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Pro-Lysyl Oxidase Processing in Cancers and Eye Pathologies: Comparison
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Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Yaser Peymanfar.

Lysyl oxidases are multifunctional proteins derived from five lysyl oxidase paralogues (LOX) and lysyl oxidase-like 1 through lysyl oxidase-like 4 (LOXL1–LOXL4). All participate in the biosynthesis of and maturation of connective tissues by catalyzing the oxidative deamination of lysine residues in collagens and elastin, which ultimately results in the development of cross-links required to function. In addition, the five LOX genes have been linked to fibrosis and cancer when overexpressed, while tumor suppression by the propeptide derived from pro-LOX has been documented. Similarly, in diabetic retinopathy, LOX overexpression, activity, and elevated LOX propeptide have been documented.

  • lysyl oxidase
  • lysyl oxidase propeptide
  • diabetes
  • eye pathologies
  • Cancer

1. Introduction

Lysyl oxidases are encoded by a family of five paralogue genes known as lysyl oxidase (LOX) and lysyl oxidase like-1, -2, -3, and -4 (LOXL1–LOXL4). All are synthesized as pro-proteins which are structurally conserved in vertebrates [1], with LOX and LOXL1 being more closely related to each other [2] than to LOXL2–LOXL4 [3]. These pro-proteins contain a conserved C-terminal enzyme domain, while the propeptide regions of LOX and LOXL1 are each largely unique in sequence [4]. By contrast, LOXL2–LOXL4 propeptides are more similar to each other and all three contain four conserved Scavenger Receptor Cysteine-Rich (SRCR) domains, which typically serve as protein–protein binding domains in other proteins [5,6][5][6]. LOX is processed and activated by cleavage of its N-terminal pro-peptide catalyzed principally by Bone Morphogenetic Protein-1 (BMP-1) or BMP-1-related procollagen C-proteinases Tolloid Like-1 and -2 following secretion into the extracellular environment [7]. LOXL1 is similarly processed by BMP1 [8], while LOXL2 undergoes processing by furin enzymes required for type IV collagen crosslinking [9,10][9][10].
The lysyl oxidase family proteins all participate in the biosynthetic maturation of collagens and elastin by catalyzing the extracellular oxidation of the ε-amino group of peptidyl lysine or peptidyl hydroxy lysine residues in procollagens and tropoelastin to form the corresponding aldehydes, which are required for the subsequent formation of the biosynthetic cross-links and the function of the extracellular matrix [4]. In tumor biology, in general, abnormal high levels of lysyl oxidase paralogues expressed by tumor cells and/or associated stromal cells correlate well with poor outcomes in cancer.

