Differential chemokine activation of CC chemokine receptor 1-regulated pathways: ligand selective activation of Galpha 14-coupled pathways.
Chemokines regulate the chemotaxis, development, and differentiation of many cell types enabling the regulation of routine immunosurveillance and immunological adaptation. CC chemokine receptor 1 (CCR1) is the target of 11 chemokines. This promiscuity of receptor-ligand interactions and the potential for functional redundancy has led us to investigate the selective activation of CCR1-coupled pathways by known CCR1 agonists. Chemokines leukotactin-1, macrophage inflammatory protein (MIP)-1alpha, monocyte chemotactic peptide (MCP)-3, RANTES, and MIP-1delta all inhibited adenylyl cyclase activity in cells transiently transfected with CCR1. In contrast, only MIP-1delta was unable to signal via G14-, G16- or chimeric 16z44-coupled pathways. In a stable cell line expressing CCR1 and Galpha14, all of these five chemokines along with hemofiltrate CC chemokine (HCC)-1 and myeloid progenitor inhibitory factor (MPIF)-1 were able to stimulate G(i/o)-coupled pathways, but MIP-1delta, HCC-1 and MPIF-1 were unable to activate G14-mediated stimulation of phospholipase Cbeta activity. In addition, MIP-1delta was unable to promote the phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase. This suggests that different chemokines are able to selectively activate CCR1-coupled pathways, probably because of different intrinsic ligand efficacies. CCR1 and Galpha14 or Galpha16 are co-expressed in several cell types and we hypothesize that selective activation of chemokine receptors provides a mechanism by which chemokines are able to fine-tune intracellular signaling pathways.
Tian
Yaji
Y
Department of Biochemistry, The Molecular Neuroscience Center, and The Biotechnology Research Institute, Hong Kong University of Science and Technology, Kowloon, Hong Kong, China.
New
David C
DC
Department of Biochemistry, The Molecular Neuroscience Center, and The Biotechnology Research Institute, Hong Kong University of Science and Technology, Kowloon, Hong Kong, China.
Yung
Lisa Y
LY
Department of Biochemistry, The Molecular Neuroscience Center, and The Biotechnology Research Institute, Hong Kong University of Science and Technology, Kowloon, Hong Kong, China.
Allen
Rodger A
RA
Celltech R & D, Slough, GB.
Slocombe
Patrick M
PM
Celltech R & D, Slough, GB.
Twomey
Breda M
BM
Celltech R & D, Slough, GB.
Lee
Maggie M K
MMK
Department of Biochemistry, The Molecular Neuroscience Center, and The Biotechnology Research Institute, Hong Kong University of Science and Technology, Kowloon, Hong Kong, China.
Wong
Yung H
YH
Department of Biochemistry, The Molecular Neuroscience Center, and The Biotechnology Research Institute, Hong Kong University of Science and Technology, Kowloon, Hong Kong, China.
D000818:Animals; D019556:COS Cells; D002460:Cell Line; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte; D002522:Chlorocebus aethiops; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008024:Ligands; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
C515300:CCR1 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines; D044385:GTP-Binding Protein alpha Subunits; D008024:Ligands; D019402:Macrophage Inflammatory Proteins; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases