Table 2.
Extracellular substrates of GrA and suggested biological impact.
| Substrate | Suggested biological impact | References |
|---|---|---|
| Basement membrane proteoglycans | Liberation basic fibroblast growth factor, protection against inhibition by natural high molecular weight inhibitors, lymphocyte migration. | (87) |
| Collagen IV | Influence on lymphocyte migration, anoikis, cell adhesion. Reduction adhesion of epithelial cells with cell-basement membrane. | (88, 97) |
| Fibronectin | Influence on lymphocyte migration (through fibrin clots), anoikis, cell adhesion. Reduction adhesion of epithelial cells with cell-basement membrane. | (89, 97) |
| Myelin basic protein (MBP) | MBP degradation resulting in myelin destruction. Pathogenesis multiple sclerosis. | (98) |
| Pro-urokinase plasminogen activator | Convert single-chain human pro-urokinase into active two-chain enzyme Roles in plasmin generation | (99) |
| Thrombin-like receptor on neurites Platelet thrombin receptor | Neurite retraction, reversed stellation of astrocytes Desensitized response to thrombin-induced aggregation by platelets | (92) (93, 94) |
| Unidentified (likely) cell surface receptora | Pro-inflammatory cytokine production by fibroblasts, epithelial cells, monocytes, and macrophages. | (21, 31, 85, 86, 95) |
| Proteinase-activated receptor 2 (PAR-2)b | Protease-activated receptor-2 activating peptide (SLIGRL) is yielded. Roles in promoting inflammation. | (100) |
Sower et al. found a 5-fold difference in potency between thrombin and GrA suggesting that granule-associated proteases may signal through other membrane proteins than the thrombin receptor. However, no such receptor has been identified yet. Release of pro-inflammatory cytokines is suggested to be on their own or potentiating LPS-induced responses (21, 31, 85, 86, 95).
Hansen et al. found that treatment of P20 peptide (corresponding to the cleavage/activation site of the wt-r PAR-2 N terminus) with GrA for 20 h yielded 22 ± 2% (n = 3) conversion to the PAR-2 -activating peptide. However, calcium mobilization experiments did not show activation of PAR-2 by GrA (data not shown in paper) (100) and another study notes that the tryptase fails to induce Ca influx to efficiently cleave various PAR sub-types (data not shown in paper) (21).
As most studies have been performed in vitro or in mouse/rat models it is unclear to what extent these findings have physiological relevance in humans.