The chemokine monocyte chemoattractant protein-1 induces functional responses through dimerization of its receptor CCR2

被引:186
作者
Rodríguez-Frade, JM [1 ]
Vila-Coro, AJ [1 ]
de Ana, AM [1 ]
Albar, JP [1 ]
Martínez-A, C [1 ]
Mellado, M [1 ]
机构
[1] Univ Autonoma Madrid, Consejo Super Inves Cient, Ctr Nacl Biotecnol, Dept Immunol & Oncol, E-28049 Madrid, Spain
关键词
chemotaxis; inflammation; HIV type 1;
D O I
10.1073/pnas.96.7.3628
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Cytokines interact with hematopoietin superfamily receptors and stimulate receptor dimerization. We demonstrate that chemoattractant cytokines (chemokines) also trigger biological responses through receptor dimerization. Functional responses are induced after pairwise crosslinking of chemokine receptors by bivalent agonistic antichemokine receptor mAb, but not by their Fab fragments. Monocyte chemoattractant protein (MCP)-1-triggered receptor dimerization was studied in human embryonic kidney (HEK)-293 cells cotransfected with genes coding for the CCR2b receptor tagged with YSK or Myc sequences. After MCP-1 stimulation, immunoprecipitation with Myc-specific antibodies revealed YSK-tagged receptors in immunoblotting. Receptor dimerization also was validated by chemical crosslinking in both HEK-293 cells and the human monocytic cell line Mono Mac 1. Finally, we constructed a loss-of-function CCR2bY139F mutant that acted as a dominant negative, blocking signaling through the CCR2 wild-type receptor. This study provides functional support for a model in which the MCP-1 receptor is activated by ligand-induced homodimerization, allowing discussion of the similarities between bacterial and leukocyte chemotaxis.
引用
收藏
页码:3628 / 3633
页数:6
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