LOXL2
Description
The LOXL2 (lysyl oxidase like 2) is a protein-coding gene located on chromosome 8.
Lysyl oxidase homolog 2 is an enzyme that in humans is encoded by the LOXL2 gene. 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. LOXL2 can also crosslink collagen type IV and hence influence the sprouting of new blood vessels. LOXL2 is an enzyme that is up-regulated in several types of cancer and is associated with a poorer prognosis. LOXL2 changes the structure of histones (proteins that are attached to DNA) and thus changes the shape of the cells, making it easier for the cancer cells to metastasize. An antibody that inhibits the activity of LOXL2, simtuzumab, is currently in clinical trials for the treatment of several types of cancer and fibrotic diseases such as liver fibrosis.
LOXL2 plays a key role in regulating gene expression by modifying histone proteins. It specifically deaminates trimethylated 'Lys-4' of histone H3 (H3K4me3), a mark associated with active gene transcription, leading to transcriptional repression. LOXL2 also deaminates methylated TAF10, a component of the TFIID complex involved in transcription initiation, resulting in the release of TAF10 and further repression of gene expression. Notably, LOXL2's activity is specific to H3K4me3 and does not affect other histone methylation states like H3K9me3 or H3K27me3. Beyond histone modification, LOXL2 also participates in epithelial to mesenchymal transition (EMT), a process crucial for development and cancer progression. It interacts with SNAI1, a key EMT regulator, and contributes to the repression of E-cadherin, a cell-cell adhesion protein, possibly through histone deamination. During EMT, LOXL2 interacts with SNAI1 to negatively regulate pericentromeric heterochromatin transcription, leading to chromatin reorganization and mesenchymal characteristics. LOXL2 also interacts with HSPA5, an endoplasmic reticulum protein, triggering the unfolded protein response pathway and promoting EMT. Moreover, LOXL2 is involved in E-cadherin repression following hypoxia, a condition often associated with tumor aggressiveness. Outside of the nucleus, LOXL2 acts as a critical enzyme in the extracellular matrix, mediating cross-linking of collagen and elastin through oxidative deamination of lysine residues. This function contributes to the structural integrity of tissues and plays a role in angiogenesis and chondrocyte differentiation.
LOXL2 is also known as LOR, LOR2, WS9-14.