2. LOX-PP Is Not Trash: Its Role in Tumor Suppression

The notion that LOX-PP, released extracellularly during the biosynthesis of the active LOX enzyme (Figure 1), could have its own function came from the observation that the tumor suppressor function linked to the phenotypic reversion of c-H-ras transformed fibroblasts depended in some way on the restoration of LOX expression [12,13][11][12]. At the time it was assumed that LOX enzyme activity fulfilled this function. However, treatment of phenotypically reverted c-H-ras transformed fibroblasts with the selective suicide substrate inhibitor of LOX, β-aminopripiontrile (BAPN), failed to re-transform these cells, and failed to induce a transformed phenotype [14][13]. This finding led to the hypothesis that LOX-PP, produced stoichiometrically with the LOX enzyme, could promote phenotypic reversion, which was ultimately demonstrated [14][13]. Subsequent follow-up studies identified several signaling pathways and binding partners inhibited by LOX-PP which mediated ras-effectors signaling, and inhibited xenograft growth in mice. Subsequent studies demonstrated that the anti-tumor activity of LOX-PP is through the direct or indirect inhibition of the Hsp70 and the suppresion of the MAPK/ERK pathway [13[12][14],15], Akt, FGFRs, [16,17][15][16] RPTPĸ signaling [18][17], FAK [19][18], and others [20][19] depending on the cellular or cancer context [4,21][4][20]. LOX-PP can inhibit tumorigenesis by reducing the vascular endothelial growth factor (VEGF) in human umbilical vein endothelial cells and the suppression of vascular tube formation in chick chorioallantoic membranes [22,23][21][22]. Induction of LOX-PP expression by the adenoviral vector reduced cancer cell migration and hampered the expression of angiogenic factors MMP2 and MMP9 [24][23]. LOX-PP was shown to have an interaction with EGF and the tumor endothelial marker-8 (TEM-8) on the surface of activated endothelial cells and to possibly control angiogenesis [21][20].
Figure 1. Diagram illustrating LOX and LOX-PP biogenesis. LOX is synthesized as a 50 kD inactive Pro-LOX and processed extracellularly by proteolytic cleavage into a functional 32 kD LOX enzyme and an 18 kD propeptide (LOX-PP). Additional proteolytic processing sites of Pro-LOX have recently been identified. LOX-PP has both intracellular and extracellular targets.
LOX-PP is generated extracellularly by the proteolytic processing of pro-lysyl oxidase at Gly168/Asp169 by procollagen C-proteinases and is likely to target FGFRs and other cell surface receptors [17,21][16][20] (Figure 1). However, LOX-PP also can re-enter cells in order to interact with its intracellular targets. A major mechanism of LOX-PP uptake is by macropinocytosis that in most cases is a receptor-independent mode of endocytosis [25][24]. LOX-PP has a very high pI in part due to its high content (12%) of arginine residues, and evidence indicates that LOX-PP in endosomes increases the internal pH of endosomes, which may lead to cytoplasmic release permitting the LOX-PP targeting of intracellular cytoplasmic signaling molecules, rather than the simple trafficking of LOX-PP to lysozomes for degradation [25][24]. A new question then becomes how can LOX-PP inhibit so many targets, and which target(s) is (are) most important for its tumor inhibitory function? Structure prediction tools have revealed that LOX-PP has a mostly intrinsically disordered structure, which is consistent with its ability to target multiple proteins [26][25]. Intrinsically disordered proteins adopt biologically active conformations when interacting with targets. Some disordered proteins have multiple functional binding partners [27][26], which is also the case for LOX-PP.

3. LOX, LOX-PP and Eye Pathologies

3.1. Diabetic Retinopathy

The rising incidence of diabetes has led to a dramatic increase in diabetic complications worldwide. Despite the introduction of treatment strategies, diabetic retinopathy (DR) remains a major cause of blindness and is one of the most common microvascular complications of diabetes [54,55,56,57][27][28][29][30] for which no preventive therapy is currently available. A significant clinical manifestation of DR is retinal vascular cell death and the breakdown of the blood retinal barrier (BRB) leading to excess vascular leakage and macular edema [58][31]. The BRB is compromised by the thickening of the retinal capillary BM, a hallmark of DR [59][32]. The biogenesis and maturation of the vascular BM is dependent on LOX-mediated cross-linking of ECM components. Aberrant LOX activity results in abnormal post-translational modification of BM collagens, affects its functionality, and predisposes connective tissues to certain diseases [60,61,62,63][33][34][35][36]. Several studies have reported elevated LOX activity and increased collagen cross-linking in diabetic tissues such as the lungs of diabetic rats [64][37] and the skin of diabetic patients where elevated LOX activity correlated with duration of diabetes, glycemic control, and long-term complications [65][38]. By contrast, abnormally low biosynthetic collagen cross-linking and low lysyl oxidase levels occur in diabetic bone [66[39][40],67], pointing to different functional regulatory pathways in different tissues. To add to this complexity, a recent study indicated that LOX upregulation may contribute to ECM production independent of its crosslinking function [68][41]. This raises the possibility that LOX upregulation in diabetes could promote vascular BM thickening and play a pathogenic role in DR by both enzymatic and non-enzymatic mechanisms. Interestingly, LOX propeptide (LOX-PP), which has no LOX enzyme activity, released during LOX processing, was recently shown to promote apoptosis in various diseased tissues, including diabetic retinas [24,69,70,71][23][42][43][44]. These reports raise the possibility that a high glucose condition increases LOX and LOX-PP levels, which in turn promote apoptosis and increased retinal vascular permeability [71,72,73,74,75][44][45][46][47][48]. By contrast, a study reported decreased LOX activity in the vitreous of eyes with proliferative diabetic retinopathy [76][49]. Here, vitreous samples obtained from patients were compared for LOX mRNA levels and specific activity of LOX, MMP-2 and -9 with those obtained from autopsy eyes, while a different study reported increased LOX mRNA levels in human retinal pigmented cells exposed to high glucose. Ongoing studies are investigating possible links between abnormal LOX and LOX-PP levels and the development of retinal vascular cell loss and capillary leakage, and whether a strategy targeting LOX and LOX-PP could be effective in preventing vascular lesions in DR.

