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LYPD3 (LY6/PLAUR domain containing 3)

Written2008-10Benedikte Jacobsen, Michael Ploug
Finsen Laboratory 3735, Rigshospitalet, Copenhagen Biocenter, 2200 Copenhagen N, Denmark

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)C4.4A
Other aliasMIG-C4
HGNC (Hugo) LYPD3
LocusID (NCBI) 27076
Atlas_Id 44245
Location 19q13.31  [Link to chromosome band 19q13]
Location_base_pair Starts at 43964946 and ends at 43969831 bp from pter ( according to hg19-Feb_2009)  [Mapping LYPD3.png]
Fusion genes
(updated 2016)
APOL1 (22q12.3) / LYPD3 (19q13.31)

DNA/RNA

Note The gene for human C4.4A is located on chromosome 19q13, only 180 kb apart from the urokinase-type plasminogen activator receptor (uPAR) gene, in a cluster encompassing all presently known glycosylphosphatidylinositol (GPI)-anchored, multi-domain proteins of the Ly6/uPAR/alpha-neurotoxin (LU) domain family.
 
  Figure 1: Position of the C4.4A gene in the uPAR-like gene cluster on chromosome 19q13. The intron-exon organisation of the C4.4A gene reveals that separate exons encode the two LU domains of C4.4A, each of them with an internal phase-1 intron at loop 2, which in the three-finger LU fold is surface-exposed.
Description 4870 bp; 5 exons (Figure 1).
Transcription Transcription of the C4.4A gene is regulated by the transcription factor C/EBPbeta (Fries et al., 2007).

Protein

Note C4.4A is a GPI-anchored, multi-domain member of the Ly6/uPAR/alpha-neurotoxin (LU) protein domain family. C4.4A was identified by two independent groups seeking to identify cancer-related genes, the first observing that C4.4A was expressed in a metastasizing rat pancreatic adenocarcinoma cell line, but not on its non-metastasizing counterpart (Matzku et al., 1989), and the second showing the upregulation of C4.4A in an in vitro model system for wound healing in the urothelium, mimicking the progression of urothelial cancer (Smith et al., 2001). These findings suggested a putative role of C4.4A in cancer invasion and metastasis.
Description C4.4A consists of 346 amino acid residues, including a 30 residues signal peptide at the N-terminal and a C-terminal signal sequence for GPI anchorage (38 residues) that are cleaved post-translationally, yielding a mature protein of 278 residues, anchored to the cell membrane via GPI (Figure 2A). It contains two LU domains (domains I and II), each of about 90 amino acids, and a serine-, threonine-, proline-rich (STP-rich) region. LU domains adopt a "three-fingered" folding topology, that is characterized by 4 consensus disulfide bonds and an invariant C-terminal asparagine (Figure 2B). Intriguingly, domain I of C4.4A lacks one consensus cysteine bond, which is crucial to the proper folding of the single domain LU proteins. The STP-rich region is highly O-glycosylated, with 17 potential O-glycosylation sites. None of the 6 potential N-glycosylation sites of C4.4A are, however, located in this region. Differential degrees of glycosylation can probably explain the large variation in molecular weight observed in C4.4A from different sources (Hansen et al., 2004), deviating from the theoretical value of 36 kDa.
 
  Figure 2: Protein structure of C4.4A.
A - Structural representation of the two LU domains and the STP-rich region of C4.4A (modified from Hansen et al., 2004). Insert: Ribbon diagram of the three-finger fold of a single LU domain (made in PyMOL™(DeLano Scientific), using PDB coordinates 1NEA).
B - Disulfide connectivity in C4.4A, with LU consensus cysteine bonds highlighted in yellow.
Expression C4.4A is expressed in the suprabasal cells of squamous epithelia found in e.g. esophagus and skin, the basal layer being devoid of C4.4A (Figure 3A), and in the amnion membrane in human term placenta (Figure 3C) (Hansen et al., 2004). In mouse skin wound healing, which is a tissue remodelling process often used as a surrogate model for cancer invasion, C4.4A is upregulated by the migrating keratinocytes. C4.4A expression is also increased in phorbolester-induced hyperplasia of murine skin (Hansen et al., 2004), in the progression to melanoma (Seiter et al., 2001) and in urothelial transitional cell carcinomas (Smith et al., 2001).
The preferential expression of C4.4A in normal epithelia of the squamous type is paralleled in cancer, where it is expressed in the tumour component of primarily squamous cell carcinomas (SCC) and only to a lesser extent in adenocarcinomas (AC) (Wang et al., 2006), as demonstrated in non-small cell lung cancer (NSCLC) (Figure 3D) (Hansen et al., 2007).
In esophageal squamous cell carcinomas (ESCC), C4.4A expression as present in the normal mucosa is lost upon transition to dysplasia and carcinoma in situ, but reappears at the invasive front of the tumour and in lymph node metastases (Figure 3B) (Hansen et al., 2008).
 
