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LOXL3 (lysyl oxidase-like 3)

Written2008-10Kornelia Molnarne Szauter, Katalin Csiszar
John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_nameslysyl oxidase-like 3
HGNC (Hugo) LOXL3
LocusID (NCBI) 84695
Atlas_Id 44000
Location 2p13.1  [Link to chromosome band 2p13]
Location_base_pair Starts at 74759386 and ends at 74781091 bp from pter ( according to hg19-Feb_2009)  [Mapping LOXL3.png]
Fusion genes
(updated 2016)
LOXL3 (2p13.1) / SIPA1L1 (14q24.2)

DNA/RNA

Note LOXL3 is part of the lysyl oxidase (LOX) family, the members of which are secreted extracellular matrix enzymes. LOXL3 contains a C-terminal region that is conserved in all five isoforms of this copper-dependent amine oxidase family. The domains included within this region are a copper-binding site, lysyl and tyrosine residues that form the lysyltyrosine-quinone cofactor (LTQ) and a cytokine receptor-like domain. The N-terminal region of the full-length LOXL3 contains four SRCR (scavenger receptor cysteine-rich) domains that have high levels of homology with the SRCR domains within LOXL2 and LOXL4, but not with the N-terminal part of LOX or LOXL that do not contain SRCR domains.
Description The human LOXL3 gene has 14 exons that span more than 21 kb of genomic sequence located on chromosome 2p13.3. The LOXL3 gene has been described to have a 2262 bases (Jourdan-LeSaux et al., 2001) long open reading frame (reported as 2226 bp by Maki et al., 2001) and a 3' UTR of 787 bases.
Transcription The human LOXL3 cDNA is 3121 bases long. The 3' UTR has three consensus polyadenylation signal sequences. In the 3' UTR there are three AU-rich sequence elements that are usually found within the 3' trailer region of unstable mRNAs.
Alternative splicing was detected in ESTs that appear to represent tissue-specific splice forms of the LOXL3 mRNA. The alternatively spliced LOXL3 mRNA lacks exons 1, 2, 3, and 5 with an exon-intron structure distinct from the full-length LOXL3, and additionally, contains 80 bps in its 5' UTR and 561 bps in its 3'UTR. The protein deduced from this alternative mRNA retains the structural C-terminal elements of a LOX family protein and the fourth SRCR domain at its N-terminus and is predicted to encode a polypeptide of 392 amino acids with a predicted molecular mass of 44 kDa.

In Northern blot analyses of multiple human tissue samples, LOXL3 mRNA was detected at 3.1 kb using PCR-generated (Maki et al., 2001) and at 3.3 kb using EST-derived probes (Jourdan-LeSaux et al., 2001).