3.2. Keratoconus

Keratoconus (KC) is a corneal disease characterized by progressive central cornea thinning and conical protrusion of the cornea. The cellular mechanisms underlying the development and progression of the disease remain unclear. Morphological changes in different structures of KC corneas including epithelium, basement membrane, nerve fibers, Bowman’s layer, stroma, Descemet membrane, and endothelium have been identified. Additionally, the diversity of the structures appear to represent temporal differences during disease progression [77][50]. Other observations support the involvement of several biochemical events that regulate cellular and extracellular processes, proliferation, differentiation, and apoptosis of keratocytes, and oxidative damage [78][51]. The disease can be diagnosed by assessing clinical signs such as stromal thinning, together with accurate computer-assisted video-keratography. KC has a prevalence of approximately 1:2000. The involvement of LOX has been identified during the development of KC. In particular, a number of studies have reported a lower expression and reduced activity of LOX and/or cross-linking defects in corneas of individuals with KC [79,80,81][52][53][54]. Decreased expression of LOX appears to contribute to the structural deformity of the KC cornea [80][53]. The risk of KC development may be associated with specific LOX polymorphisms [82][55]. Moreover, abnormal LOX activity is a risk factor for KC, and genetic evidence indicates LOX variants likely increase susceptibility to developing KC [83][56]. Furthermore, LOX is differentially up-regulated in corneal epithelial cells of KC patients compared to those in healthy controls [84][57]. The structural deformity of the KC cornea may be related to unbalanced expressions of collagens (no change) and LOX (upregulated), and elevated MMP9 in the corneal epithelium. In recent years, a number of studies have revealed inflammatory cytokines and matrix-remodeling enzymes to participate in the development of KC [85][58]. Family-based and case control studies have revealed that variations in the LOX gene could increase susceptibility of KC development. Interestingly, mutational screening of LOX in a cohort of 225 sporadic and 77 familial KC cases showed no involvement of LOX with KC [86][59]. Genetic variants in additional genes may interact with changes in LOX. It is notable that a novel gene for KC has been localized to a 5.6-Mb interval on 13q32 [87][60]. The 13q location is notable because all known genes at this locus were not mutated and therefore excluded as functionally relevant to KC. How this locus is functionally relevant to KC remains unknown, to the researchers' knowledge. Although there is increasing evidence that LOX is involved in the pathogenesis and progression of KC, further studies are needed to dissect LOX’s role including other factors and gain deeper insight into the molecular mechanisms underlying KC development [83][56].

3.3. Glaucoma

Among patients with primary open angle glaucoma (POAG), the prevalence of pseudoexfoliation appears to be linked to geographic variation. Lysyl oxidase-like 1 (LOXL1) gene polymorphisms have been widely studied in different ethnic populations. The literature suggests conflicting reports related to LOXL1 gene variants and glaucoma, in particular, related to pseudoexfoliation and primary open angle glaucoma. A recent study of the north Indian population reported a lack of association between the LOXL1 gene polymorphisms and primary open angle glaucoma [88][61] consistent with a study that suggests that LOXL1 polymorphisms are not associated with POAG risk, based on meta-analysis [89][62]. However, a prevalence of pseudoexfoliation glaucoma risk was reported to be associated with variants of the LOXL1 gene in an Irish population [90][63], supported by additional studies indicating an association of LOXL1 gene polymorphisms and POAG in Turkish patients [91[64][65],92], Spanish population [93][66], Greek patients [94][67], and German patients [95][68]. Further population-based studies on a large-scale basis are necessary to identify the worldwide distribution of pseudoexfoliation and primary open angle glaucomatous development and the relationship with LOXL1. To gain insights into the role of rare LOXL1 variants among different ethnic groups, transcriptome analyses could reveal further information and identify specific pathways and their associations with LOXL1. LOXL1 remains a potential target to better understand the pathophysiology of the abnormal matrix, in particular, interactions with matrix components in relation to genetic factors present in ethnic populations. Ultimately, modulation of LOXL1 gene expression could be promising and present a potential strategy for treatment of pesudoexfoliation and primary open angle glaucoma.

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