Regulation of the Human Chemokine Receptor CCR1
Regulation of the Human Chemokine Receptor CCR1
复制标题
人类趋化因子受体 CCR1 的调节
DOI：
--
复制
发表时间：
2000
影响因子：
4.8
通讯作者：
R. Snyderman
中科院分区：
文献类型：
--
作者：
R. Richardson;Bryan C. Pridgen;B. Haribabu;R. Snyderman
为了研究 CCR1 趋化因子受体的调节，对大鼠嗜碱性白血病 (RBL-2H3) 细胞系进行修饰，使其稳定表达表位标记的受体。这些细胞对 RANTES（根据正常 T 表达和分泌的激活进行调节）、巨噬细胞炎症蛋白 1α 和单核细胞趋化蛋白 2 作出反应，介导磷脂酶 C 激活、细胞内 Ca2+ 动员和胞吐作用。激活后，CCR1 经历磷酸化和脱敏（通过 GTP 酶刺激和 Ca2+ 动员减弱来测量）。特定丝氨酸和苏氨酸残基（S2和S3）的丙氨酸取代或CCR1的胞质尾部（ΔCCR1）的截短消除了受体磷酸化和G蛋白激活的脱敏，但没有消除Ca2+动员的脱敏。相对于 S1 和 CCR1，S2、S3 和 ΔCCR1 也能抵抗内化，介导更大的磷脂酰肌醇水解和持续的 Ca2+ 动员，并且仅被 RANTES 部分脱敏。为了研究 CCR1 交叉调节，产生了共表达 CCR1 和白细胞介素 8 受体（CXCR1、CXCR2 或 CXCR2 磷酸化缺陷突变体 331T）的 RBL 细胞。 Interleukin-8 刺激 CXCR1 或 CXCR2 使 CCR1 交叉磷酸化，并使其刺激 GTPase 活性和 Ca2+ 动员的能力交叉脱敏。有趣的是，CCR1 使 CXCR2 交叉磷酸化和交叉脱敏，但 CXCR1 则不然。尽管缺乏受体磷酸化，S3 和 ΔCCR1 的 Ca2+ 动员也被 CXCR1 和 CXCR2 交叉脱敏。与野生型 CCR1 相比，S3 和 ΔCCR1 产生持续信号，对 CXCR1 和 CXCR2 产生交叉磷酸化和交叉脱敏反应。总而言之，这些结果表明，CCR1 介导的反应在信号传导途径的几个步骤中受到调节，包括受体/G 蛋白偶联水平上的受体磷酸化以及磷脂酶 C 激活水平上的未知机制。此外，趋化因子受体之间的选择性交叉调节部分是信号强度的结果（即更大的磷脂酰肌醇水解和持续的 Ca2+ 动员），这与受体对磷酸化的敏感性成反比。由于许多趋化因子激活多种趋化因子受体，因此这些受体之间的选择性交叉调节可能在其免疫调节中发挥作用。
To investigate the regulation of the CCR1 chemokine receptor, a rat basophilic leukemia (RBL-2H3) cell line was modified to stably express epitope-tagged receptor. These cells responded to RANTES (regulated upon activation normal T expressed and secreted), macrophage inflammatory protein-1α, and monocyte chemotactic protein-2 to mediate phospholipase C activation, intracellular Ca2+ mobilization and exocytosis. Upon activation, CCR1 underwent phosphorylation and desensitization as measured by diminished GTPase stimulation and Ca2+mobilization. Alanine substitution of specific serine and threonine residues (S2 and S3) or truncation of the cytoplasmic tail (ΔCCR1) of CCR1 abolished receptor phosphorylation and desensitization of G protein activation but did not abolish desensitization of Ca2+ mobilization. S2, S3, and ΔCCR1 were also resistant to internalization, mediated greater phosphatidylinositol hydrolysis and sustained Ca2+ mobilization, and were only partially desensitized by RANTES, relative to S1 and CCR1. To study CCR1 cross-regulation, RBL cells co-expressing CCR1 and receptors for interleukin-8 (CXCR1, CXCR2, or a phosphorylation-deficient mutant of CXCR2, 331T) were produced. Interleukin-8 stimulation of CXCR1 or CXCR2 cross-phosphorylated CCR1 and cross-desensitized its ability to stimulate GTPase activity and Ca2+ mobilization. Interestingly, CCR1 cross-phosphorylated and cross-desensitized CXCR2, but not CXCR1. Ca2+ mobilization by S3 and ΔCCR1 were also cross-desensitized by CXCR1 and CXCR2 despite lack of receptor phosphorylation. In contrast to wild type CCR1, S3 and ΔCCR1, which produced sustained signals, cross-phosphorylated and cross-desensitized responses to CXCR1 as well as CXCR2. Taken together, these results indicate that CCR1-mediated responses are regulated at several steps in the signaling pathway, by receptor phosphorylation at the level of receptor/G protein coupling and by an unknown mechanism at the level of phospholipase C activation. Moreover selective cross-regulation among chemokine receptors is, in part, a consequence of the strength of signaling (i.e. greater phosphatidylinositol hydrolysis and sustained Ca2+ mobilization) which is inversely corrolated with the receptor's susceptibility to phosphorylation. Since many chemokines activate multiple chemokine receptors, selective cross-regulation among such receptors may play a role in their immunomodulation.
登录
查看更多内容
蛋白激酶 C 的磷酸化会降低禽类磷脂酶 C-β 的催化活性。
DOI：
--
发表时间：
1999
期刊：
The Biochemical journal
影响因子：
--
作者：
Filtz,TM;Cunningham,ML;Stanig,KJ;Paterson,A;Harden,TK
通讯作者：
Harden,TK
DOI：
10.1016/s0021-9258(17)42123-5
发表时间：
1994-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
S. Mueller;W. Schraw;A. Richmond
通讯作者：
S. Mueller;W. Schraw;A. Richmond
巨噬细胞炎症蛋白 1 α 增强生长因子刺激的磷脂酰胆碱代谢，并增加人生长因子依赖性细胞系 M07e 中的 cAMP 水平，这些事件与生长抑制相关。
DOI：
--
发表时间：
1995
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Mantel,C;Aronica,S;Luo,Z;Marshall,MS;Kim,YJ;Cooper,S;Hague,N;Broxmeyer,HE
通讯作者：
Broxmeyer,HE
DOI：
--
发表时间：
1993-11
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Hydar Ali;R. Richardson;E. Tomhave;J. Didsbury;Ralph Snyderman
通讯作者：
Hydar Ali;R. Richardson;E. Tomhave;J. Didsbury;Ralph Snyderman
G 蛋白偶联激酶的磷酸化可抑制信号传导并促进单核细胞趋化蛋白 1 受体的内化。
DOI：
--
发表时间：
1996
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Franci,C;Gosling,J;Tsou,CL;Coughlin,SR;Charo,IF
通讯作者：
Charo,IF