Protein

Note Western blot analysis of HT-1080 cells detected the recombinant cellular and secreted form of the LOXL3 protein as a band of 97 kDa, slightly larger than the predicted overall mass of 83.6 kDa for the recombinant LOXL3, a size difference probably due to cell-type dependent glycosylation.
Description The predicted LOXL3 protein is 753 (also reported as 754, Jourdan-LeSaux et al., 2001) amino acids long with a 25 amino acid long predicted signal peptide and with a calculated molecular mass of approximately 80.3 kDa. The C-terminal region, (aa. 529-729, Maki et al., 2001) contains the conserved lysyl oxidase domain, including the putative copper binding sequence (aa. 601-611, Maki et al., 2001; 601-612, Jourdan-LeSaux et al., 2001), the lysyl (aa. 634, Maki et al., 2001; 639, Jourdan-LeSaux et al., 2001) and tyrosyl (aa. 689, Maki et al., 2001; 670, Jourdan-LeSaux et al., 2001) residues that form the lysyltyrosylquinone cofactor, and the cytokine receptor-like motif (aa. 666-727, Jourdan-LeSaux et al., 2001). In the N-terminal region the four scavenger receptor cysteine-rich domains are located at aa. 44-144, 186-281, 307-407, and 417-526 (Jourdan-LeSaux et al., 2001) and a putative nuclear localization signal is at aa. 293-311. The processed LOXL3 polypeptide contains three putative O-glycosylation sites and five potential N-glycosylation sites. There is a putative BMP-1 processing site between amino acid residues 446-448 (Jourdan-LeSaux et al., 2001).
Expression Tissues: Human LOXL3 mRNA is expressed in leucocytes, in the adult human aorta, neurons, spinal cord, brain, heart, uterus, ovary, testis, prostate, small intestine and spleen. Low mRNA expression was found in the kidney, skeletal muscle and placenta. Expression of the human LOXL3 splice variant mRNA was detected in the kidney, pancreas, spleen and thymus, indicating distinct tissue specificity.
Human LOXL3 protein was detected in the testis, and lung at 44kDa, corresponding to the short spice variant. In the placenta, and colon both the splice product 44 kDa and the full-length 67 kDa LOXL3 were reported.
In mice, LOXL3 protein expression was reported in the tunica media of the adult heart, in aortic smooth muscle cells, and in the cytoplasm of the myocardium. Nuclear localization was detected in the kidney and liver. Cytoplasmic LOXL3 was present in hepatocytes. In the kidney, LOXL3 protein is expressed in the distal and proximal convoluted tubes and the collecting tubes. Strong LOXL3 protein expression was noted in embryonic murine chondrocytes and in skin, epidermis and dermis.
Cell lines: Human LOXL3 mRNA was expressed in the highly invasive breast cancer cell line Hs578T, highly invasive/metastatic human MDA435 cells derived from pleural effusion from a female patient with an infiltrating ductal carcinoma, and human A375P melanoma cell lines. No LOXL3 mRNA expression was detected in MCF7, T47D and MDA MB-231 breast cancer lines.
Murine LOXL3 mRNA was expressed in the C2C12 myoblast cell line, and the highly metastatic HaCa4 squamous cell carcinoma and CarB spindle cell carcinoma cell lines.
Localisation Nuclear localization was noted in the mouse kidney and liver. In transiently transfected MDKC cells LOXL3 showed perinuclear localization. Cytoplasmic expression was found in the murine myocardium and in hepatocytes. Recombinant LOXL3 protein in human HT-1080 fibrosarcoma cell lines localized both intra- and extracellularly.
Function LOXL3 likely functions as an amine oxidase, as BetaAPN (Beta-aminopropionitrile) inhibitable enzymatic activity was noted for a recombinant human LOXL3 generated in an E. coli expression system. The recombinant full length LOXL3 showed high catalytic activity towards collagen type I, IV, VIII, X and lower activity against collagen type VI substrates. The splice variant LOXL3 showed highest activity against type IV collagen as a substrate.
Homology LOXL3 has high level of homology with the C-terminal domains of LOX, LOXL1, LOXL2 and LOXL4 and homology with the four N-terminal SRCR domains within LOXL2 and LOXL4.

Implicated in

Note
  
Entity Breast cancer
Note LOXL3 mRNA was expressed in Hs578T highly invasive breast cancer cells, but not in poorly invasive and non-metastatic breast cancer cells MCF7 and T47D.
Disease Breast cancer invasion.
  
  
Entity Epithelial-mesenchymal transition (EMT) - tumor progression
Note LOXL3 interacts and collaborates with SNAI1 (SNAIL, 20q13.2) to downregulate E-cadherin expression. Overexpression of LOXL3 in MDCK epithelial cells induces an EMT process.
  

Bibliography

Cloning and characterization of a human lysyl oxidase-like 3 gene (hLOXL3).
Huang Y, Dai J, Tang R, Zhao W, Zhou Z, Wang W, Ying K, Xie Y, Mao Y.
Matrix Biol. 2001 Apr;20(2):153-7.
PMID 11334717
 
Central nervous system, uterus, heart, and leukocyte expression of the LOXL3 gene, encoding a novel lysyl oxidase-like protein.
Jourdan-Le Saux C, Tomsche A, Ujfalusi A, Jia L, Csiszar K.
Genomics. 2001 Jun 1;74(2):211-8.
PMID 11386757
 
Post-translational modifications of collagen upon BMP-induced osteoblast differentiation.
Kaku M, Mochida Y, Atsawasuwan P, Parisuthiman D, Yamauchi M.
Biochem Biophys Res Commun. 2007 Aug 3;359(3):463-8. Epub 2007 May 25.
PMID 17553463
 