  Figure 3: Expression of C4.4A in normal and malignant human tissue.
Staining of human tissue sections with a polyclonal rabbit anti-C4.4A antibody produced at the Finsen Laboratory (Copenhagen, Denmark). C4.4A-negative basal cells are indicated by an arrow in panels A and B. (A and B, reproduced from Hansen et al., 2008; C and D, from Jacobsen, unpublished).
Localisation C4.4A is tethered to the cell membrane via a GPI-anchor, but can under certain conditions also be found intracellularly. A soluble fragment of C4.4A, termed C4.4A', resulting from cleavage in the protease-sensitive region between domain II and the STP-rich region, releasing the two N-terminal LU domains, has been described in esophageal tissue (Hansen et al., 2008).
Function Structural homology of C4.4A to the urokinase receptor, uPAR, is not reflected at the functional level, the function of C4.4A still being unknown. Circumstancial evidence, nevertheless, points to a role of C4.4A in the modulation of cell/cell and/or cell/matrix interactions:
1) The carbohydrate-binding protein galectin-3, which has been reported to be involved in cell/cell interactions, cell adhesion, migration, invasion and metastasis, has been identified as a ligand for C4.4A (Paret et al., 2005).
2) C4.4A and the cell adhesion molecule E-cadherin are co-expressed in the normal esophageal mucosa, and both are down-regulated in the progression to dysplasia (Hansen et al., 2008).
3) C4.4A-positive and not C4.4A-negative tumour cells are capable of penetrating a matrigel, and this process can be inhibited by a monoclonal anti-C4.4A antibody (Rosel et al., 1998).
4) Encapsulation of lung metastases in rats, arising after an intrafootpad injection with pancreatic tumour cells, disappears, when these tumour cells are transfected with C4.4A (Rosel et al., 1998).
5) C4.4A has recently been reported to be a novel substrate for the extracellular matrix-degrading metalloproteases ADAM10 and ADAM17 (A Disintegrin And Metalloprotease domain), which have been implicated in cell migration and proliferation, with a bearing on tumour invasion and metastasis (Esselens et al., 2008).
Homology C4.4A shows homology to uPAR and other multi-domain proteins of the Ly6/uPAR/alpha-neurotoxin protein domain family (PRV-1/CD177, TEX101, PRO4356, GPQH2552).

Implicated in

Note
  
Entity Non-small cell lung cancer (NSCLC)
Disease In an immunohistochemical study encompassing 104 patients with NSCLC, high levels of C4.4A were found in 77% of SCC and in 24% of AC (Hansen et al., 2007). Preliminary data on the expression of C4.4A in premalignant lesions of NSCLC indicate that C4.4A is present already at very early stages of lung cancer progression.
Prognosis A high level of C4.4A in NSCLC tissue correlates to a poorer survival of the patients (Figure 4). In the above-mentioned study, it was shown that this correlation primarily could be ascribed to a dramatic effect on the patients with AC and C4.4A levels above the median, all dying within 2 years (Hansen et al., 2007).
 
Figure 4: Impact of C4.4A on the prognosis of NSCLC patients.
Kaplan-Meier survival curves for 104 patients with NSCLC (A) and the histological subgroup with adenocarcinomas (B), stratified by expression levels of C4.4A (modified from Hansen et al., 2007, with permission).
  
  
Entity Esophageal squamous cell carcinoma (ESCC)
Note C4.4A is absent in dysplastic esophageal epithelium as well as in early invasive ESCC, but shows a pronounced expression at the invasive front of the tumour deeper in the esophageal wall and in lymph node metastases, making C4.4A a possible new histological marker of invasion and metastasis in human ESCC (Hansen et al., 2008).
  

Bibliography

Developmentally regulated expression of metastasis-associated antigens in the rat.
Claas C, Herrmann K, Matzku S, Moller P, Zoller M.
Cell Growth Differ. 1996 May; 7(5): 663-78.
PMID 8732676
 
Metastasis-associated C4.4A, a GPI-anchored protein cleaved by ADAM10 and ADAM17.
Esselens CW, Malapeira J, Colome N, Moss M, Canals F, Arribas J.
Biol Chem. 2008 Aug 8. [Epub ahead of print]
PMID 18690780
 
CEBPbeta, JunD and c-Jun contribute to the transcriptional activation of the metastasis-associated C4.4A gene.
Fries F, Nazarenko I, Hess J, Claas A, Angel P, Zoller M.
Int J Cancer. 2007; 120(10): 2135-47.
PMID 17278103
 
