Disease relevance of CTSG

• Cathepsin G (CTSG), a serine protease released from activated neutrophils, may cause platelet activation, leading to intravascular thrombosis, thus contributing to cardiovascular and cerebrovascular disease [1].
• Applying the candidate gene approach, we screened the 5'-flanking region and the entire coding region of the CTSG gene for genetic variation by using polymerase chain reaction/single-strand conformation polymorphism analysis from 96 patients at high risk for myocardial infarction (MI) [1].
• We conclude that the PMN neutral serine proteinases elastase and cathepsin G can mediate marked changes in glomerular permeability in vivo due to their proteolytic activity, and thus, may contribute to the proteinuria observed in PMN-dependent models of GN [2].
• Experiments with Serratia protease-treated and Bernard-Soulier platelets showed that neither platelet surface GPIb nor cathepsin G-induced proteolysis of GPIb were required for the cathepsin G-induced redistribution of the remnant of the GPIb-IX complex or the cathepsin G-induced increase in platelet surface P-selectin [3].
• Myeloid leukemia with promyelocytic features in transgenic mice expressing hCG-NuMA-RARalpha [4].

Psychiatry related information on CTSG

• These findings indicate that cathepsin G is capable of cleaving the beta-amyloid precursor protein to liberate the free NH2-terminus of the A beta protein and may have access to areas where this material is deposited in Alzheimer's disease [5].
• In primates at least, neutralization of the biological effects of CG during this critical period results in a reduction of blood progesterone levels and the interruption of pregnancy [6].

High impact information on CTSG

• Monospecific antiserums to the azurophilic markers myeloperoxidase, elastase, cathepsin G and lysozyme, and to the specific granule markers lactoferrin and lysozyme, were labeled with fluorescein and rhodamine and were used to demonstrate two antigens in the same cell simultaneously [7].
• Serine proteinases such as thrombin, mast cell tryptase, trypsin, or cathepsin G, for example, are highly active mediators with diverse biological activities [8].
• These findings identify an important role for CG in integrin-dependent PMN effector functions that are separate from and downstream of integrin-dependent adhesion [9].
• In addition, cathepsin G is also a potent chemoattractant for neutrophils and a chemokinetic stimulant for T cells [10].
• Cathepsin G-induced monocyte chemotaxis is partially pertussis toxin sensitive implying the involvement of a G protein-coupled receptor [10].

Chemical compound and disease context of CTSG

• Our data suggest that oxidation of MPI during chronic bronchitis may lead to cathepsin G-mediated lung tissue degradation and that heparin may be a useful adjuvant of MPI-based therapy of acute lung inflammation in cystic fibrosis [11].
• Active site mapping of the serine proteases human leukocyte elastase, cathepsin G, porcine pancreatic elastase, rat mast cell proteases I and II. Bovine chymotrypsin A alpha, and Staphylococcus aureus protease V-8 using tripeptide thiobenzyl ester substrates [12].
• Treatment of cathepsin G with diisopropyl fluorophosphate significantly reduced its bactericidal activity against Capnocytophaga spp. but not against Escherichia coli or A. actinomycetemcomitans [13].
• ICI 200,355 had no effect on baseline secretion or on the secretory response to chymase, cathepsin G or Pseudomonas aeruginosa elastase [14].
• SC-39026 is inactive against hog pancreatic elastase, bovine alpha-chymotrypsin and Pseudomonas aeruginosa elastase, but does inhibit human neutrophil cathepsin G with an IC50 of approximately 2.5 microM [15].

Biological context of CTSG

• We show here that cathepsin G, CGL-1, and CGL-2 are linked on an approximately 50-kilobase locus found on human chromosome 14 at band q11 [16].
• However, cathepsin G resulted in minimal decreases in the binding to fixed platelets of MoAbs TM60 (directed against the thrombin binding site on GPIb alpha) and WM23 (directed against the macroglycopeptide portion of GPIb alpha) [3].
• We found that degradation of HCII by CG or LE generated products with potent PMN chemotactic activity, which did not stimulate the PMN oxidative burst [17].
• Amino acid sequence analysis led to the conclusion that both neutrophil elastase and cathepsin G cleave HC at Ile66, which does not affect HC activity, and at Val439, near the reactive site Leu444, which inactivates HC [18].
• In a competitive binding assay, cathepsin G bound to thrombospondin 1 reversibly and saturably with a dissociation constant in the low nanomolar range [19].

Anatomical context of CTSG

• We infused microgram quantities of active or inactive PMN elastase and cathepsin G into the renal arteries of rats [2].
• For example, human neutrophil elastase and cathepsin G are expressed only in myelomonocytic precursors, and cytotoxic-T-cell serine proteases are found only in cytotoxic lymphocytes [16].
• First, although only the GPIb alpha subunit of this putative complex is known to be directly linked to the platelet cytoskeleton via actin-binding protein, cytochalasin B inhibited the ADP/epinephrine-, cathepsin G-, and TRAP-induced decrease in platelet surface GPV [20].
• Elastase and cathepsin G of human monocytes. Quantification of cellular content, release in response to stimuli, and heterogeneity in elastase-mediated proteolytic activity [21].
• The present work establishes that U937 cells contain cathepsin G, an enzyme heretofore found only in neutrophils [22].

