Bidirectional regulation of neutrophil migration by mitogen-activated protein kinases

Abstract

To kill invading bacteria, neutrophils must interpret spatial cues, migrate, and reach target sites. Although initiation of chemotactic migration has been extensively studied, little is known about its termination. Here we report 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.

The Leukocyte Chemotactic Receptor FPR1 Is Functionally Expressed on Human Lens Epithelial Cells

“…This function of FHL 124 cell FPR1 is supported by the observed fMLFmediated activation of ERK 1/2 and p38 in FHL 124 cells. These MAP kinases were recently reported to be important for the regulation of neutrophil chemotaxis (36). It is intriguing to hypothesize that they may also regulate the directed growth of lens epithelial cells, albeit on a much longer time scale.…”

“…In the literature it has been repeatedly described that FPR1 leads to phosphorylation of MAP kinases like ERK 1/2 or p38 (35)(36)(37). Therefore, we stimulated serum-starved FHL 124 cells with 10 M fMLF and determined MAPK phosphorylation at different time points between 0 and 30 min.…”

The small GTPase Rap1b negatively regulates neutrophil chemotaxis and transcellular diapedesis by inhibiting Akt activation

“…pathways, which are reportedly important for neutrophil migration (Liu et al, 2012), remained unchanged in Rap1b / neutrophils (Fig. 7 D).…”

WD40-repeat proteins control the flow of Gβγ signaling for directional cell migration

“…[15][16][17][18][19][20] It remains to be seen if WDR26 and RACK1 influence Gβγ-mediated activation of these effectors, and whether this regulation contributes to directional migration in leukocytes.…”

“…6 In addition to the PI3K pathway, several other pathways, including those mediated by PLCβ 2/3 , PLA 2 , p38 MAPK, pREX1 and mTORC2 have now been shown to act in parallel or in concert with the PI3K pathway to regulate leukocyte migration. [15][16][17][18][19][20] These pathways are all activated downstream of Gβγ. However, beside PI3Kγ, PLCβ2/3 and pREX1, which are directly activated by Gβγ, the biochemical nature of the other pathways involved in leukocyte chemotaxis remains poorly defined because the direct binding targets of Gβγ have not been identified.…”