Disease relevance of MMP26

• Higher levels of MMP-26 mRNA were also detected in DCIS cells by in situ hybridization [1].
• Endometase/matrilysin-2 in human breast ductal carcinoma in situ and its inhibition by tissue inhibitors of metalloproteinases-2 and -4: a putative role in the initiation of breast cancer invasion [1].
• The role of MMP-26 in prostate cancer progression is unknown [2].
• Here, we showed that the levels of MMP-26 protein in human prostate carcinomas from multiple patients were significantly higher than those in prostatitis, benign prostate hyperplasia, and normal prostate glandular tissues [2].
• The aim of this study was to examine matrilysin-2 expression and determine whether it is correlated with progression of human esophageal squamous cell carcinoma (ESCC) [3].

High impact information on MMP26

• Earlier, we determined that the estrogen-ER complex stimulates the transcriptional activity of the matrix metalloproteinase 26 (MMP-26) gene promoter [4].
• MMP-26 targets the NH(2)-terminal region of ERbeta coding for the divergent NH(2)-terminal A/B domain that is responsible for the ligand-independent transactivation function [4].
• MMP-26 is not expressed in normal mammary epithelium [4].
• In contrast to many tumor-promoting MMPs, the expression of MMP-26 in DCIS correlated with a longer patient survival [4].
• The levels of MMP-26 are strongly up-regulated in ductal carcinoma in situ (DCIS) [4].

Chemical compound and disease context of MMP26

• To investigate the contribution of MMP-26 to cancer cell invasion via the activation of MMP-9, highly invasive and metastatic human prostate carcinoma cells, androgen-repressed prostate cancer (ARCaP) cells were selected as a working model [2].
• Expression of MMP-26 is elevated in users of levonorgestrel implants who experienced irregular uterine bleeding [5].

Biological context of MMP26

• The mRNA and protein level of MMP26 in chorionic villi was highest at Weeks 6-7, and decreased thereafter, reaching its lowest level at the second trimester [6].
• The expression patterns of MMP26 in human placenta suggests complicated roles for MMP26 during the processes of placentation and hematopoiesis, perhaps working in concert with other members of the MMP family, such as MMP9 [6].
• Interestingly, inhibitor titration studies revealed that only approximately 5% of the total MMP-26 molecules was catalytically active, indicating that the thiol groups of Cys(82) in the active molecules may be dissociated or removed from the active site zinc ions [7].
• Peptide libraries were used to profile the substrate specificity of MMP-26 from the P4-P4' sites [7].
• By using a novel cloning strategy, we identified three previously unknown human MMPs, i.e. MMP-21, MMP-26 and MMP-28, in comprehensive gene libraries [8].

Anatomical context of MMP26

• MMP26 was widely localized to villous cytotrophoblast cells, syncytiotrophoblast cells, and to column trophoblasts during early pregnancy [6].
• Notably, intense expression of MMP26 was found in fetal nucleated red cells inside the villous capillaries during gestational Weeks 6-9 [6].
• Strong expression of MMP26 mRNA was also demonstrated in fetal red cells isolated from the whole blood of fetuses at midpregnancy [6].
• We have previously reported that matrix metalloproteinase-26 (MMP-26) promotes the invasion of human prostate cancer cells via the cleavage of basement membrane proteins and by activating the zymogen form of MMP-9 [9].
• A pair of stereoisomers had only a 40-fold difference in K(i)(app) values against MMP-26 compared with a 250-fold difference against neutrophil collagenase, indicating that MMP-26 is less stereoselective for its inhibitors [7].

