Biased signaling of G protein-coupled receptors: rom a chemokine receptor CCR7 perspective
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Biased signaling of G protein-coupled receptors : rom a chemokine receptor CCR7 perspective. / Jørgensen, Astrid Sissel; Rosenkilde, Mette M; Hjortø, Gertrud M.
In: General and Comparative Endocrinology, Vol. 258, No. SI, 03.2018, p. 4-14.Research output: Contribution to journal › Review › Research › peer-review
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TY - JOUR
T1 - Biased signaling of G protein-coupled receptors
T2 - 28th Conference of European Comparative Endocrinologists
AU - Jørgensen, Astrid Sissel
AU - Rosenkilde, Mette M
AU - Hjortø, Gertrud M
N1 - Copyright © 2017 Elsevier Inc. All rights reserved.
PY - 2018/3
Y1 - 2018/3
N2 - Chemokines (chemotactic cytokines) and their associated G protein-coupled receptors (GPCRs) work in a concerted manner to govern immune cell positioning in time and space. Promiscuity of both ligands and receptors, but also biased signaling within the chemokine system, adds to the complexity of how the cell-based immune system is controlled. Bias comes in three forms; ligand-, receptor- and tissue-bias. Biased signaling is increasingly being recognized as playing an important role in contributing to the fine-tuned coordination of immune cell chemotaxis. In the current review we discuss the recent findings related to ligand- and tissue-biased signaling of CCR7 and summarize what is known about bias at other chemokine receptors. CCR7 is expressed by a subset of T-cells and by mature dendritic cells (DCs). Together with its two endogenous ligands CCL19 and CCL21, of which the carboxy terminal tail of CCL21 displays an extraordinarily strong glycosaminoglycan (GAG) binding, CCR7 plays a central role in coordinating the meeting between mature antigen presenting DCs and naïve T-cells which normally takes place in the lymph nodes (LNs). This process is a prerequisite for the initiation of an antigen-specific T-cell mediated immune response. Thus CCR7 and its ligands are key players in initiating cell-based immune responses. CCL19 and CCL21 display differential interaction- and docking-modes for CCR7 leading to stabilization of different CCR7 conformations and hereby preferential activation of distinct intracellular signaling pathways (i.e. ligand bias). In general CCL19 seems to generate a strong temporal signal, whereas CCL21 generates a weaker, but more persistent signal. Tissue differential expression of these two ligands, and the generation of a third ligand "tailless-CCL21", through DC specific protease activity (tissue bias), orchestrates DC and T-cell LN homing and priming, with each ligand serving overlapping, but also distinct roles.
AB - Chemokines (chemotactic cytokines) and their associated G protein-coupled receptors (GPCRs) work in a concerted manner to govern immune cell positioning in time and space. Promiscuity of both ligands and receptors, but also biased signaling within the chemokine system, adds to the complexity of how the cell-based immune system is controlled. Bias comes in three forms; ligand-, receptor- and tissue-bias. Biased signaling is increasingly being recognized as playing an important role in contributing to the fine-tuned coordination of immune cell chemotaxis. In the current review we discuss the recent findings related to ligand- and tissue-biased signaling of CCR7 and summarize what is known about bias at other chemokine receptors. CCR7 is expressed by a subset of T-cells and by mature dendritic cells (DCs). Together with its two endogenous ligands CCL19 and CCL21, of which the carboxy terminal tail of CCL21 displays an extraordinarily strong glycosaminoglycan (GAG) binding, CCR7 plays a central role in coordinating the meeting between mature antigen presenting DCs and naïve T-cells which normally takes place in the lymph nodes (LNs). This process is a prerequisite for the initiation of an antigen-specific T-cell mediated immune response. Thus CCR7 and its ligands are key players in initiating cell-based immune responses. CCL19 and CCL21 display differential interaction- and docking-modes for CCR7 leading to stabilization of different CCR7 conformations and hereby preferential activation of distinct intracellular signaling pathways (i.e. ligand bias). In general CCL19 seems to generate a strong temporal signal, whereas CCL21 generates a weaker, but more persistent signal. Tissue differential expression of these two ligands, and the generation of a third ligand "tailless-CCL21", through DC specific protease activity (tissue bias), orchestrates DC and T-cell LN homing and priming, with each ligand serving overlapping, but also distinct roles.
KW - Journal Article
KW - Review
U2 - 10.1016/j.ygcen.2017.07.004
DO - 10.1016/j.ygcen.2017.07.004
M3 - Review
C2 - 28694053
VL - 258
SP - 4
EP - 14
JO - General and Comparative Endocrinology
JF - General and Comparative Endocrinology
SN - 0016-6480
IS - SI
Y2 - 21 August 2016 through 25 August 2016
ER -
ID: 182199210