A molecular role for lysyl oxidase in breast cancer invasion.
Kirschmann DA, Seftor EA, Fong SF, Nieva DR, Sullivan CM, Edwards EM, Sommer P, Csiszar K, Hendrix MJ.
Cancer Res. 2002 Aug 1;62(15):4478-83.
PMID 12154058
 
A tissue-specific variant of the human lysyl oxidase-like protein 3 (LOXL3) functions as an amine oxidase with substrate specificity.
Lee JE, Kim Y.
J Biol Chem. 2006 Dec 8;281(49):37282-90. Epub 2006 Oct 3.
PMID 17018530
 
Cloning and characterization of a fourth human lysyl oxidase isoenzyme.
Maki JM, Kivirikko KI.
Biochem J. 2001 Apr 15;355(Pt 2):381-7.
PMID 11284725
 
Structural and functional diversity of lysyl oxidase and the LOX-like proteins.
Molnar J, Fong KS, He QP, Hayashi K, Kim Y, Fong SF, Fogelgren B, Szauter KM, Mink M, Csiszar K.
Biochim Biophys Acta. 2003 Apr 11;1647(1-2):220-4. (Review).
PMID 12686136
 
A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression.
Peinado H, Del Carmen Iglesias-de la Cruz M, Olmeda D, Csiszar K, Fong KS, Vega S, Nieto MA, Cano A, Portillo F.
EMBO J. 2005 Oct 5;24(19):3446-58. Epub 2005 Aug 18.
PMID 16096638
 

Citation

This paper should be referenced as such :
Szauter, KM ; Csiszar, K
LOXL3 (lysyl oxidase-like 3)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(9):644-646.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/LOXL3ID44000ch2p13.html


