Regulatory Protein ¦Â-arrestin2 Affects Cell Chemokine And Cytokine Transcription Of The Study

Chemotaxis mediated by chemokine receptors, such as CXCR4, play a key role in lymphocyte homing and hematopoiesis as well as in breast cancer metastasis. We have previously demonstrated that ?-arrestin2 functions to attenuate CXCR4-meidated G protein activation and to enhance CXCR4 internalization. Here we further show that expression of (-arrestin2 in both HeLa and HEK293 cells significantly enhanced the chemotactic efficacy of stromal-cell derived factor 1( (SDF-1(), the specific agonist of CXCR4. While the suppression of (-arrestin2 endogenous expression by antisense or RNAi technology considerably attenuated SDF-1(-induced cell migration. Expression of (-arrestin2 also augmented chemokine receptor CCR5-mediated but not EGF receptor-mediated chemotaxis, indicating the specific effect of (-arrestin2. Further analysis reveals that expression of (-arrestin2 strengthened CXCR4-mediated activation of both p38 MAPK and ERK and the suppression of (-arrestin2 expression blocked the activation of two kinases. Interestingly, inhibition of p38 MAPK activation (but not ERK activation) by its inhibitors or by expression of a dominant negative mutant of p38 MAPK could effectively block the chemotactic effect of (-arrestin2. Expression of a dominant negative mutant of ASK1 also exerted the similar blocking effect. Taken together, our study suggests that (-arrestin2 can function not only as a regulator of CXCR4 signaling but also as a mediator of SDF-1(-induced chemotaxis and this is probably via the ASK1/p38 MAPK pathway.