Associations of MMP26 with chemical compounds

• To explore MMP-26 active site structure-activity, a series of new potent mercaptosulfide MMP inhibitors (MMPIs) with Leu or homophenylalanine (Homophe) side chains at the P1' site were selected [10].
• Several unique structural and regulatory features, including an unusual 'cysteine-switch' motif, discriminate broad-spectrum MMP-26 from most other MMPs [8].
• RESULT(S): Endometrium from women with a normal menstrual cycle and users of levonorgestrel implants expresses MMP-26, TIMP-3, and TIMP-4 [5].
• An expression of MMP-26 in the estrogen-dependent neoplasms is likely to contribute to the inactivation of AAT, to the follow-up liberation of the Ser protease activity, and because of these biochemical events, to promote matrix destruction and malignant progression [11].
• We recently discovered that AAT is efficiently cleaved by a novel metalloproteinase, MMP-26, which exhibits an unconventional PH(81)CGVPD Cys switch motif and is autocatalytically activated in cells and tissues [11].

Enzymatic interactions of MMP26

• MMP-26 cleaved Phe(352)-Leu(353) and Pro(357)-Met(358) in the reactive loop of alpha(1)-proteinase inhibitor and His(140)-Val(141) in insulin-like growth factor-binding protein-1, probably rendering these substrates inactive [7].
• Endometase may selectively cleave extracellular matrix proteins, inactivate serpins, and process cytokines [12].

Co-localisations of MMP26

• Double immunofluorescence staining and confocal laser scanning microscopic images revealed that MMP-26 and MMP-9 were co-localized in parental and MMP-26 sense-transfected ARCaP cells [2].

Regulatory relationships of MMP26

• TIMP-2 and TIMP-4 also inhibited the activation of pro-MMP-9 by MMP-26 in vitro [1].
• MMP-26 was capable of activating pro-MMP-9 by cleavage at the Ala(93)-Met(94) site of the prepro-enzyme [2].
• MMP-26 was neither co-expressed with its close homologue matrilysin-1 nor with the proliferation marker Ki-67 [13].
• Beta-catenin regulates the gene of MMP-26, a novel metalloproteinase expressed both in carcinomas and normal epithelial cells [14].

Other interactions of MMP26

• Here we report that tissue inhibitor of metalloproteinases (TIMP)-2 and TIMP-4 are potent inhibitors of MMP-26, with apparent K(i) values of 1.6 and 0.62 nM, respectively [1].
• MAIN OUTCOME MEASURE(S): Expression of MMP-26, TIMP-3, and TIMP-4 by immunohistochemistry and semiquantitative analysis of staining intensity by using the H score [5].
• OBJECTIVE: To determine the expression of matrix metalloproteinase (MMP-26) and tissue inhibitor of MMP (TIMP) in the endometrium of women with normal menstrual cycles compared with users of levonorgestrel implants [5].
• Expression of matrilysin-2, matrix metalloproteinase (MMP)-26, has been implicated in the progression of several types of human cancer [3].
• Expression of matrilysin-2 was significantly correlated with nuclear beta-catenin expression and MMP-9 expression [3].

Analytical, diagnostic and therapeutic context of MMP26

• Protein sequence analysis and homology modeling further verified that MMP-26 has an intermediate S1' pocket formed by Leu-204, His-208, and Tyr-230 [10].
• Matrilysin-2 expression retained its significant predictive value for overall and disease-free survival in multivariate analysis [3].
• In the present study, we identified the expression and localization of MMP26/endometase/ matrilysin-2 in human placentae at different stages of gestation using methods of reverse transcriptase-polymerase chain reaction, in situ hybridization, and immunohistochemistry [6].
• In KC and HaCaT cell cultures, 12-phorbol-13-myristate-acetate, epidermal growth factor, tumor necrosis factor-alpha, transforming growth factor-beta1, interleukin-1 (IL-1)beta, IL-6, insulin-like growth factor, gamma-IFN, retinoic acid, dexamethasone, four matrices or ras-transformation were unable to upregulate MMP-26 expression [13].
• Sequential deletion and mutation analysis, and electrophoretic mobility-shift assay have identified the T-cell factor-4 (Tcf-4) motif and the activator protein-1 site as the major regulatory elements of the MMP-26 promoter [15].

References