Store-operated Ca entry (SOCE) plays a role in the polarization of neutrophil-like HL-60 cells by regulating the activation of akt, src, and rho family gtpases

Abstract

Neutrophil polarization is a basic activity involved in the innate immune response, and it may be initiated by extracellular Ca 2+ entry, a process primarily mediated through store-operated Ca 2+ entry (SOCE). Yet, the mechanisms by which SOCE participates in cell polarization remain unclear. We hypothesized that Akt-and Src-dependent pathways, traditionally linked to neutrophil polarization, may interact with SOCE in this event. In this study, SKF96365 and 2-APB, inhibitors of SOCE as proved by their inhibition on Mn 2+ influx, were observed to inhibit the formyl-methionyl-leucyl- phenylalanine (fMLP)-induced influx of Ca 2+ , the activation of Akt, Src, Rac1, Rac2, and Cdc42, and the polarization of differentiated HL-60 (dHL-60) cells. Downregulation of stromal interaction molecule 1 (STIM1), a Ca 2+ sensor identified to induce SOCE, by siRNA led to decreases in the following indexes: Ca 2+ entry, activation of Akt, Src, Rac2 (rather than Rac1) and Cdc42, and fMLP-induced polarization. This study suggests that SOCE might be the predominant form of Ca 2+ entry involved in the regulation of cell polarization, and it may act through the Akt/Src/Rac pathways, as modeled in dHL-60 cells. It also suggests that STIM1 is a key modulator of cell polarization, potentially serving as a target for the designation of anti-immune deficiency therapies. © 2012 S. Karger AG, Basel.