PAR2 is a member of the large family of
7-transmembrane receptors that couple to guanosine-nucleotide-binding proteins and also belongs to the
protease-activated receptor family. PAR2 is activated by several endogenous and exogenous proteases through proteolytic cleavage of its extracellular amino terminus between arginine and serine. The newly exposed
N-terminus serves as tethered activation ligand that binds to a conserved region on extracellular loop 2 (ECL2), thereby activating the receptor. These receptors can also be activated non-proteolytically by exogenous peptide sequences that mimic the terminal amino acids of the tethered ligand. Alternatively, cleavage by other proteases at non-signaling sites can render the receptor unresponsive to further protease exposure. Another PAR2 cleaving protease is tryptase, the main protease of mast cells, which by PAR2 proteolytic cleavage induces calcium signaling and proliferation. PARs have been identified as substrates of
kallikreins, which have been related to various inflammatory and tumorigenic processes. In case of PAR2, particularly speaking about
kallikrein-4,
-5,
-6 a
-14. PAR2 is known to transactivate
TLR4 and
epidermal growth factor receptor in diseases. == Function ==