The LOXL2 gene is located on chromosome 8p21.2-p21.3 (Jourdan-Le Saux et al., 1998). It is composed of fourteen exons and thirteen introns, distributed through approximately 107 kb of genomic DNA (Fong et al., 2007). Two transcripts of sizes 3.6 kb and 4.9 kb have been reported, with the smaller transcript much more abundant and resulting from three possible termination sites located 690 bp, 740 bp and 900 bp 3 of the termination codon (Jourdan-Le Saux et al., 1999). The termination site used for the larger 4.9 kb transcript has not been described. Intron 4 contains a polymorphic CA-repeat microsatellite (Fong et al., 2007) and there are at least 17 SNPs within the LOXL2 gene (Akagawa et al., 2007). The LOXL2 gene also contains a CpG island of approximately 1150 bp, starting 176 bases upstream of the transcriptional start and extending into intron 1 (Fong et al., 2007).

The LOXL2 promoter region contains numerous putative binding sites for transcription factors, including WT1, SP1, NF-kB and AP-1 (Fong et al., 2007).
LOXL2 gene expression is induced by TGF-b1 or indomethacin, and inhibited by retinoic acid or phorbol ester (Saito et al., 1997). It has also been described as a type II TGF-b receptor-dependent gene in lung adenocarcinoma subtypes (Borczuk et al., 2005). LOXL2 expression could be induced in MCF-7 breast cancer cells cultured on a collagen I matrix conditioned by fibroblasts (Kirschmann et al., 2002), in H292 human airway epithelial cells exposed to mite allergen (Vroling et al., 2007), and in MC3T3-E1 osteoblastic cells exposed to active vitamin D3 in culture (Nagaoka et al., 2008). LOXL2 is also induced by hypoxia. Hypoxia-inducible factor-1 alpha (HIF-1a) stimulates LOXL2 mRNA transcription in fibroblasts and renal tubular epithelial cells (Higgins et al., 2007; Salnikow et al., 2008). This upregulation was inhibited in fibroblasts by siRNA targeting the ETS1 transcription factor (Salnikow et al., 2008).
Transcription of the LOXL2 gene may also be affected by the methylation status of its CpG island (Fong et al., 2007).

No known pseudogene.

The LOXL2 transcript encodes for a 774-amino acid protein containing a predicted signal peptide of 22 amino acids, yielding an 87 kDa protein based on sequence analysis and produced by in vitro translation. In addition, there are three potential N-linked glycosylation sites (Saito et al., 1997). Western analysis of secreted proteins from LOXL2-transfected cells detected a protein of approximately 95 kDa, likely a glycosylated LOXL2 protein, and a protein of 63 kDa, which is an extracellular proteolytically processed form of LOXL2 (Akiri et al., 2003; Vadasz et al., 2005; Fong et al., 2007; Hollosi et al., 2009). Western analysis of cellular proteins isolated from LOXL2-transfected normal mammary epithelial cells revealed a 95 kDa protein similar to the secreted form and no processed form in the soluble cellular protein collection, with two additional LOXL2 proteins in the insoluble cellular protein collection: a 105 kDa protein that may be an alternately glycosylated full-length form, as well as a 50 kDa protein, which is another proteolytically processed form of LOXL2 (Hollosi et al., 2009). Although other LOX family members are processed extracellularly into their mature forms by bone morphogenetic protein-1 and related enzymes (Borel et al., 2001; Csiszar, 2001; Uzel et al., 2001), no potential processing site(s) or responsible enzymes have been identified for LOXL2.

Tissue expression of LOXL2 mRNA has been described in extracts of spleen, thymus, prostate, testis, uterus, small intestine, colon, heart, brain, placenta, lung, liver, kidney, pancreas, skeletal muscle and bone (Jourdan-Le Saux et al., 1999; Pires Martins et al., 2001). LOXL2 was more highly expressed in fetal heart compared to adult heart, and was found in the left and right atrium and ventricles, and the apex of the adult heart, as well as the aorta (Pires Martins et al., 2001; Molnar et al., 2003).
As for normal cell types, LOXL2 mRNA expression has been reported in fibroblasts (Saito et al., 1997; Pires Martins et al., 2001; Kirschmann et al., 2002), melanocytes and B-cells (Pires Martins et al., 2001), syncytiotrophoblasts and cytotrophoblasts (Jourdan-Le Saux et al., 1999; Hein et al., 2001), bone marrow stromal cells (Monticone et al., 2004), and astrocytes from the optic nerve head (Urban et al., 2007). LOXL2 protein has been detected in syncytiotrophoblasts and cytotrophoblasts (Hein et al., 2001), bone marrow stromal cells (Monticone et al., 2004), colonic enteroendocrine cells and esophageal squamous cells (Fong et al., 2007), and mammary epithelial cells (Hollosi et al., 2009).

In cell culture, LOXL2 has been detected extracellularly (Akiri et al., 2003; Vadasz et al., 2005; Fong et al., 2007; Hollosi et al., 2009) and intracellularly (Fong et al., 2007; Hollosi et al., 2009), and also localized to the perinuclear compartment (Peinado et al., 2005). In tissues, LOXL2 has been localized to the cytoplasm in colonic enteroendocrine cells and esophageal squamous cells towards the lumen surface (Fong et al., 2007), and associated with the luminal membrane surface in mammary gland acini (Hollosi et al., 2009).

