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LOXL4 (lysyl oxidase-like 4)

Written2007-04Kornelia Molnarne Szauter, Tibor Gorogh, Katalin Csiszar
Cardiovascular Research Center, Associate Chair for Research, CAM Department, John A. Burns School of Medicine, Associate Member, Cancer Research Center of Hawaii, University of Hawaii, 1960 East West Road, Biomed T415, Honolulu, HI 96822

(Note : for Links provided by Atlas : click)

Identity

Other namesLOXC (mouse)
EER-7 (endothelial estrogen-regulated gene-7)
HGNC (Hugo) LOXL4
LocusID (NCBI) 84171
Atlas_Id 41193
Location 10q24.2  [Link to chromosome band 10q24]
Location_base_pair Starts at 100007443 and ends at 100028007 bp from pter ( according to hg19-Feb_2009)  [Mapping LOXL4.png]
Fusion genes
(updated 2016)
LOXL4 (10q24.2) / FAM222B (17q11.2)LOXL4 (10q24.2) / MPO (17q22)

DNA/RNA

Note LOXL4 (lysyl oxidase-like 4) is a member of the lysyl oxidase (LOX) family. Its C-terminal region is conserved in all five members of this copper-dependent amine oxidase family and includes 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 LOXL4 contains four scavenger receptor cysteine-rich (SRCR) domains and has homology with LOXL2 and LOXL3, but not with LOX or LOXL that do not contain these domains. The second SRCR domain contains a 13 amino acid insertion that is unique to LOXL4.
Description The LOXL4 genomic sequence is 14.095 kb with an open reading frame of 2.278 kb and a 5' UTR of 384 bases. The TATA-box is at -25 and the TRE sequence, TGACTCA (TPA-responsive element), is at -75. The GATA domain is located at -113 and -669, and the RFX1 transactivator binding site, GGAA, is found at -149. Sp1 transcription factor consensus sequence, GGCGGC, is at -181, CCAAT (CP1-factor) at -257 and -892 and the repetitive sequence motif GAAA at -310 and 329. No GC box is present in the promoter region.
Transcription The 14 exons of the LOXL4 gene make up an mRNA of 3.877 kb with a coding region of 2.278 kb. Transcriptional start site is at +384 upstream of the translation initiation codon (ATG). The first stop codon (TGA) is at position 14.480. In the 3' UTR there is a 1230 bp untranslated trailer sequence and two consensus polyadenylation signals have been located 30 bp and 322 upstream of the poly-A tail.

