β-Arrestin2 Is Critically Involved in CXCR4-mediated Chemotaxis, and This Is Mediated by Its Enhancement of p38 MAPK Activation

Abstract

Chemotaxis mediated by chemokine receptors such as CXCR4 plays a key role in lymphocyte homing and hematopoiesis as well as in breast cancer metastasis. We have demonstrated previously that ␤-arrestin2 functions to attenuate CXCR4-mediated G protein activation and to enhance CXCR4 internalization. Here we show further that the expression of ␤-arrestin2 in both HeLa and human embryonic kidney 293 cells significantly enhances the chemotactic efficacy of stromal cell-derived factor 1␣, the specific agonist of CXCR4, whereas the suppression of ␤-arrestin2 endogenous expression by antisense or RNA-mediated interference technology considerably attenuates stromal cell-derived factor 1␣-induced cell migration. Expression of ␤-arrestin2 also augmented chemokine receptor CCR5-mediated but not epidermal growth factor 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 dominantnegative mutant of p38 MAPK effectively blocked the chemotactic effect of ␤-arrestin2. Expression of a dominant-negative mutant of ASK1 also exerted the similar blocking effect. The results of our study suggest that ␤-arrestin2 can function not only as a regulator of CXCR4 signaling but also as a mediator of stromal cellderived factor 1␣-induced chemotaxis and that this activity probably occurs via the ASK1/p38 MAPK pathway.

Soluble Fractalkine Prevents Monocyte Chemoattractant Protein-1-Induced Monocyte Migration via Inhibition of Stress-Activated Protein Kinase 2/p38 and Matrix Metalloproteinase Activities

“…Indeed, several reports have shown that SAPK2/p38 is involved in chemokine-induced chemotaxis of cells (16,34,70,71). Our study also presents evidence that SAPK2/p38 and SAPK1/JNK1, but not ERKs, intervene in the control of MCP-1-induced MonoMac6 migration.…”

Fenoterol, a β2-adrenoceptor agonist, inhibits LPS-induced membrane-bound CD14, TLR4/CD14 complex, and inflammatory cytokines production through β-arrestin-2 in THP-1 cell line

“…For example, β-arrestin-2-dependent stabilization of cytosolic IκBα and inhibition of NF-κB activation following LPS stimulation are essential for rapid and sufficient production of NO in response to microbial attack [14] . Moreover, there is accumulating evidence that β-arrestin-2, which is expressed abundantly in the spleen, is functionally involved in some important immune responses, such as regulation of lymphocyte chemotaxis and homing [24,25] . In the present study we used RNA interference against β-arrestin-2 to test its role in anti-inflammatory effects stimulated by β 2 -AR.…”

Receptor tyrosine kinases positively regulate BACE activity and Amyloid-β production through enhancing BACE internalization

“…The RNAi plasmid for human c-Src was constructed as described [31]. A 22-mer oligonucleotide (oligo1) corresponding to nucleotide 594-615 of the c-Src coding sequence was first inserted into the pBS/U6 vector (a generous gift from Dr Yang Shi, Dept.…”

“…Stable expression clones were selected and maintained in G418 (300 mg/ml). For transient transfection, HEK293 cells were transfected by the calcium phosphate-DNA co-precipitation method as described previously [31].…”