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Human lysyl oxidase-like 2.

ABSTRACT: Lysyl oxidase like-2 (LOXL2) belongs to the lysyl oxidase (LOX) family, which comprises Cu(2+)- and lysine tyrosylquinone (LTQ)-dependent amine oxidases. LOXL2 is proposed to function similarly to LOX in the extracellular matrix (ECM) by promoting crosslinking of collagen and elastin. LOXL2 has also been proposed to regulate extracellular and intracellular cell signaling pathways. Dysregulation of LOXL2 has been linked to many diseases, including cancer, pro-oncogenic angiogenesis, fibrosis and heart diseases. In this review, we will give an overview of the current understandings and hypotheses regarding the molecular functions of LOXL2.

SUBMITTER: Moon HJ

PROVIDER: S-EPMC6309629 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Human lysyl oxidase-like 2.

Moon Hee-Jung HJ Finney Joel J Ronnebaum Trey T Mure Minae M

Bioorganic chemistry 20140801

Lysyl oxidase like-2 (LOXL2) belongs to the lysyl oxidase (LOX) family, which comprises Cu(2+)- and lysine tyrosylquinone (LTQ)-dependent amine oxidases. LOXL2 is proposed to function similarly to LOX in the extracellular matrix (ECM) by promoting crosslinking of collagen and elastin. LOXL2 has also been proposed to regulate extracellular and intracellular cell signaling pathways. Dysregulation of LOXL2 has been linked to many diseases, including cancer, pro-oncogenic angiogenesis, fibrosis and ...[more]

PMID: 25146937

Similar Datasets

The Interactome of Cancer-Related Lysyl Oxidase and Lysyl Oxidase-Like Proteins.

Project description:The members of the lysyl oxidase (LOX) family are amine oxidases, which initiate the covalent cross-linking of the extracellular matrix (ECM), regulate ECM stiffness, and contribute to cancer progression. The aim of this study was to build the first draft of the interactome of the five members of the LOX family in order to determine its molecular functions, the biological and signaling pathways mediating these functions, the biological processes it is involved in, and if and how it is rewired in cancer. In vitro binding assays, based on surface plasmon resonance and bio-layer interferometry, combined with queries of interaction databases and interaction datasets, were used to retrieve interaction data. The interactome was then analyzed using computational tools. We identified 31 new interactions and 14 new partners of LOXL2, including the α5β1 integrin, and built an interactome comprising 320 proteins, 5 glycosaminoglycans, and 399 interactions. This network participates in ECM organization, degradation and cross-linking, cell-ECM interactions mediated by non-integrin and integrin receptors, protein folding and chaperone activity, organ and blood vessel development, cellular response to stress, and signal transduction. We showed that this network is rewired in colorectal carcinoma, leading to a switch from ECM organization to protein folding and chaperone activity.

| S-EPMC7794802 | biostudies-literature

Focus on molecules: lysyl oxidase.

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| S-EPMC3371289 | biostudies-literature

Inhibition of angiogenesis in endothelial cells by Human Lysyl oxidase propeptide.

Project description:Angiogenesis is a critical process involved in normal physiology. Pathological angiogenesis is observed in vascular diseases and neoplasia. The propeptide domain of LOX (LOX-PP) has been shown to inhibit tumorigenesis in various cancers. In this study, we explored the role of both overexpressed and recombinant LOX-PP in naïve human umbilical vein endothelial cell with the addition of vascular endothelial growth factor (VEGF). Primarily, we observed a significant reduction in the angiogenesis signaling pathways upon LOX-PP overexpression by proteomic analysis. Further functional analysis showed that the VEGF induced cell proliferation, migration, adhesion and tube formation was inhibited by LOX-PP. Moreover, LOX-PP arrested cells at S-phase, reduced F-actin levels and decreased phosphorylation of focal adhesion kinase (FAK) and extracellular signal regulated kinase (ERK). The anti-angiogenic effect of LOX-PP was further confirmed by the reduction in the vascular network formation in chick chorioallantoic membrane (CAM). These results indicate that inhibition of angiogenesis events is not only achieved by overexpressing LOX-PP but also by addition of rLOX-PP. Taken together our findings discovered the anti-angiogenic role of LOX-PP in endothelial cells which suggests that harnessing this potential can be a promising strategy to inhibit angiogenesis.

| S-EPMC6041307 | biostudies-literature

Serum Lysyl Oxidase Levels and Lysyl Oxidase Gene Polymorphism in Ovarian Cancer Patients of Eastern Indian Population.

