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LOXL2

Official Full Name
lysyl oxidase like 2
Organism
Homo sapiens
GeneID
4017
Background
This gene encodes a member of the lysyl oxidase gene family. The prototypic member of the family is essential to the biogenesis of connective tissue, encoding an extracellular copper-dependent amine oxidase that catalyses the first step in the formation of crosslinks in collagens and elastin. A highly conserved amino acid sequence at the C-terminus end appears to be sufficient for amine oxidase activity, suggesting that each family member may retain this function. The N-terminus is poorly conserved and may impart additional roles in developmental regulation, senescence, tumor suppression, cell growth control, and chemotaxis to each member of the family. [provided by RefSeq, Jul 2008]
Synonyms
LOR; LOR2; WS9-14;
Protein Sequence
MERPLCSHLCSCLAMLALLSPLSLAQYDSWPHYPEYFQQPAPEYHQPQAPANVAKIQLRLAGQKRKHSEGRVEVYYDGQWGTVCDDDFSIHAAHVVCRELGYVEAKSWTASSSYGKGEGPIWLDNLHCTGNEATLAACTSNGWGVTDCKHTEDVGVVCSDKRIPGFKFDNSLINQIENLNIQVEDIRIRAILSTYRKRTPVMEGYVEVKEGKTWKQICDKHWTAKNSRVVCGMFGFPGERTYNTKVYKMFASRRKQRYWPFSMDCTGTEAHISSCKLGPQVSLDPMKNVTCENGLPAVVSCVPGQVFSPDGPSRFRKAYKPEQPLVRLRGGAYIGEGRVEVLKNGEWGTVCDDKWDLVSASVVCRELGFGSAKEAVTGSRLGQGIGPIHLNEIQCTGNEKSIIDCKFNAESQGCNHEEDAGVRCNTPAMGLQKKLRLNGGRNPYEGRVEVLVERNGSLVWGMVCGQNWGIVEAMVVCRQLGLGFASNAFQETWYWHGDVNSNKVVMSGVKCSGTELSLAHCRHDGEDVACPQGGVQYGAGVACSETAPDLVLNAEMVQQTTYLEDRPMFMLQCAMEENCLSASAAQTDPTTGYRRLLRFSSQIHNNGQSDFRPKNGRHAWIWHDCHRHYHSMEVFTHYDLLNLNGTKVAEGHKASFCLEDTECEGDIQKNYECANFGDQGITMGCWDMYRHDIDCQWVDITDVPPGDYLFQVVINPNFEVAESDYSNNIMKCRSRYDGHRIWMYNCHIGGSFSEETEKKFEHFSGLLNNQLSPQ
Open
Disease
Cardiac arrest, Colorectal cancer
Approved Drug
0
Clinical Trial Drug
2 +
Discontinued Drug
0

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Detailed Information

LOXL2 (Lysyl Oxidase Like 2) is a critical member of the lysyl oxidase (LOX) family, playing a central role in extracellular matrix (ECM) remodeling and collagen crosslinking. Over the past two decades, LOXL2 has gained widespread attention due to its multifaceted involvement in fibrotic diseases and tumors. In particular, its enzymatic activity, transcriptional regulation, and non-enzymatic functions have positioned it as a potential diagnostic marker and therapeutic target across various cancers.

Structure and Evolutionary Characteristics

From an evolutionary and structural standpoint, the human LOX family is classified into two subfamilies. Subfamily 1 includes LOX and LOXL1, while subfamily 2 comprises LOXL2, LOXL3, and LOXL4. All LOX family members share a highly conserved C-terminal amine oxidase catalytic domain, which includes a copper-binding site and a lysine tyrosylquinone (LTQ) cofactor. The LTQ cofactor forms through post-translational modifications involving conserved lysine and tyrosine residues, and it is essential for enzymatic deamination functions. In LOXL2, the copper-binding site is made up of histidine residues H626, H628, and H630, which are critical for the maturation of the LTQ cofactor and enzymatic function.

Distinct from LOX and LOXL1, which require proteolytic cleavage for activation, LOXL2 to LOXL4 contain four scavenger receptor cysteine-rich (SRCR) domains in their N-terminal region. These domains are believed to mediate protein–protein interactions and have been found to interact with collagen IV, fibronectin, RNA-binding proteins, and potentially histone modifiers.

Interestingly, LOXL2's SRCR domains have also been implicated in non-oxidase activities. These include the deacetylation of ALDOA at K13 and modification of transcription factors such as STAT3, indicating a broader range of cellular functions beyond ECM remodeling.

