Mesotrypsin: A New Inhibitor-Resistant Protease From, a Zymogen in Human Pancreatic Tissue and Fluid

Rinderknecht, H.; Renner, Ian G.; Abramson, Stephen B.; Carmack, C

doi:10.1016/s0016-5085(84)80117-1

Cited by 119 publications

(56 citation statements)

References 19 publications

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“…However, rat mesotrypsin remains unknown and it is unclear whether or not mesotrypsin may be unique to humans. Although no inhibitor-resistant trypsin activity was found in pancreatic extracts from rats (Rinderknecht et al 1984), it seems that mesotrypsin-like enzymes are widespread in the animal kingdom (Sahin-Tó th 2005). Rat trypsinogen V, which was detected at the protein level (Hara and Shiota 2004), was expected to exhibit mesotrypsin-like inhibitor-resistance and inhibitor-degrading properties (Szmola et al 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Firstly, mesotrypsin is resistant to trypsin inhibitors, such as the Kunitz-type soybean trypsin inhibitor or the Kazaltype pancreatic secretory trypsin inhibitor. This resistance is not seen with cationic and anionic trypsin (Rinderknecht et al 1984;Nyaruhucha et al 1997;Katona et al 2002). The replacement of the highly conserved Gly198, which is found in the two other isoforms, by an arginine residue contributes to the resistance to inhibitors and the stabilization of mesotrypsin (Katona et al 2002).…”

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confidence: 97%

“…It is well known that the human pancreas secretes three isoforms of trypsinogen, which are encoded by the PRSS (proteinase, serine) genes PRSS1 (cationic trypsinogen), PRSS2 (anionic trypsinogen) and PRSS3 (mesotrypsinogen). Unlike cationic and anionic trypsinogens, mesotrypsinogen is only a minor constituent in human pancreatic juice, accounting for less than 5% of trypsinogens (Scheele et al 1981;Rinderknecht et al 1984;Kukor et al 2003).…”

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confidence: 99%

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Mesotrypsin, a brain trypsin, activates selectively proteinase‐activated receptor‐1, but not proteinase‐activated receptor‐2, in rat astrocytes

Wang

Luo

Wartmann

et al. 2006

Journal of Neurochemistry

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Proteinase-activated receptors (PARs), a subfamily of G protein-coupled receptors, which are activated by serine proteases, such as trypsin, play pivotal roles in the CNS. Mesotrypsin (trypsin IV) has been identified as a brain-specific trypsin isoform. However, its potential physiological role concerning PAR activation in the brain is largely unknown. Here, we show for the first time that mesotrypsin, encoded by the PRSS3 (proteinase, serine) gene, evokes a transient and pronounced Ca 2+ mobilization in both primary rat astrocytes and retinal ganglion RGC-5 cells, suggesting a physiological role of mesotrypsin in brain cells. Mesotrypsin mediates Ca 2+ responses in rat astrocytes in a concentration-dependent manner, with a 50% effective concentration (EC 50 ) value of 25 nM. The maximal effect of mesotrypsin on Ca 2+ mobilization in rat astrocytes is much higher than that observed in 1321N1 human astrocytoma cells, indicating that the activity of mesotrypsin is species-specific. The pre-treatment of cells with thrombin or the PAR-1-specific peptide TRag (AlapFluoro-Phe-Arg-Cha-HomoArg-Tyr-NH 2 , synthetic thrombin receptor agonist peptide), but not the PAR-2-specific peptide, reduces significantly the mesotrypsin-induced Ca 2+ response.Treatment with the PAR-1 antagonist SCH79797 confirms that mesotrypsin selectively activates PAR-1 in rat astrocytes. Unlike mesotrypsin, the two other trypsin isoforms, cationic and anionic trypsin, activate multiple PARs in rat astrocytes. Therefore, our data suggest that brain-specific mesotrypsin, via the regulation of PAR-1, is likely to be involved in multiple physiological/pathological processes in the brain. Keywords: anionic trypsin, calcium signaling, cationic trypsin, mesotrypsin, proteinase-activated receptors. The proteinase-activated receptors (PARs) are a four-member subfamily of G protein-coupled receptors. They are widely expressed in the CNS, including neurons, astrocytes, microglial cells, oligodendrocytes and rat brain capillary endothelial cells, and play a pivotal role in multiple physiological and pathological processes in the brain, such as ischemic stroke and astrogliosis (Striggow et al. 2000(Striggow et al. , 2001Dömötör et al. 2002;Suo et al. 2002;Wang et al. 2002a;Xi et al. 2003;Wang et al. 2004;Nicole et al. 2005). PAR is activated by proteolytic cleavage of its N-terminus by certain serine proteinases, such as thrombin and trypsin. Thus, a new N-terminus is unmasked, acting as a tethered ligand. This ligand can interact with the extracellular loop-2, initiating multiple signal transductions (Wang and Reiser 2003). Trypsin, which is primarily isolated from human pancreas, can activate not only PAR-2 and PAR-4, but also PAR-1 (Nystedt et al. 1995;Böhm et al. 1996;Xu et al. 1998;Wang et al. 2002a;Wang et al. 2004). It is well known that the human pancreas secretes three isoforms of trypsinogen, which are encoded by the PRSS (proteinase, serine) genes PRSS1 (cationic trypsinogen), PRSS2 (anionic trypsinogen) and PRSS3 (mesotrypsinogen). Unlike c...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 97%

mentioning

confidence: 99%

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Mesotrypsin, a brain trypsin, activates selectively proteinase‐activated receptor‐1, but not proteinase‐activated receptor‐2, in rat astrocytes

