Constitutive and chemokine-dependent internalization and recycling of CXCR7 in breast cancer cells to degrade chemokine ligands.
Constitutive and chemokine-dependent internalization and recycling of CXCR7 in breast cancer cells to degrade chemokine ligands.
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DOI：
10.1038/onc.2010.212
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发表时间：
2010-08-12
期刊：
影响因子：
8
通讯作者：
Luker, G. D.
中科院分区：
文献类型：
--
作者：
Luker, K. E.;Steele, J. M.;Mihalko, L. A.;Ray, P.;Luker, G. D.
关键词：
CXCR7是趋化因子的一种受体，包括CXCL12（基质细胞衍生因子 - 1），CXCL12是一种促进乳腺癌和其他恶性肿瘤生长和转移的分子。基于近期观察到CXCR7可结合CXCL12，我们研究了CXCR7依赖的趋化因子摄取机制。表达CXCR7的乳腺癌细胞可在浓度<1ng/ml时积累趋化因子CXCL12和CXC11，这与表达CXCR4的细胞不同。网格蛋白介导的内吞作用抑制剂可减少CXCR7依赖的趋化因子积累。在CXCR7介导的内化作用之后，CXCL12转运至溶酶体并被降解，尽管CXCR7的水平保持稳定。CXCR7减少了细胞外空间中的CXCL12，限制了可用于急性刺激CXCR4信号传导的趋化因子数量。即使在没有配体的情况下，CXCR7也会持续内化并循环至细胞膜，并且添加趋化因子不会显著增强受体内化。浓度低于配体 - 受体结合解离常数（Kd）的趋化因子不会改变细胞表面CXCR7的水平。较高浓度的趋化因子配体降低了CXCR7在细胞表面的总表达量，但不影响受体内化，这表明受体循环受到抑制。CXCR7依赖的趋化因子摄取和受体运输受β - 抑制蛋白2调节。这些研究确定了CXCR7调节细胞外空间中趋化因子配体可用性的机制。
CXCR7 is a receptor for chemokines including CXCL12 (SDF-1), a molecule that promotes tumor growth and metastasis in breast cancer and other malignancies. Building upon the recent observation that CXCR7 sequesters CXCL12, we investigated mechanisms for CXCR7-dependent uptake of chemokines. Breast cancer cells expressing CXCR7 accumulated chemokines CXCL12 and CXC11 present at concentrations < 1 ng/ml, unlike cells expressing CXCR4. CXCR7-dependent accumulation of chemokines was reduced by inhibitors of clathrin-mediated endocytosis. Following CXCR7-mediated internalization, CXCL12 trafficked to lysosomes and was degraded, although levels of CXCR7 remained stable. CXCR7 reduced CXCL12 in the extracellular space, limiting amounts of chemokine available to acutely stimulate signaling through CXCR4. CXCR7 constitutively internalized and recycled to the cell membrane even in the absence of ligand, and addition of chemokines did not significantly enhance receptor internalization. Chemokines at concentrations less than the Kd for ligand-receptor binding did not alter levels of CXCR7 at the cell surface. Higher concentrations of chemokine ligands reduced total cell surface expression of CXCR7 without affecting receptor internalization, indicating that receptor recycling was inhibited. CXCR7-dependent uptake of chemokines and receptor trafficking were regulated by β-arrestin 2. These studies establish mechanisms through which CXCR7 regulates availability of chemokine ligands in the extracellular space.
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影响因子：
3.7
作者：
Laguri, Cedric;Sadir, Rabia;Rueda, Patricia;Baleux, Francoise;Gans, Pierre;Arenzana-Seisdedos, Fernando;Lortat-Jacob, Hugues
通讯作者：
Lortat-Jacob, Hugues
影响因子：
11.8
作者：
Macia, Eric;Ehrlich, Marcelo;Kirchhausen, Tomas
通讯作者：
Kirchhausen, Tomas
影响因子：
4.8
作者：
Kollmar, Otto;Rupertus, Kathrin;Menger, Michael D.
通讯作者：
Menger, Michael D.
影响因子：
3.9
作者：
Hansell, C. A. H.;Simpson, C. V.;Nibbs, R. J. B.
通讯作者：
Nibbs, R. J. B.
影响因子：
2.9
作者：
Hoogewerf, AJ;Kuschert, GSV;Wells, TNC
通讯作者：
Wells, TNC