A beta-arrestin-dependent scaffold is associated with prolonged MAPK activation in pseudopodia during protease-activated receptor-2-induced chemotaxis - PubMed (original) (raw)

. 2003 Sep 5;278(36):34418-26.

doi: 10.1074/jbc.M300573200. Epub 2003 Jun 23.

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A beta-arrestin-dependent scaffold is associated with prolonged MAPK activation in pseudopodia during protease-activated receptor-2-induced chemotaxis

Lan Ge et al. J Biol Chem. 2003.

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Abstract

Cell motility during wound healing and inflammation is often dependent on the ability of the cell to sense a gradient of agonist. The first step in this process is the extension of a pseudopod in the direction of the agonist, and a diverse set of signals mediate pseudopod extension by different receptors. We have reported previously that protease-activated receptor-2 (PAR-2), a proinflammatory receptor that is highly expressed in motile cells such as neutrophils, macrophages, and tumor cells, is one of a growing family of receptors that utilizes a beta-arrestin-dependent mechanism for activation of the 42-44-kDa members of the MAPK family (extracellular signal-regulated kinases 1 and 2; ERK1/2). beta-Arrestin-bound PAR-2 serves as a scaffold to sequester a pool of activated ERK1/2 in the cytosol; however, a specific role for the sequestered kinase activity has not been established. We now show that PAR-2 activation promotes ERK1/2- and beta-arrestin-dependent reorganization of the actin cytoskeleton, polarized pseudopodia extension, and chemotaxis. Using subcellular fractionation, confocal microscopy, and physical isolation of pseudopodial proteins, we demonstrate that the previously identified PAR-2/beta-arrestin/ERK1/2 scaffolding complex is enriched in the pseudopodia, where it appears to prolong ERK1/2 activation. These studies suggest that the formation of a beta-arrestin/ERK1/2 signaling complex at the leading edge may be involved in localized actin assembly and chemotaxis and provide the first example of a distinct cellular consequence of beta-arrestin-sequestered ERK1/2 activity.

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