Associations of CTSG with chemical compounds

• The human neutrophil serine proteinases, elastase and cathepsin G, can mediate glomerular injury in vivo [2].
• The effects of neutrophil cathepsin G on the glycoprotein (GP) Ib-IX complex of washed platelets were examined [3].
• First, flow cytometric studies showed that cathepsin G, TRAP, and ADP/epinephrine decreased the platelet surface expression of GPV without changing the total platelet content of GPV [20].
• A detailed kinetic investigation showed that the inhibition of heparin-bound cathepsin G by the three proteins proceeded via a two-step mechanism [23].
• Release of this peptide was blocked by pretreating cathepsin G with phenylmethylsulfonyl fluoride, strongly implying that oxidation introduced proteolytic cleavage sites into cathepsin G [24].

Physical interactions of CTSG

• In summary, neutrophil cathepsin G modulates the platelet surface expression of the GPIb-IX complex both by proteolysis of the vWF binding site on GPIb alpha and by a cytoskeletal-mediated redistribution of the remainder of the complex [3].
• The protein is secreted rather than stored in the cell, has a similar size to plasma alpha 1 ACh (68 kDa) and can complex with human cathepsin G [25].
• Cathepsin G reaches the subendothelial matrix through an increase in cell permeability and injures endothelial cell morphology by detaching matrix-bound PAI-1 [26].
• Human endothelial cell damage by neutrophil-derived cathepsin G. Role of cytoskeleton rearrangement and matrix-bound plasminogen activator inhibitor-1 [26].
• TNF-alpha and PAF alone induced modest (two- to threefold) increases in cell surface-bound cathepsin G, but exhibited a marked dose- and time-dependent priming effect for subsequent chemoattractant-induced responses (up to 15- to 25-fold increases in cell surface expression) [27].

Enzymatic interactions of CTSG

• Human leukocyte elastase (HLE) hydrolysed baboon aortic elastin 8 times faster than human cathepsin G [28].
• From several PMN-derived proteases tested, only cathepsin G had the capacity to cleave CTAP-III into NAP-2 with high specificity and in a relatively short period of time (30 min) [29].
• Plasma membrane elastase and cathepsin G from U937 cells cleave C3 into C3a- and C3b-like fragments; further incubation leads to C3c- and C3dg-like fragments, as judged from SDS-PAGE analysis of the digests [30].
• Inhibition of neutrophil cathepsin G by oxidized mucus proteinase inhibitor. Effect of heparin [11].
• Examination of enzyme-treated recombinant cytokines by gel electrophoresis revealed that cathepsin-G cleaved LT into a 12.6-kDa fragment and leukocyte elastase fragmented LT into a 14.1-kDa product [31].

Regulatory relationships of CTSG

• HCII can be proteolytically inactivated by cathepsin G (CG) and elastase (LE), which are released by stimulated PMN [32].
• Pretreatment of HMVECs with beta-thromboglobulin enhanced monocyte arrest in the presence of cathepsin G generating NAP-2 [33].
• Owing to its availability on the surface of SDF-1-responsive cells and its rapid effect, cathepsin G is likely to play a significant role in down-regulating SDF-1 activity [34].
• The foregoing data, as well as the requirement of catalytically active NE to trigger alphaIIbbeta3 activation and potentiate threshold of cathepsin G-initiated platelet aggregation, led us to examine whether the structure of this integrin was affected by NE [35].
• INTRODUCTION: Preliminary studies have shown that high molecular mass kininogen (HK) inhibits cathepsin G-induced platelet activation [36].

Other interactions of CTSG

• Cathepsin G resulted in a concentration- and time-dependent decrease in the platelet surface GPIb-IX complex, as determined by flow cytometry, binding of exogenous von Willebrand factor (vWF) in the presence of ristocetin, and ristocetin-induced platelet agglutination [3].
• Methionine sulfoxide and proteolytic cleavage contribute to the inactivation of cathepsin G by hypochlorous acid: an oxidative mechanism for regulation of serine proteinases by myeloperoxidase [24].
• This finding led us to question whether thrombospondin 1 also binds and inhibits the other major serine proteinase of neutrophils, cathepsin G [19].
• The coding sequences of CG, CGL-1, and CGL-2 are 65-75% identical at the DNA level [37].
• Neutrophil cathepsin G was identified as the principal protease to produce delta23 and delta26 CCL15 [38].

Analytical, diagnostic and therapeutic context of CTSG

• Electrophoretic, Western blotting, and amino-terminal sequence analyses revealed that cathepsin G cleaves factor V at several sites (Phe1031, Leu1447, Tyr1518, and potentially Tyr696), ultimately generating an amino-terminal 103 kDa heavy chain and a carboxy-terminal 80 kDa light chain (FVaCG) [39].
• The distribution of cathepsin G-containing cells was examined by immunohistochemistry in the temporal cortex of both Alzheimer's and aged control samples [5].
• Twenty-three sera negative for ANCA were also tested for antibodies to BPI and cathepsin G using ELISA [40].
• This low activity of cathepsin G might be explained by the presence of alpha 1-antichymotrypsin, which was detected by laser nephlometric immunoassay and immunoblot analysis [41].
• Following incubation of sheep CG and NE with human alpha(1)-antichymotrypsin and alpha(1)-proteinase inhibitor, complexes with apparent molecular masses of 89 and 81 kDa respectively were observed by SDS-PAGE [42].

References