Protein

Note Western blot analysis of HT-1080 cells detected the recombinant and secreted LOXL4 form as slightly larger than the cellular 85 kDa form probably due to glycosylation or other modifications, some of which may be cell type dependent.
Description The predicted LOXL4 protein is 756 amino acids including a 24 amino acid signal peptide, with a molecular mass of approximately 84.5 kDa.
Expression In tissues the LOXL4 mRNA is expressed in the placenta, trachea, lung, kidney, pancreas, testis, aorta liver, fetal liver and at lover levels in several other tissues that include the heart, skeletal muscle, spleen, prostate, ovary, small intestine, colon, bladder, and thyroid, adrenal, salivary and mammary glands. LOXL4 mRNA was also reported in vocal cord, laryngeal, hypopharyngeal, parotid and oropharyngeal carcinoma tumor biopsies. The LOXL4 mRNA was reported in cultured fibroblasts, smooth muscle cells, MDA-MB-231 breast cancer and osteosarcoma (OHS) cells. Both mRNA and immunohistochemistry analyses demonstrated LOXL4 expression in head and neck squamous cell carcinoma (HNSSC) tissues and cultured cell lines. No mRNA expression was detected in HCT-116 and DLD-1 colon, MCF7, T47D and Hs578T breast and DU-145 prostate cancer lines.
The mouse homologue of LOXL4, reported as LOXC, was identified as a mRNA expressed in calcified ATDC5 cells, MC3T3-E1 cells, C3H10T1/2 embryonic fibroblast and myoblastic C2C12 cells. Up-regulation of the LOXL4 mRNA (EER-7) was reported 100-fold in human umbilical vein endothelial cells (HUVECs) transfected with estrogen receptor (alpha and beta) in response to treatment with 17beta-estrogen.
Localisation The recombinant LOXL4 protein in human HT-1080 fibrosarcoma cell line localized both intra- and extracellularly. In HNSCC, LOXL4 immunohistochemical staining was prevalently cytoplasmic in poorly differentiated cases with increasing perinuclear staining in well-differentiated areas. In HTB-43 pharyngeal SCC cells LOXL4 staining revealed a punctate pattern within cells with perinuclear enrichment. This pattern suggested containment of LOXL4 in the endomembrane sytem of cells at sites of synthesis and vesicular transport for secretion at the cell surface. Flow cytometry (FACS) analysis demonstrated that approximately 15% of these cells had LOXL4 localized on their surface. In contrast, LOXL4 expression was not detected (or only to a very low extent) in cultured normal epithelial cells derived from oral mucosa samples.
Function LOXL4 may function as an active amine oxidase, as betaAPN (beta-aminopropionitrile) inhibitable enzymatically active recombinant human LOXL4 was generated in an E. coli expression system and positively evaluated for its catalytic activity with a diamine substrate. The mouse homologue of LOXL4, LOXC, showed similar betaAPN inhibitable catalytic activity when tested using a collagen substrate.
Homology LOXL4 has homology with the C-terminal domains to LOX, LOXL1, LOXL2 and LOXL3 and homology with the four N-terminal SRCR domains of LOXL2 and LOXL3.

Implicated in

Note
Entity Breast cancer invasion
Note LOXL4 mRNA was expressed in MDA-MB-231 highly invasive breast cancer cells, but not in poorly invasive and non-metastatic breast cancer cells MCF7 and T47D.
Disease Breast cancer
  
Entity Human head and neck squamous cell carcinoma (HNSSC)
Note LOXL4 mRNA was detected in 16 HNSSC cell lines, obtained from recurrent and primary tumors, whereas no expression was detected in normal epithelial cells. LOXL4 was also found over-expressed in 71% of invasive HNSSC tumors and primary tumors of the glottic larynx, parotic gland, oropharynx and nose synus, primary and metastatic tumors of the larynx, hypopharynx and tongue and metastatic tumor of the thyroid glandand in 90% of primary or metastatic HNSSC cell lines.
Disease Invasive head and neck carcinoma
Prognosis Significant correlation was found between LOXL4 expression and regional lymph node metastases and strong LOXL4 expression was present in metastatic HNSCC cell lines. There is no information regarding LOXL4 expression in distant metastases as patients with distant metastases are predominantly treated not surgically, but with radio - and/or chemotherapy.
Cytogenetics Isochromosome i(10)(q10) was found associated with an amplification of the LOXL4 gene locus at 10q24 in a subset of interphase nuclei in UTSCC19A and HLAC78 head and neck carcinoma cells.
  

Bibliography

A novel human lysyl oxidase-like gene (LOXL4) on chromosome 10q24 has an altered scavenger receptor cysteine rich domain.
Asuncion L, Fogelgren B, Fong KS, Fong SF, Kim Y, Csiszar K
Matrix biology : journal of the International Society for Matrix Biology. 2001 ; 20 (7) : 487-491.
PMID 11691588
 
Molecular cloning and biological activity of a novel lysyl oxidase-related gene expressed in cartilage.
Ito H, Akiyama H, Iguchi H, Iyama K, Miyamoto M, Ohsawa K, Nakamura T
The Journal of biological chemistry. 2001 ; 276 (26) : 24023-24029.
PMID 11292829
 
