Alendronate promotes plasmin‐mediated MMP‐9 inactivation by exposing cryptic plasmin degradation sites within the MMP‐9 catalytic domain

Farina, Antonietta R.; Cappabianca, Lucia; Ianni, Natalia Di; Ruggeri, Pierdomenico; Ragone, Marzia; Merolle, Stefania; Gulino, Alberto; Mackay, Andrew R.

doi:10.1016/j.febslet.2012.05.048

Cited by 9 publications

(15 citation statements)

References 54 publications

(86 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Gelatinase B/MMP-9 activation is achieved by proteolytic removal of this sequence by enzymes that include: trypsin, cathepsin G, kallikrien, elastase, chymase, neutrophil elastase and the MMPs-1, -2, -3, -7, -10, -13 and -26 [12]. Debate exists, however, as to whether plasmin can directly activate gelatinase B/MMP-9 [12,41]. Indirect plasmin-mediated gelatinase B/MMP-9 activation is achieved via MMP-1, MMP-3 and MMP-7 [12].…”

Section: The Gelatinase B/mmp-9 Proteinmentioning

confidence: 99%

“…The gelatinase B/MMP-9 catalytic domain contains six disulphide bonds that are necessary for intracellular trafficking and gelatinase B/MMP-9 secretion [45]. The gelatinase B/MMP-9 catalytic site also contains cryptic plasmin degradation sites that are exposed by divalent cation chelators and by the bisphosphonate alendronate (Fosamax) and upon degradation irreversibly inhibit gelatinase B/MMP-9 catalytic activity [41]. …”

Section: The Gelatinase B/mmp-9 Proteinmentioning

confidence: 99%

“…KLK7 and meprin-α also remove this domain from gelatinase B/MMP-9 [50,51,52]. A novel 82 kDa inactive pro-gelatinase B/MMP-9 form has been described in human leukaemic cells, which also escapes TIMP inhibition [53,54] and a similar sized human pro-gelatinase B/MMP-9 isoform is generated by the action of plasmin [41]. …”

Section: The Gelatinase B/mmp-9 Proteinmentioning

confidence: 99%

“…Gelatinase B/MMP-9 enzymatic activity is inhibited by the universal systemic protease inhibitor α2-macrogloblin [160], members of the tissue inhibitors of metalloproteinases (TIMPs) family [161,162] and is also antagonized by its own isolated hemopexin domain [41,163]. TIMPs 1–4 are 20–30 kDa glycoprotein MMP inhibitors that depend upon disulphide bridges between 6 cysteine pairs for their inhibitory activity [161,162,164].…”

Section: Gelatinase B/mmp-9 Expression Bioavailability Activity mentioning

confidence: 99%

See 3 more Smart Citations

Gelatinase B/MMP-9 in Tumour Pathogenesis and Progression

Farina

Mackay

2014

Cancers

170

142

View full text Add to dashboard Cite

Since its original identification as a leukocyte gelatinase/type V collagenase and tumour type IV collagenase, gelatinase B/matrix metalloproteinase (MMP)-9 is now recognised as playing a central role in many aspects of tumour progression. In this review, we relate current concepts concerning the many ways in which gelatinase B/MMP-9 influences tumour biology. Following a brief outline of the gelatinase B/MMP-9 gene and protein, we analyse the role(s) of gelatinase B/MMP-9 in different phases of the tumorigenic process, and compare the importance of gelatinase B/MMP-9 source in the carcinogenic process. What becomes apparent is the importance of inflammatory cell-derived gelatinase B/MMP-9 in tumour promotion, early progression and triggering of the “angiogenic switch”, the integral relationship between inflammatory, stromal and tumour components with respect to gelatinase B/MMP-9 production and activation, and the fundamental role for gelatinase B/MMP-9 in the formation and maintenance of tumour stem cell and metastatic niches. It is also apparent that gelatinase B/MMP-9 plays important tumour suppressing functions, producing endogenous angiogenesis inhibitors, promoting inflammatory anti-tumour activity, and inducing apoptosis. The fundamental roles of gelatinase B/MMP-9 in cancer biology underpins the need for specific therapeutic inhibitors of gelatinase B/MMP-9 function, the use of which must take into account and substitute for tumour-suppressing gelatinase B/MMP-9 activity and also limit inhibition of physiological gelatinase B/MMP-9 function.