Post-Translational Modifications and Structural Data

LOXL2 undergoes various post-translational modifications that are essential for its activity and localization. It has three N-glycosylation sites (N288, N455, and N644) and seventeen disulfide bonds that maintain its structural integrity. Structurally, LOXL2 mainly exists as a monomer, with partial dimerization through interactions between SRCR domains 1 and 2. Low-resolution models and 3D structural predictions have provided insights into its architecture, paving the way for rational drug design.

Physiological and Pathological Functions

As an extracellular enzyme, LOXL2 plays a pivotal role in ECM crosslinking by catalyzing the oxidative deamination of lysine and hydroxylysine residues in collagen and elastin. This function is critical for tissue integrity and fibrosis. Abnormal upregulation of LOXL2 is strongly associated with pathologies such as idiopathic pulmonary fibrosis, liver cirrhosis, and cardiovascular fibrosis. More importantly, LOXL2 is overexpressed in multiple cancers, including breast, lung, liver, esophageal, and pancreatic cancers.

Since its identification as a pro-tumorigenic factor in 2003, numerous studies have confirmed the role of LOXL2 in cancer progression. Its expression level is frequently correlated with poor prognosis, lower overall survival (OS), and shorter disease-free survival (DFS). Additionally, LOXL2 has been found in the cytoplasm, nucleus, and perinuclear regions of tumor cells, where it participates in processes unrelated to its oxidase function, such as transcriptional regulation and chromatin remodeling.

Regulation of LOXL2 Expression

Understanding how LOXL2 is regulated is key to leveraging it as a therapeutic target. Its expression is influenced by multiple levels of control—transcriptional, post-transcriptional, and post-translational.

Hypoxia is one of the strongest inducers of LOXL2 expression. Hypoxia-inducible factor 1 (HIF-1) binds to response elements within intron 1 of the LOXL2 gene to upregulate transcription. It also recruits histone demethylases such as KDM4C and KDM4B to demethylate H3K9, further enhancing LOXL2 transcription. Additionally, HIF2α induced by extracellular ATP through the P2Y2-AKT-PGK1 pathway contributes to LOXL2 upregulation.

Besides hypoxia, extracellular matrix stiffness can trigger LOXL2 expression. In hepatocellular carcinoma cells, stiffness activates the integrin β1/α5-JNK-AP1 pathway, while in M2 macrophages, it triggers the integrin β5-FAK-MEK1/2-ERK1/2 cascade, indirectly elevating HIF-1 levels and thereby promoting LOXL2 expression.

Other signaling axes are also involved. For example, c-FOS induces the expression of Wnt ligands (Wnt7b and Wnt9a), which then activate transcription factors ZEB1 and ZEB2 to enhance LOXL2 transcription. Moreover, the deubiquitinase ZRANB1 stabilizes SP1 by deubiquitination, indirectly increasing LOXL2 expression.

LOXL2 expression is regulated by multiple pathways including extracellular ATP, hypoxia, and ECM remodeling via transcription factors like HIF1/2, KDM4B/C, c-FOS, and SP1. Figure 1. LOXL2 regulation. (Cano A, et al., 2023)

Emerging Insights from Comparative Genomics

Recent research has unveiled additional, evolutionarily significant roles for LOXL2. A comparative genomic study identified a deletion in the human LOXL2 promoter relative to chimpanzees, resulting in the loss of a SNAI2 binding site and altered transcriptional regulation. Introducing the conserved chimpanzee sequence into human cells led to gene expression changes related to myelination and synaptic functions. These findings suggest that LOXL2 might also be involved in neuronal differentiation and brain evolution.

Clinical Implications and Biomarker Potential

With accumulating evidence showing LOXL2 overexpression in a range of malignancies, it has emerged as a potential biomarker for diagnosis, prognosis, and therapeutic stratification. Elevated LOXL2 levels in patient serum have been linked to idiopathic pulmonary fibrosis, cardiac fibrosis, and other fibrotic disorders. Its presence in the tumor microenvironment and correlation with invasiveness, metastasis, and therapy resistance highlight its potential as both a predictive and prognostic biomarker.

Beyond being a marker, LOXL2 is a promising therapeutic target. Inhibitors targeting its catalytic activity, such as monoclonal antibodies and small molecules, have entered preclinical and early clinical development. However, due to its non-enzymatic functions, complete inhibition strategies may need to encompass both catalytic and scaffolding functions.

References

  1. Cano A, Eraso P, Mazón MJ, et al. LOXL2 in Cancer: A Two-Decade Perspective. Int J Mol Sci. 2023 Sep 21;24(18):14405.
  2. Wen B, Xu LY, Li EM. LOXL2 in cancer: regulation, downstream effectors and novel roles. Biochim Biophys Acta Rev Cancer. 2020 Dec;1874(2):188435.
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