Wang

Luo

Wartmann

et al. 2006

Journal of Neurochemistry

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“…It is proportionately the least instrumental of the three trypsinogen isoenzymes (PRSS1, PRSS2, and PRSS3), 9,10 responsible for less than 10% of the total trypsinogen activity in normal pancreatic juice. 11 It is inherently resistant to and actively degrades trypsin inhibitors. 10 PRSS3 was originally identified in a study assembling a pancreas complementary DNA (cDNA) library and traced to human chromosome 9p13.3 region.…”

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confidence: 99%

High‐level expression of PRSS3 correlates with metastasis and poor prognosis in patients with gastric cancer

Wang

Feng

et al. 2019

Journal of Surgical Oncology

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Background and Objectives Serine protease‐3 (PRSS3) is a known contributor to the genesis and development of malignant tumors, although its role in gastric cancer (GC) is still unclear. Methods PRSS3 expression in GC tissue samples and its relationship with clinicopathological features were analyzed. Effects of GC cellular responses to the introduction of small interfering RNA (siRNA)‐mediated and short hairpin RNA (shRNA)‐mediated interference with tumor PRSS3 expression were also assessed. Results PRSS3 was significantly upregulated in GC tissues, and PRSS3 protein levels were higher in tumors that developed metastases soon after the surgery compared with those that remained metastasis‐free. High expression of PRSS3 was associated with tumor N staging and independently predictive of postoperative prognosis in patients with GC. The V1 variant of PRSS3 was primarily detected in GC tissue and cell lines, the others (V2‐V4) being scarcely detectable. Methylation and demethylation drugs had no impact on expression levels of any PRSS3 transcriptional variant. The downregulated PRSS3 expression suppressed GC cell growth, migration, and invasion in vitro and in vivo. Conclusions PRSS3 appears to act as an oncogene of GC. High PRSS3 expression portends postoperative metastasis, serving as an effective biomarker of poor therapeutic outcomes.

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“…peptides [2,4,5], indicating that the specificity pocket and the catalytic machinery per se are intact. This stands in contrast to reports showing that mutations of Gly193 (chymo#) in thrombin or factor XI resulted in perturbation of the oxyanion hole and impaired catalysis [6,7].…”

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confidence: 99%

Human mesotrypsin exhibits restricted S1′ subsite specificity with a strong preference for small polar side chains

Szepessy

Sahin–Tóth

2006

The FEBS Journal

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Mesotrypsin, an inhibitor‐resistant human trypsin isoform, does not activate or degrade pancreatic protease zymogens at a significant rate. These observations led to the proposal that mesotrypsin is a defective digestive protease on protein substrates. Surprisingly, the studies reported here with α1‐antitrypsin (α1AT) revealed that, even though mesotrypsin was completely resistant to this serpin‐type inhibitor, it selectively cleaved the Lys10–Thr11 peptide bond at the N‐terminus. Analyzing a library of α1AT mutants in which Thr11 was mutated to various amino acids, we found that mesotrypsin hydrolyzed lysyl peptide bonds containing Thr or Ser at the P1′ position with relatively high specificity (kcat/KM∼105 m−1·s−1). Compared with Thr or Ser, P1′ Gly or Met inhibited cleavage 13‐ and 25‐fold, respectively, whereas P1′ Asn, Asp, Ile, Phe or Tyr resulted in 100–200‐fold diminished rates of proteolysis, and Pro abolished cleavage completely. Consistent with the Ser/Thr P1′ preference, mesotrypsin cleaved the Arg358–Ser359 reactive‐site peptide bond of α1AT Pittsburgh and was rapidly inactivated by the serpin mechanism (ka∼106 m−1 s−1). Taken together, the results indicate that mesotrypsin is not a defective protease on polypeptide substrates in general, but exhibits a relatively high specificity for Lys/Arg–Ser/Thr peptide bonds. This restricted, thrombin‐like subsite specificity explains why mesotrypsin cannot activate pancreatic zymogens, but might activate certain proteinase‐activated receptors. The observations also identify α1AT Pittsburgh as an effective mesotrypsin inhibitor and the serpin mechanism as a viable stratagem to overcome the inhibitor‐resistance of mesotrypsin.

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Mesotrypsin: A New Inhibitor-Resistant Protease From, a Zymogen in Human Pancreatic Tissue and Fluid

Cited by 119 publications

References 19 publications

Mesotrypsin, a brain trypsin, activates selectively proteinase‐activated receptor‐1, but not proteinase‐activated receptor‐2, in rat astrocytes

Mesotrypsin, a brain trypsin, activates selectively proteinase‐activated receptor‐1, but not proteinase‐activated receptor‐2, in rat astrocytes

High‐level expression of PRSS3 correlates with metastasis and poor prognosis in patients with gastric cancer

Human mesotrypsin exhibits restricted S1′ subsite specificity with a strong preference for small polar side chains

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