Serine protease 3 (PRSS3) (PRSS3)

Serine protease 3 (PRSS3), commonly known as mesotrypsin, is an atypical isoform of the trypsin family of serine proteases, primarily produced in the pancreas and also found in the brain and skin [2, 4, 12]. Unlike canonical trypsins, mesotrypsin is uniquely characterized by its resistance to, and ability to degrade, natural trypsin inhibitors like SPINK1, which suggests its primary physiological role is the digestion of foods rich in dietary inhibitors [8, 13]. In various malignancies, including pancreatic, breast, and prostate cancers, mesotrypsin is frequently overexpressed and acts as a potent driver of tumor progression and metastasis [1, 3, 11]. It facilitates these processes through the cleavage of specific substrates such as CD109 and the amyloid precursor protein, as well as the activation of protease-activated receptor 2 (PAR2), leading to enhanced cell invasion and proliferation [3, 7, 12]. Although no therapeutic agents targeting mesotrypsin are currently approved for clinical use, it is recognized as a significant therapeutic target, particularly for metastatic disease [1, 6]. Research is currently focused on developing selective small-molecule inhibitors, such as diminazene and CP13, and engineered protein scaffolds that can effectively inhibit its activity while avoiding off-target effects on other closely related digestive trypsins [5, 9, 11]. Selective inhibition of mesotrypsin represents a promising strategy for curbing cancer malignancy and potentially preventing the progression of pancreatitis caused by inhibitor degradation [7, 13].

Other names

MesotrypsinTrypsin-3Trypsin IIITrypsin IVBrain trypsinogenPancreatic trypsinogen IIIMTGT9Protease, serine 3

Competitive or allosteric inhibition of the proteolytic activity of mesotrypsin, preventing the degradation of endogenous inhibitors and the activation of pro-tumorigenic signaling pathways such as PAR2 activation and CD109 shedding.