Cloning and characterization of a fifth human lysyl oxidase isoenzyme: the third member of the lysyl oxidase-related subfamily with four scavenger receptor cysteine-rich domains.
Mäki JM, Tikkanen H, Kivirikko KI
Matrix biology : journal of the International Society for Matrix Biology. 2001 ; 20 (7) : 493-496.
PMID 11691589
 
Estrogen receptors alpha and beta have similar activities in multiple endothelial cell pathways.
Evans MJ, Harris HA, Miller CP, Karathanasis SK, Adelman SJ
Endocrinology. 2002 ; 143 (10) : 3785-3795.
PMID 12239089
 
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 research. 2002 ; 62 (15) : 4478-4483.
PMID 12154058
 
Overexpression of a novel lysyl oxidase-like gene in human head and neck squamous cell carcinomas.
Holtmeier C, Görögh T, Beier U, Meyer J, Hoffmann M, Gottschlich S, Heidorn K, Ambrosch P, Maune S
Anticancer research. 2003 ; 23 (3B) : 2585-2591.
PMID 12894545
 
Expression and purification of enzymatically active forms of the human lysyl oxidase-like protein 4.
Kim MS, Kim SS, Jung ST, Park JY, Yoo HW, Ko J, Csiszar K, Choi SY, Kim Y
The Journal of biological chemistry. 2003 ; 278 (52) : 52071-52074.
PMID 14551188
 
Selective upregulation and amplification of the lysyl oxidase like-4 (LOXL4) gene in head and neck squamous cell carcinoma.
Görögh T, Weise JB, Holtmeier C, Rudolph P, Hedderich J, Gottschlich S, Hoffmann M, Ambrosch P, Csiszar K
The Journal of pathology. 2007 ; 212 (1) : 74-82.
PMID 17354256
 

Citation

This paper should be referenced as such :
Szauter, Kornelia M
LOXL4 (lysyl oxidase-like 4)
Atlas Genet Cytogenet Oncol Haematol. 2007;11(4):274-275.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/LOXL4ID41193ch10q24.html


