Biased signaling by agonists of protease activated receptor 2

Jiang, Yuhong, Yau, Mei-Kwan, Kok, W. Mei, Lim, Junxian, Wu, Kai-Chen, Liu, Ligong, Hill, Timothy A., Suen, Jacky Y. and Fairlie, David P. (2017) Biased signaling by agonists of protease activated receptor 2. ACS Chemical Biology, 12 5: 1217-1226. doi:10.1021/acschembio.6b01088

Author Jiang, Yuhong
Yau, Mei-Kwan
Kok, W. Mei
Lim, Junxian
Wu, Kai-Chen
Liu, Ligong
Hill, Timothy A.
Suen, Jacky Y.
Fairlie, David P.
Title Biased signaling by agonists of protease activated receptor 2
Journal name ACS Chemical Biology   Check publisher's open access policy
ISSN 1554-8937
Publication date 2017-05-19
Sub-type Article (original research)
DOI 10.1021/acschembio.6b01088
Open Access Status Not yet assessed
Volume 12
Issue 5
Start page 1217
End page 1226
Total pages 10
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Formatted abstract
Protease activated receptor 2 (PAR2) is associated with metabolism, obesity, inflammatory, respiratory and gastrointestinal disorders, pain, cancer, and other diseases. The extracellular N-terminus of PAR2 is a common target for multiple proteases, which cleave it at different sites to generate different N-termini that activate different PAR2-mediated intracellular signaling pathways. There are no synthetic PAR2 ligands that reproduce the same signaling profiles and potencies as proteases. Structure-activity relationships here for 26 compounds spanned a signaling bias over 3 log units, culminating in three small ligands as biased agonist tools for interrogating PAR2 functions. DF253 (2f-LAAAAI-NH2) triggered PAR2-mediated calcium release (EC50 2 μM) but not ERK1/2 phosphorylation (EC50 > 100 μM) in CHO cells transfected with hPAR2. AY77 (Isox-Cha-Chg-NH2) was a more potent calcium-biased agonist (EC50 40 nM, Ca2+ EC50 2 μM, ERK1/2), while its analogue AY254 (Isox-Cha-Chg-A-R-NH2) was an ERK-biased agonist (EC50 2 nM, ERK1/2; EC50 80 nM, Ca2+). Signaling bias led to different functional responses in human colorectal carcinoma cells (HT29). AY254, but not AY77 or DF253, attenuated cytokine-induced caspase 3/8 activation, promoted scratch-wound healing, and induced IL-8 secretion, all via PAR2-ERK1/2 signaling. Different ligand components were responsible for different PAR2 signaling and functions, clues that can potentially lead to drugs that modulate different pathway-selective cellular and physiological responses.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

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