Project description:(1) Background: Lysyl oxidase (LOX) plays a dual role in carcinogenesis and studies show a higher risk of cancer in LOX G473A variants. The present study evaluated the pattern of LOX G473A polymorphism (rs1800449) and serum LOX levels in ovarian cancer patients. (2) Methods: Serum LOX levels were estimated by enzyme linked immunosorbent assay (ELISA). A polymorphism of rs1800449 of LOX gene was detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Selected samples were sequenced for external validation. (3) Results: A majority of study participants were from low socio-economic status. Serum LOX level was significantly higher in ovarian cancer patients as compared to control. Serum LOX level in early-stage ovarian cancer was significantly lower as compared to advanced stage (FIGO stage III & IV). Wild type GG genotype was used as reference. Genotypes AA were associated with a significant risk of epithelial ovarian cancer (OR 3.208; p value- 0.033). A allele of rs1800449 polymorphism of LOX gene, the odds ratio was 1.866 (95% Confidence Interval 1.112-3.16) p value = 0.017 (4) Conclusions: A allele of rs1800449 polymorphism of LOX gene presents an increased risk of ovarian cancer in East Indian population. Serum LOX levels could be a potential biomarker for the diagnosis and prognosis of ovarian cancer.

| S-EPMC8774920 | biostudies-literature

Characterization of recombinant lysyl oxidase propeptide.

Project description:Lysyl oxidase enzyme activity is critical for the biosynthesis of mature and functional collagens and elastin. In addition, lysyl oxidase has tumor suppressor activity that has been shown to depend on the propeptide region (LOX-PP) derived from pro-lysyl oxidase (Pro-LOX) and not on lysyl oxidase enzyme activity. Pro-LOX is secreted as a 50 kDa proenzyme and then undergoes biosynthetic proteolytic processing to active approximately 30 kDa LOX enzyme and LOX-PP. The present study reports the efficient recombinant expression and purification of rat LOX-PP. Moreover, using enzymatic deglycosylation and DTT derivatization combined with mass spectrometry technologies, it is shown for the first time that rLOX-PP and naturally occurring LOX-PP contain both N- and O-linked carbohydrates. Structure predictions furthermore suggest that LOX-PP is a mostly disordered protein, which was experimentally confirmed in circular dichroism studies. Due to its high isoelectric point and its disordered structure, we propose that LOX-PP can associate with extracellular and intracellular binding partners to affect its known biological activities as a tumor suppressor and inhibitor of cell proliferation.

| S-EPMC2847845 | biostudies-literature

Targeting lysyl oxidase reduces peritoneal fibrosis.

Project description:BackgroundAbdominal surgery and disease cause persistent abdominal adhesions, pelvic pain, infertility and occasionally, bowel obstruction. Current treatments are ineffective and the aetiology is unclear, although excessive collagen deposition is a consistent feature. Lysyl oxidase (Lox) is a key enzyme required for crosslinking and deposition of insoluble collagen, so we investigated whether targeting Lox might be an approach to reduce abdominal adhesions.MethodsFemale C57Bl/6 mice were treated intraperitoneally with multiwalled carbon nanotubes (NT) to induce fibrosis, together with chemical (ß-aminoproprionitrile-BAPN) or miRNA Lox inhibitors, progesterone or dexamethasone. Fibrotic lesions on the diaphragm, and expression of fibrosis-related genes in abdominal wall peritoneal mesothelial cells (PMC) were measured. Effects of BAPN and dexamethasone on collagen fibre alignment were observed by TEM. Isolated PMC were cultured with interleukin-1 alpha (IL-1α) and progesterone to determine effects on Lox mRNA in vitro.ResultsNT-induced fibrosis and collagen deposition on the diaphragm was ameliorated by BAPN, Lox miRNA, or steroids. BAPN and dexamethasone disrupted collagen fibres. NT increased PMC Lox, Col1a1, Col3a1 and Bmp1 mRNA, which was inhibited by steroids. Progesterone significantly inhibited IL-1α induced Lox expression by PMC in vitro.ConclusionOur results provide proof-of-concept that targeting peritoneal Lox could be an effective approach in ameliorating fibrosis and adhesion development.

| S-EPMC5553776 | biostudies-literature

A Three-Dimensional Model of Human Lysyl Oxidase, a Cross-Linking Enzyme.

Project description:Lysyl oxidase (LOX) is a cross-linking enzyme identified 50 years ago, but its 3D structure is still unknown. We have thus built a 3D model of human LOX by homology modeling using the X-ray structure of human lysyl oxidase-like 2 as a template. This model is the first one to recapitulate all known biochemical features of LOX, namely, the coordination of the copper ion and the formation of the lysine tyrosylquinone cofactor and the disulfide bridges. Furthermore, this model is stable during a 1 μs molecular dynamics simulation. The catalytic site is located in a groove surrounded by two loops. The distance between these loops fluctuated during the simulations, which suggests that the groove forms a hinge with a variable opening, which is able to accommodate the various sizes of LOX substrates. This 3D model is a pre-requisite to perform docking experiments with LOX substrates and other partners to identify binding sites and to design new LOX inhibitors specific for therapeutic purpose.

| S-EPMC6647939 | biostudies-literature

Knock-Out of the Five Lysyl-Oxidase Family Genes Enables Identification of Lysyl-Oxidase Pro-Enzyme Regulated Genes.

