PAR-2 belongs to a family of transmembrane G-protein coupled receptors (PAR1–PAR4) that are proteolytically activated by serine proteases. Specifically, the serine proteases (including trypsin or mast cell tryptase) cleave the extracellular amino terminal domain exposing a newly created N-terminus tethered ligand that undergoes a conformational change, binds and subsequently activates the receptors.

Within the epidermis, PAR-2 is expressed in keratinocytes, but not in melanocytes and is involved in the regulation of skin pigmentation through melanocyte-keratinocyte interactions.

Studies completed on keratinocyte PAR-2 indicate that it may influence melanosome incorporation and phagocytosis by keratinocytes and play a regulatory role in skin pigmentation. Therefore, modulation of PAR-2 activity augments or decreases melanosome transfer and in turn skin pigmentation.

PAR-2 activation can be achieved by synthetic peptides corresponding to the sequence of the N-terminal ligand.

Interestingly, PAR-2 expression and induction by ultraviolet irradiation is dependent on skin type, with a higher overall expression and induction in darker skin individuals.

Activation of PAR-2 enhances melanosome transfer, while inhibition of PAR-2 by serine protease inhibitors can result in reduced melanosomal transfer and distribution. It has been shown that this inhibition leads to a dose-dependent lightening of skin pigmentation.

Study examining the effect of serine protease inhibitor RWJ-50353 on epidermal equivalents shows an accumulation of melanosomes in melanocytes, with an increase in early stage melanosomes compared to untreated controls. They hypothesize that the keratinocytes inability to receive the presented melanosomes leads to an accumulation of melanosomes in the melanocytic dendrite and a concomitant negative feedback mechanism that slows pigment production.

It was additionally showen that Yucatan swine skin treated with RWJ-50353 for an 8 week period demonstrated a dose dependent, reversible skin lightening effect. “Natural” therapies derived from soybeans have been explored for their safety and efficacy as depigmentation treatments. Soybean contained small serine proteases such as Kunitz-type trypsin inhibitor (soybean trypsin inhibitor, STI) and the Bowman-Birk protease inhibitor (BBI).  STI and BBI are found in the seeds of soybeans, but not in the other regions of the plant.

STI inhibits trypsin proteolysis by forming a stable stoichiometric complex and BBI inhibits trypsin and chymotrypsin at separate reactive sites. Soymilk inhibits the protease-activated receptor-2 (PAR-2) pathway expressed on keratinocytes.

Soymilk also contains other constituents that may induce skin lightening such as trace amounts of free fatty acids and their acyl CoA esters that can inhibit trypsin and may participate in PAR-2 inhibition. Soybeans contain isoflavones, which are antioxidants that may reduce tyrosinase’s DOPA oxidase activity. In addition, soybeans contain phospholipids which the authors suggest may assist in the epidermal delivery of STI and BBI without the assistance of liposomes, when soy milk is used as a topical treatment.