Proteinase-activated receptor-2 in the skin: Receptor expression, activation and function during health and disease

Abstract

Proteinase-activated receptors (PARs) are G-protein-coupled receptors with seven transmembrane domains that are activated by specific proteolytic cleavage of the extracellular N-terminus. To date, four PARs are known (PAR(1-4)). They are stimulated by a variety of serine proteinases. PAR(1), PAR(3) and PAR(4) are cleaved by thrombin. Both PAR(1) and PAR(4) can be activated by trypsin as well; and PAR1 can also be activated by matrix metalloproteinase-1. PAR(2) can be activated by a variety of endogenous serine proteinases with trypsin-like specificity. However, the receptor can additionally be stimulated by various proteinases produced by pathogenic organisms. It can also be inactivated by certain proteinases. PAR(2) is expressed by many cell types present in the skin, including epidermal keratinocytes, fibroblasts, endothelial cells as well as by afferent neuron terminals. Moreover, functional PAR(2) is expressed by cells crucially involved in innate and adaptive immunity such as eosinophils, neutrophils, monocytes, macrophages, dendritic cells, mast cells and T cells. Activation of the receptor leads to the production of various cytokines and chemokines which modulate skin homeostasis, immune and inflammatory responses as well as tumor surveillance.

Hepatocyte Growth Factor Activator Inhibitor Type 1 Maintains the Assembly of Keratin into Desmosomes in Keratinocytes by Regulating Protease-Activated Receptor 2–Dependent p38 Signaling

“…40 Recent studies have suggested that PAR-2 is crucially involved in these protease-mediated skin abnormalities. 27,30,31 PAR-2 is expressed by keratinocytes and plays an important physiological role in the epidermis. Abnormal expression or activity of PAR-2 has been associated with several inflammatory skin disorders involving barrier abnormalities, such as atopic dermatitis, Netherton syndrome, psoriasis, and peeling skin syndrome.…”

“…35 PAR-2 is widely expressed in the skin and activated by trypsin-like proteases. 27 Thus, we hypothesized that activation of p38 MAPK signaling in HAI-1 KD HaCaT cells may be caused by inadequate activity of trypsinlike serine protease(s) in the absence of sufficient HAI-1. To confirm this hypothesis, we examined the effect of a PAR-2 agonist (SLIGR) and an antagonist (FSLLRY) on the activation of p38 MAPK in HaCaT cells.…”

“…17,27,30 The evidence suggested that the most important cognate protease of HAI-1 in keratinocytes is matriptase. 24 Therefore, we hypothesized that the activity of matriptase was enhanced because of insufficient HAI-1, which eventually led to PAR-2 activation in HAI KD HaCaT cells.…”

“…27 In the skin, PAR-2 is widely expressed by almost all cell types, especially keratinocytes. It has been implicated in the regulation of keratinocyte proliferation and differentiation, epidermal barrier function, and inflammation.…”

The effects of phototherapy and melanocytes on keratinocytes

“…PAR-2 is activated by trypsin-like serine proteases and is expressed by almost all cell types, particularly by keratinocytes (18). It has been demonstrated that PAR-2 is expressed predominantly in the granular layer of epidermis, suggesting that PAR-2 may be associated with epidermal mutations (19).…”