External links

Nomenclature
HGNC (Hugo)LOXL4   17171
Cards
AtlasLOXL4ID41193ch10q24
Entrez_Gene (NCBI)LOXL4  84171  lysyl oxidase like 4
AliasesLOXC
GeneCards (Weizmann)LOXL4
Ensembl hg19 (Hinxton)ENSG00000138131 [Gene_View]  chr10:100007443-100028007 [Contig_View]  LOXL4 [Vega]
Ensembl hg38 (Hinxton)ENSG00000138131 [Gene_View]  chr10:100007443-100028007 [Contig_View]  LOXL4 [Vega]
ICGC DataPortalENSG00000138131
TCGA cBioPortalLOXL4
AceView (NCBI)LOXL4
Genatlas (Paris)LOXL4
WikiGenes84171
SOURCE (Princeton)LOXL4
Genomic and cartography
GoldenPath hg19 (UCSC)LOXL4  -     chr10:100007443-100028007 -  10q24   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)LOXL4  -     10q24   [Description]    (hg38-Dec_2013)
EnsemblLOXL4 - 10q24 [CytoView hg19]  LOXL4 - 10q24 [CytoView hg38]
Mapping of homologs : NCBILOXL4 [Mapview hg19]  LOXL4 [Mapview hg38]
OMIM607318   
Gene and transcription
Genbank (Entrez)AF338441 AF395336 AK025542 AK172781 AY036093
RefSeq transcript (Entrez)NM_032211
RefSeq genomic (Entrez)NC_000010 NC_018921 NT_030059 NW_004929376
Consensus coding sequences : CCDS (NCBI)LOXL4
Cluster EST : UnigeneHs.671890 [ NCBI ]
CGAP (NCI)Hs.671890
Alternative Splicing GalleryENSG00000138131
Gene ExpressionLOXL4 [ NCBI-GEO ]   LOXL4 [ EBI - ARRAY_EXPRESS ]   LOXL4 [ SEEK ]   LOXL4 [ MEM ]
Gene Expression Viewer (FireBrowse)LOXL4 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)84171
GTEX Portal (Tissue expression)LOXL4
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ96JB6 (Uniprot)
NextProtQ96JB6  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ96JB6
Splice isoforms : SwissVarQ96JB6 (Swissvar)
Catalytic activity : Enzyme1.4.3.- [ Enzyme-Expasy ]   1.4.3.-1.4.3.- [ IntEnz-EBI ]   1.4.3.- [ BRENDA ]   1.4.3.- [ KEGG ]   
PhosPhoSitePlusQ96JB6
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)  
DMDM Disease mutations84171
Blocks (Seattle)LOXL4
SuperfamilyQ96JB6
Human Protein AtlasENSG00000138131
Peptide AtlasQ96JB6
HPRD09538
IPIIPI00306402   
Protein Interaction databases
DIP (DOE-UCLA)Q96JB6
IntAct (EBI)Q96JB6
FunCoupENSG00000138131
BioGRIDLOXL4
STRING (EMBL)LOXL4
ZODIACLOXL4
Ontologies - Pathways
QuickGOQ96JB6
Ontology : AmiGOscavenger receptor activity  copper ion binding  protein binding  extracellular space  receptor-mediated endocytosis  membrane  oxidoreductase activity, acting on the CH-NH2 group of donors, oxygen as acceptor  receptor complex  oxidation-reduction process  extracellular exosome  
Ontology : EGO-EBIscavenger receptor activity  copper ion binding  protein binding  extracellular space  receptor-mediated endocytosis  membrane  oxidoreductase activity, acting on the CH-NH2 group of donors, oxygen as acceptor  receptor complex  oxidation-reduction process  extracellular exosome  
REACTOMEQ96JB6 [protein]
REACTOME PathwaysR-HSA-2243919 Crosslinking of collagen fibrils [pathway]
REACTOME PathwaysR-HSA-1566948 Elastic fibre formation [pathway]
NDEx Network
Atlas of Cancer Signalling NetworkLOXL4
Wikipedia pathwaysLOXL4
Orthology - Evolution
OrthoDB84171
GeneTree (enSembl)ENSG00000138131
Phylogenetic Trees/Animal Genes : TreeFamLOXL4
Homologs : HomoloGeneLOXL4
Homology/Alignments : Family Browser (UCSC)LOXL4
Gene fusions - Rearrangements
Polymorphisms : SNP, variants
NCBI Variation ViewerLOXL4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)LOXL4
dbVarLOXL4
ClinVarLOXL4
1000_GenomesLOXL4 
Exome Variant ServerLOXL4
ExAC (Exome Aggregation Consortium)LOXL4 (select the gene name)
Genetic variants : HAPMAP84171
Genomic Variants (DGV)LOXL4 [DGVbeta]
Mutations
ICGC Data PortalLOXL4 
TCGA Data PortalLOXL4 
Broad Tumor PortalLOXL4
OASIS PortalLOXL4 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICLOXL4 
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 LOXL4
DgiDB (Drug Gene Interaction Database)LOXL4
DoCM (Curated mutations)LOXL4 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)LOXL4 (select a term)
intoGenLOXL4
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)10:100007443-100028007  ENSG00000138131
CONAN: Copy Number AnalysisLOXL4 
Mutations and Diseases : HGMDLOXL4
OMIM607318   
MedgenLOXL4
Genetic Testing Registry LOXL4
NextProtQ96JB6 [Medical]
TSGene84171
GENETestsLOXL4
Huge Navigator LOXL4 [HugePedia]
snp3D : Map Gene to Disease84171
BioCentury BCIQLOXL4
ClinGenLOXL4
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD84171
Chemical/Pharm GKB GenePA30431
Clinical trialLOXL4
Miscellaneous
canSAR (ICR)LOXL4 (select the gene name)
Probes
Litterature
PubMed34 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineLOXL4
EVEXLOXL4
GoPubMedLOXL4
iHOPLOXL4
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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