kinase (Erk) potentiated G protein-coupled receptor kinase GRK2 activity and inhibited neutrophil migration, whereas p38 MAPK acted as a non-canonical GRK that phosphorylated the formyl peptide receptor FPR1 and facilitated neutrophil migration by blocking GRK2 function. Therefore, the dynamic balance between Erk and p38 MAPK controls neutrophil “stop” and “go” behaviors, ensuring neutrophils precisely reach their final destination as the first line of host-defense.
|Commitee:||Carnegie, Graeme K., Fukai, Torhu, Lau, Lester F., Minshall, Richard D., Xu, Jingsong, Zhao, Youyang|
|School:||University of Illinois at Chicago|
|School Location:||United States -- Illinois|
|Source:||DAI-B 75/03(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Cellular biology, Immunology|
|Keywords:||Chemotaxis, Global inhibitors, MAPK, Moesin, Myosin phosphatase, Receptor internalization|
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