β-arrestin2 is critically involved in CXCR4-mediated chemotaxis, and this is mediated by its enhancement of p38 MAPK activation
β-arrestin2 is critically involved in CXCR4-mediated chemotaxis, and this is mediated by its enhancement of p38 MAPK activation
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DOI：
10.1074/jbc.m207294200
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发表时间：
2002-12-20
影响因子：
4.8
通讯作者：
Pei, G
中科院分区：
文献类型：
--
作者：
Sun, Y;Cheng, ZJ;Pei, G
趋化因子受体如CXCR 4介导的趋化性在淋巴细胞归巢和造血以及乳腺癌转移中起关键作用。我们以前已经证明，β-arrestin 2功能减弱CXCR 4介导的G蛋白激活和增强CXCR 4内化。在这里，我们进一步表明，在HeLa细胞和人胚肾293细胞中的β-arrestin 2的表达显着增强了基质细胞衍生因子1 α，CXCR 4的特异性激动剂的趋化作用，而抑制β-arrestin 2的内源性表达的反义或RNA介导的干扰技术大大减弱基质细胞衍生因子1 α诱导的细胞迁移。β-arrestin 2的表达也增强了趋化因子受体CCR 5介导的趋化性，但不增强表皮生长因子受体介导的趋化性，表明β-arrestin 2的特异性作用。进一步的分析表明，β-arrestin 2的表达增强了CXCR 4介导的p38 MAPK和ERK的激活，抑制β-arrestin 2的表达阻断了这两种激酶的激活。有趣的是，抑制p38 MAPK激活（但不是ERK激活）的抑制剂或表达的显性负突变的p38 MAPK有效地阻断了β-arrestin 2的趋化作用。ASK 1的显性失活突变体的表达也发挥了类似的阻断作用。我们的研究结果表明，β-arrestin 2不仅可以作为CXCR 4信号转导的调节剂，而且还可以作为基质细胞衍生因子Ia诱导的趋化性的介质，并且这种活性可能通过ASK 1/p38 MAPK途径发生。
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 beta-arrestin2 functions to attenuate CXCR4-mediated G protein activation and to enhance CXCR4 internalization. Here we show further that the expression of beta-arrestin2 in both HeLa and human embryonic kidney 293 cells significantly enhances the chemotactic efficacy of stromal cell-derived factor 1alpha, the specific agonist of CXCR4, whereas the suppression of beta-arrestin2 endogenous expression by antisense or RNA-mediated interference technology considerably attenuates stromal cell-derived factor 1alpha-induced cell migration. Expression of beta-arrestin2 also augmented chemokine receptor CCR5-mediated but not epidermal growth factor receptor-mediated chemotaxis, indicating the specific effect of beta-arrestin2. Further analysis reveals that expression of beta-arrestin2 strengthened CXCR4-mediated activation of both p38 MAPK and ERK, and the suppression of beta-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 effectively blocked the chemotactic effect of beta-arrestin2. Expression of a dominant-negative mutant of ASK1 also exerted the similar blocking effect. The results of our study suggest that beta-arrestin2 can function not only as a regulator of CXCR4 signaling but also as a mediator of stromal cell-derived factor la-induced chemotaxis and that this activity probably occurs via the ASK1/p38 MAPK pathway.