Project description:The five lysyl-oxidase genes share similar enzymatic activities and contribute to tumor progression. We have knocked out the five lysyl-oxidase genes in MDA-MB-231 breast cancer cells using CRISPR/Cas9 in order to identify genes that are regulated by LOX but not by other lysyl-oxidases and in order to study such genes in more mechanistic detail in the future. Re-expression of the full-length cDNA encoding LOX identified four genes whose expression was downregulated in the knock-out cells and rescued following LOX re-expression but not re-expression of other lysyl-oxidases. These were the AGR2, STOX2, DNAJB11 and DNAJC3 genes. AGR2 and STOX2 were previously identified as promoters of tumor progression. In addition, we identified several genes that were not downregulated in the knock-out cells but were strongly upregulated following LOX or LOXL3 re-expression. Some of these, such as the DERL3 gene, also promote tumor progression. There was very little proteolytic processing of the re-expressed LOX pro-enzyme in the MDA-MB-231 cells, while in the HEK293 cells, the LOX pro-enzyme was efficiently cleaved. We introduced point mutations into the known BMP-1 and ADAMTS2/14 cleavage sites of LOX. The BMP-1 mutant was secreted but not cleaved, while the LOX double mutant dmutLOX was not cleaved or secreted. However, even in the presence of the irreversible LOX inhibitor β-aminoproprionitrile (BAPN), these point-mutated LOX variants induced the expression of these genes, suggesting that the LOX pro-enzyme has hitherto unrecognized biological functions.

| S-EPMC9570307 | biostudies-literature

Effect of Lysyl Oxidase G473 A Polymorphism on Lysyl Oxidase and Total Soluble Collagen Expression in Oral Submucous Fibrosis.

Project description:BackgroundOral submucous fibrosis (OSF) is a debilitating collagen-metabolic disorder leading to submucosal fibrosis and trismus. Lysyl oxidase (LOX), a critical collagen biosynthetic enzyme, is up-regulated in OSF. Polymorphisms in the Lysyl oxidase gene have been associated with increased risk of OSF and might affect normal collagen synthesis, accumulation, or degradation, crucial in determining fibrosis severity.MethodsOne hundred OSF cases and 100 controls were genotyped for LOX G473A(Arg158Gln) polymorphism by polymerase chain reaction-restriction fragment length polymorphism. The expression of LOX was estimated both by quantitative mRNA analysis and western blot. Total soluble collagen was evaluated from mucosal tissue obtained from OSF cases. Immunohistochemical (IHC) localization of type 1 collagen was performed in mucosal tissue obtained from patients carrying various genotypes.ResultsHeterozygous G473A genotype was significantly higher in OSF cases [2.063(95% CI =1.059-4.016)], among 26-40 years age-group [4.375(95% CI=1.323-14.267),p=0.029] and in male patients [2.38 (95% CI= 1.107-5.121), p= 0.042]. LOX expression was significantly higher in cases of the heterozygous or homozygous carrier (p <0.001). We found the total soluble collagen level significantly (p <0.001) higher among patients carrying GA or AA genotype. IHC revealed focal deposition of type1 collagen in the submucosal tissue; comparatively higher deposition was evident in mucosal tissue of OSF patients carrying AA genotype.ConclusionsThese findings suggest LOX G473A polymorphism confers an increased risk of OSF and may affect collagen accumulation in OSF cases.

| S-EPMC8629460 | biostudies-literature

Lysyl Oxidase (LOX) Transcriptionally Regulates SNAI2 Expression and TIMP4 Secretion in Human Cancers.

Project description:PurposeEpithelial-to-mesenchymal transition (EMT) is important in cancer progression and metastasis. We and others have previously reported that lysyl oxidase (LOX) is overexpressed in aggressive cancers, is associated with increased mortality, and regulates EMT. However, the mechanism by which LOX mediates EMT is unknown. In this study, we investigated the effect of LOX on mediators of EMT.Experimental designWe used chromatin immunoprecipitation and promoter luciferase assays to determine the target gene of LOX. To determine the effects of SNAI2 in vivo, we used our metastatic anaplastic thyroid cancer (ATC) mouse model. To investigate the effects of LOX and SNAI2 on MMPs and TIMPs, protein arrays were used. Primary tumors from patients with metastatic, breast and colon cancer, and tissue array for thyroid cancer were assessed for SNAI2 and TIMP4 expression by immunohistochemistry.ResultsWe found that LOX knockdown decreases SNAI2 expression in cancer cell lines. Furthermore, knockdown of LOX reduced SNAI2 expression in a metastatic mouse model of thyroid cancer. We also demonstrated that LOX binds and transactivates the SNAI2 promoter. We found a direct correlation in thyroid and breast cancer samples between LOX and SNAI2 expression. To understand how LOX/SNAI2 axis mediates these effects, we performed a comprehensive analysis of MMPs/TIMPs. LOX and SNAI2 depletion reduced TIMP4 secretion. Analysis of SNAI2 and TIMP4 expression showed overexpression of both proteins in aggressive thyroid, colon, and breast tumors.ConclusionsOur findings provide new evidence that LOX regulates SNAI2 expression and that SNAI2-mediated TIMP4 secretion plays a role in cancer progression. Clin Cancer Res; 22(17); 4491-504. ©2016 AACR.

| S-EPMC8201910 | biostudies-literature

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