show abstract

Section: The Gelatinase B/mmp-9 Proteinmentioning

confidence: 99%

Section: The Gelatinase B/mmp-9 Proteinmentioning

confidence: 99%

Section: The Gelatinase B/mmp-9 Proteinmentioning

confidence: 99%

Section: Gelatinase B/mmp-9 Expression Bioavailability Activity mentioning

confidence: 99%

See 2 more Smart Citations

Gelatinase B/MMP-9 in Tumour Pathogenesis and Progression

Farina

Mackay

2014

Cancers

170

142

View full text Add to dashboard Cite

show abstract

“…A molecular scaffold has been identified and tested with SAR studies identifying potential lead compounds with IC 50 on micro molar scale (186). Alendronate and EDTA, divalent chelators, have been shown to inhibit MMP-9 activity irreversibly via plasmin-mediated inactivation (187). Cryptic plasmin degradation sites within the catalytic domain of MMP-9 become accessible to form hemopexin-domain fragments which have the inhibitory property (187).…”

Section: Regulation Of Mmps In Vascular Diseasesmentioning

confidence: 99%

Regulation and involvement of matrix metalloproteinases in vascular diseases

et al. 2016

View full text Add to dashboard Cite

Matrix metalloproteinases (MMPs) are a family of zinc dependent endopeptidases whose main function is to degrade and deposit structural proteins within the extracellular matrix (ECM). A dysregulation of MMPs is linked to vascular diseases. MMPs are classified into collagenases, gelatinases, membrane-type, metalloelastase, stromelysins, matrilysins, enamelysins, and unclassified subgroups. The production of MMPs is stimulated by factors such as oxidative stress, growth factors and inflammation which lead to its up- or down-regulation with subsequent ECM remodeling. Normally, excess activation of MMPs is controlled by their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs). An imbalance of MMPs and TIMPs has been implicated in hypertension, atherosclerotic plaque formation and instability, aortic aneurysms and varicose vein wall remodeling. Also, recent evidence suggests epigenetic regulation of some MMPs in angiogenesis and atherosclerosis. Over the years, pharmacological inhibitors of MMPs have been used to modify or prevent the development of the disease with some success. In this review, we discuss recent advances in MMP biology, and their involvement in the manifestation of vascular disease.

show abstract

Functional SNP in microRNA‐491‐5p binding site of MMP9 3′‐UTR affects cancer susceptibility

Pirooz

Jafari

Rastegari

et al. 2018

J of Cellular Biochemistry

View full text Add to dashboard Cite

MicroRNAs (miRNA) are small RNA molecules that negatively regulate gene expression through base pairing interactions between 3'-UTR of the target mRNAs and seed sequence of miRNA. Any changes in the recognition site could destroy binding sites or modify binding affinity, resulting in evasion from miRNA regulation. A putative binding site for miR-491-5p resides in 3'-UTR of MMP9, and a genetic variant (rs1056628 A → C) is present in this region. The role of MMP9 over expression well marked in various cancers. However, whether rs1056628 SNP in miR-491-5p binding site of MMP9 3'-UTR could abrogate its post-transcriptional regulation and affect cancer susceptibility remains largely unknown. To test this, the rs1056628 SNP was genotyped in 300 cases of lung, gastric and breast cancers and 200 age- and sex-matched healthy controls. The results showed that compared with the AA genotype, C was a risk genotype for all three cancers development and was also associated with gastric and breast cancers metastasis and invasion. Based on the base pairing analysis and secondary structure evaluation of MMP9 mRNA and miR-491-5p, we found that miR-491-5p had a higher binding affinity for A genotype than the C genotype. The Luciferase activity of MMP9 3'-UTR indicates differential regulation of two genetic variations of MMP9. Overexpression of miR-491-5p decreased MMP9 mRNA level in cell lines of gastric, breast and lung cancers and thus leads to decreasing of the invasion ability. Therefore, for the first time we imply that the C variant of MMP9 contributes to the likelihood of gastric, breast and lung cancers susceptibility via a novel mechanism of subtle gene regulation through miRNA binding capacity.

show abstract

Alendronate promotes plasmin‐mediated MMP‐9 inactivation by exposing cryptic plasmin degradation sites within the MMP‐9 catalytic domain

Cited by 9 publications

References 54 publications

Gelatinase B/MMP-9 in Tumour Pathogenesis and Progression

Gelatinase B/MMP-9 in Tumour Pathogenesis and Progression

Regulation and involvement of matrix metalloproteinases in vascular diseases

Functional SNP in microRNA‐491‐5p binding site of MMP9 3′‐UTR affects cancer susceptibility

Contact Info

Product

Resources

About