External links

Nomenclature
HGNC (Hugo)LOXL3   13869
Cards
AtlasLOXL3ID44000ch2p13
Entrez_Gene (NCBI)LOXL3  84695  lysyl oxidase like 3
AliasesLOXL
GeneCards (Weizmann)LOXL3
Ensembl hg19 (Hinxton)ENSG00000115318 [Gene_View]  chr2:74759386-74781091 [Contig_View]  LOXL3 [Vega]
Ensembl hg38 (Hinxton)ENSG00000115318 [Gene_View]  chr2:74759386-74781091 [Contig_View]  LOXL3 [Vega]
ICGC DataPortalENSG00000115318
TCGA cBioPortalLOXL3
AceView (NCBI)LOXL3
Genatlas (Paris)LOXL3
WikiGenes84695
SOURCE (Princeton)LOXL3
Genetics Home Reference (NIH)LOXL3
Genomic and cartography
GoldenPath hg19 (UCSC)LOXL3  -     chr2:74759386-74781091 -  2p13   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)LOXL3  -     2p13   [Description]    (hg38-Dec_2013)
EnsemblLOXL3 - 2p13 [CytoView hg19]  LOXL3 - 2p13 [CytoView hg38]
Mapping of homologs : NCBILOXL3 [Mapview hg19]  LOXL3 [Mapview hg38]
OMIM607163   
Gene and transcription
Genbank (Entrez)AF282619 AF284815 AF311313 AK309474 AK309478
RefSeq transcript (Entrez)NM_001289164 NM_001289165 NM_032603
RefSeq genomic (Entrez)NC_000002 NC_018913 NG_033047 NT_022184 NW_004929300
Consensus coding sequences : CCDS (NCBI)LOXL3
Cluster EST : UnigeneHs.469045 [ NCBI ]
CGAP (NCI)Hs.469045
Alternative Splicing GalleryENSG00000115318
Gene ExpressionLOXL3 [ NCBI-GEO ]   LOXL3 [ EBI - ARRAY_EXPRESS ]   LOXL3 [ SEEK ]   LOXL3 [ MEM ]
Gene Expression Viewer (FireBrowse)LOXL3 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)84695
GTEX Portal (Tissue expression)LOXL3
Protein : pattern, domain, 3D structure
UniProt/SwissProtP58215   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP58215  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP58215
Splice isoforms : SwissVarP58215
Catalytic activity : Enzyme1.4.3.- [ Enzyme-Expasy ]   1.4.3.-1.4.3.- [ IntEnz-EBI ]   1.4.3.- [ BRENDA ]   1.4.3.- [ KEGG ]   
PhosPhoSitePlusP58215
Domaine pattern : Prosite (Expaxy)LYSYL_OXIDASE (PS00926)    SRCR_1 (PS00420)    SRCR_2 (PS50287)   
Domains : Interpro (EBI)Lysyl_oxidase    Lysyl_oxidase_CS    SRCR    SRCR-like_dom   
Domain families : Pfam (Sanger)Lysyl_oxidase (PF01186)    SRCR (PF00530)   
Domain families : Pfam (NCBI)pfam01186    pfam00530   
Domain families : Smart (EMBL)SR (SM00202)  
Conserved Domain (NCBI)LOXL3
DMDM Disease mutations84695
Blocks (Seattle)LOXL3
SuperfamilyP58215
Human Protein AtlasENSG00000115318
Peptide AtlasP58215
HPRD06200
IPIIPI00011385   IPI00793633   IPI00916194   IPI00917524   IPI00916554   IPI00916696   IPI00916799   
Protein Interaction databases
DIP (DOE-UCLA)P58215
IntAct (EBI)P58215
FunCoupENSG00000115318
BioGRIDLOXL3
STRING (EMBL)LOXL3
ZODIACLOXL3
Ontologies - Pathways
QuickGOP58215
Ontology : AmiGOepithelial to mesenchymal transition  protein-lysine 6-oxidase activity  scavenger receptor activity  copper ion binding  protein binding  extracellular region  extracellular space  nucleus  cytoplasm  receptor-mediated endocytosis  membrane  negative regulation of transcription, DNA-templated  oxidation-reduction process  
Ontology : EGO-EBIepithelial to mesenchymal transition  protein-lysine 6-oxidase activity  scavenger receptor activity  copper ion binding  protein binding  extracellular region  extracellular space  nucleus  cytoplasm  receptor-mediated endocytosis  membrane  negative regulation of transcription, DNA-templated  oxidation-reduction process  
REACTOMEP58215 [protein]
REACTOME Pathways1566948 [pathway]   2243919 [pathway]   
NDEx NetworkLOXL3
Atlas of Cancer Signalling NetworkLOXL3
Wikipedia pathwaysLOXL3
Orthology - Evolution
OrthoDB84695
GeneTree (enSembl)ENSG00000115318
Phylogenetic Trees/Animal Genes : TreeFamLOXL3
HOVERGENP58215
HOGENOMP58215
Homologs : HomoloGeneLOXL3
Homology/Alignments : Family Browser (UCSC)LOXL3
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerLOXL3 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)LOXL3
dbVarLOXL3
ClinVarLOXL3
1000_GenomesLOXL3 
Exome Variant ServerLOXL3
ExAC (Exome Aggregation Consortium)LOXL3 (select the gene name)
Genetic variants : HAPMAP84695
Genomic Variants (DGV)LOXL3 [DGVbeta]
DECIPHER (Syndromes)2:74759386-74781091  ENSG00000115318
CONAN: Copy Number AnalysisLOXL3 
Mutations
ICGC Data PortalLOXL3 
TCGA Data PortalLOXL3 
Broad Tumor PortalLOXL3
OASIS PortalLOXL3 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICLOXL3  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDLOXL3
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch LOXL3
DgiDB (Drug Gene Interaction Database)LOXL3
DoCM (Curated mutations)LOXL3 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)LOXL3 (select a term)
intoGenLOXL3
NCG5 (London)LOXL3
Cancer3DLOXL3(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM607163   
Orphanet
MedgenLOXL3
Genetic Testing Registry LOXL3
NextProtP58215 [Medical]
TSGene84695
GENETestsLOXL3
Huge Navigator LOXL3 [HugePedia]
snp3D : Map Gene to Disease84695
BioCentury BCIQLOXL3
ClinGenLOXL3
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD84695
Chemical/Pharm GKB GenePA30430
Clinical trialLOXL3
Miscellaneous
canSAR (ICR)LOXL3 (select the gene name)
Probes
Litterature
PubMed15 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineLOXL3
EVEXLOXL3
GoPubMedLOXL3
iHOPLOXL3
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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