LOXL2, similar to its other LOX family members, has been reported to have amine oxidase activity, but unlike its family members, its enzyme activity was not inhibited by beta-aminoproprionitrile (BAPN) (Vadasz et al., 2005; Hollosi et al., 2009). Other LOX family members are known to oxidize peptidyl lysine and hydroxylysine residues in collagen and lysine residues in elastin to form the covalent cross-links that stabilize and insolubilize several fibrillar collagen types and elastin fibers (reviewed in Lucero and Kagan, 2006), and it has been reported that LOXL2 has catalytic activity against collagen type I (Vadasz et al., 2005). Treatment of MC3T3-E1 osteoblastic cells with active vitamin D3 resulted in increased LOXL2 expression (other LOX family members were not up-regulated), and increased collagen cross-links and acceleration of cross-link maturation (Nagaoka et al., 2008). As for its role in elastin fiber assembly, LOXL2 has been reported to interact with fibulin-5, which could tether LOXL2 onto microfibrils to facilitate elastic fiber assembly and maturation (Hirai et al., 2007). A single nucleotide polymorphism (SNP) in LOXL2 has been described to have an interactive effect with SNPs in the elastin/LIM kinase 1 locus in intracranial aneurysm susceptibility (Akagawa et al., 2007), and LOXL2 silencing repressed elastin gene transcription and eliminated elastic fiber formation by human umbilical vein endothelial cells (HUVEC) (Lelievre et al., 2008).
In diseases, LOXL2 has been reported to enhance the in vivo accumulation and deposition of collagen in breast tumors and glioma tumors formed by LOXL2-overexpressing cancer cells (Akiri et al., 2003). Increased LOXL2 has been described in hepatocytes from patients with Wilsons disease or primary biliary cirrhosis, which are fibrotic liver diseases (Vadasz et al., 2005); renal tubulointerstitial fibrosis from experimental unilateral ureteral obstruction and human renal samples of diabetic nephropathy, IgA nephropathy and hypertensive nephrosclerosis (Higgins et al., 2007); as well as a mouse model of chronic cholangitis which is similar to primary sclerosing cholangitis in humans (Nakken et al., 2007). Decreased LOXL2 mRNA expression was noted in human pelvic organ prolapse (Klutke et al., 2008).
LOXL2 is reduced in endothelial cells exposed to laminar shear stress, which induces reduction of atherogenicity (Chu and Peters, 2008). VE-statin/egfl7 that increases after arterial injury (Campagnolo et al., 2005), may modulate smooth muscle migration through interaction with the catalytic domain of LOXL2 and all LOX enzymes to inhibit enzyme activity (Lelievre et al., 2008). Increased LOXL2 has also been described in intracranial aneurysms, associated with a SNP in exon 5 (Akagawa et al., 2007).
LOXL2 is the only LOX family member not expressed in MC3T3-E1 osteoblastic cells (Atsawasuwan et al., 2005), and not up-regulated upon osteoblast differentiation (Kaku et al., 2007). Although expressed in bone marrow stromal cells (BMSC), LOXL2 was down-regulated in osteoblasts derived from BMSC (Qi et al., 2003; Monticone et al., 2004).
In addition, increased LOXL2 expression was observed in senescent fibroblasts, replicative senescence and stress-induced premature senescence (Saito et al., 1997; Pascal et al., 2005), and may be involved in primary open-angle glaucoma (Urban et al., 2007). LOXL2 also appears to have a role in cell proliferation (Akiri et al., 2003; Vadasz et al., 2005).
LOXL2 also has been described to have multiple roles in cancer, including epithelial-mesenchymal transition and the promotion of cancer cell adhesion, migration, invasion and metastases, and these are described in more detail in the following sections.

In the human lysyl oxidase protein family, there are five members, named LOX, LOXL1, LOXL2, LOXL3 and LOXL4. They all contain a lysine tyrosylquinone (LTQ), the only mammalian cofactor derived from the cross-linking of two amino acid side chains (Anthony, 1996), and which is unique to the LOX family. The other highly conserved motif that is unique to the LOX family is the copper-binding domain, which contains four histidines (Krebs and Krawetz, 1993). All LOX family members also contain a cytokine receptor-like (CRL) domain, which has part of the consensus sequence of Class 1 cytokine receptors (Bazan, 1990). LOXL2 has closest homology to LOXL3 and LOXL4, as these three members differ from LOX and LOXL1 by the presence of 4 SRCR domains, and may represent a separate subfamily (Asuncion et al., 2001; Maki et al., 2001).

Despite the implication of LOXL2 in several diseases and disorders, there are only sparse reports of any gene loss, polymorphisms or epigenetic alterations in the LOXL2 gene.

Loss of heterozygosity has been documented in colon and esophageal cancers at a level lower than the loss of heterozygosity documented in chromosome 8p21.2 - p21.3 for these cancers, indicating that LOXL2 is unlikely to be a tumor suppressor (Fong et al., 2007).

Increase in LOXL2 expression following treatment with the demethylating agent, 5-aza-2-deoxycytidine, in colon and breast cancer cell lines indicate that the demethylation of the LOXL2 CpG island is a possible mechanism for regulating LOXL2 gene expression (Fong et al., 2007; Hollosi et al., 2009).