Structural analysis and tissue localization of human C4.4A: a protein homologue of the urokinase receptor.
Hansen LV, Gardsvoll H, Nielsen BS, Lund LR, Dano K, Jensen ON, Ploug M.
Biochem J. 2004; 380(Pt 3): 845-57.
PMID 15012588
 
Altered expression of the urokinase receptor homologue, C4.4A, in invasive areas of human esophageal squamous cell carcinoma.
Hansen LV, Laerum OD, Illemann M, Nielsen BS, Ploug M.
Int J Cancer. 2008; 122(4): 734-41.
PMID 17849475
 
Tumour cell expression of C4.4A, a structural homologue of the urokinase receptor, correlates with poor prognosis in non-small cell lung cancer.
Hansen LV, Skov BG, Ploug M, Pappot H.
Lung Cancer. 2007; 58(2): 260-6.
PMID 17706320
 
The urokinase receptor and its structural homologue C4.4A in human cancer: expression, prognosis and pharmacological inhibition.
Jacobsen B, Ploug M.
Curr Med Chem. 2008;15(25):2559-73.
PMID 18855679
 
Antigenic differences between metastatic and nonmetastatic BSp73 rat tumor variants characterized by monoclonal antibodies.
Matzku S, Wenzel A, Liu S, Zoller M.
Cancer Res. 1989; 49(5): 1294-9.
PMID 2917359
 
Ly6 family member C4.4A binds laminins 1 and 5, associates with galectin-3 and supports cell migration.
Paret C, Bourouba M, Beer A, Miyazaki K, Schnolzer M, Fiedler S, Zoller M.
Int J Cancer. 2005; 115(5): 724-33.
PMID 15729693
 
Cloning and functional characterization of a new phosphatidyl-inositol anchored molecule of a metastasizing rat pancreatic tumor.
Rosel M, Claas C, Seiter S, Herlevsen M, Zoller M.
Oncogene. 1998; 17(15): 1989-2002.
PMID 9788443
 
Upregulation of C4.4A expression during progression of melanoma.
Seiter S, Stassar M, Rappl G, Reinhold U, Tilgen W, Zoller M.
J Invest Dermatol. 2001; 116(2): 344-7.
PMID 11180013
 
Identification of genes involved in human urothelial cell-matrix interactions: implications for the progression pathways of malignant urothelium.
Smith BA, Kennedy WJ, Harnden P, Selby PJ, Trejdosiewicz LK, Southgate J.
Cancer Res. 2001; 61(4): 1678-85.
PMID 11245483
 
[Expression and diagnostic application of C4.4A protein in squamous cell carcinoma and adenocarcinoma]
Wang W, Ding YQ, Li ZG, Han HX, Yang L.
Zhonghua Bing Li Xue Za Zhi. 2006; 35(5): 277-80. Chinese.
PMID 16776998
 
Cloning of the human homologue of the metastasis-associated rat C4.4A.
Wurfel J, Seiter S, Stassar M, Claas A, Klas R, Rosel M, Marhaba R, Savelyeva L, Schwab M, Matzku S, Zoller M.
Gene. 2001; 262(1-2): 35-41.
PMID 11179665
 

Citation

This paper should be referenced as such :
Jacobsen, B ; Ploug, M
LYPD3 (LY6/PLAUR domain containing 3)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(9):647-651.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/LYPD3ID44245ch19q13.html


External links

Nomenclature
HGNC (Hugo)LYPD3   24880
Cards
AtlasLYPD3ID44245ch19q13
Entrez_Gene (NCBI)LYPD3  27076  LY6/PLAUR domain containing 3
AliasesC4.4A
GeneCards (Weizmann)LYPD3
Ensembl hg19 (Hinxton)ENSG00000124466 [Gene_View]  chr19:43964946-43969831 [Contig_View]  LYPD3 [Vega]
Ensembl hg38 (Hinxton)ENSG00000124466 [Gene_View]  chr19:43964946-43969831 [Contig_View]  LYPD3 [Vega]
ICGC DataPortalENSG00000124466
TCGA cBioPortalLYPD3
AceView (NCBI)LYPD3
Genatlas (Paris)LYPD3
WikiGenes27076
SOURCE (Princeton)LYPD3
Genetics Home Reference (NIH)LYPD3
Genomic and cartography
GoldenPath hg19 (UCSC)LYPD3  -     chr19:43964946-43969831 -  19q13.31   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)LYPD3  -     19q13.31   [Description]    (hg38-Dec_2013)
EnsemblLYPD3 - 19q13.31 [CytoView hg19]  LYPD3 - 19q13.31 [CytoView hg38]
Mapping of homologs : NCBILYPD3 [Mapview hg19]  LYPD3 [Mapview hg38]
OMIM609484   
Gene and transcription
Genbank (Entrez)AF082889 AJ223603 AK075464 AK290905 AK314773
RefSeq transcript (Entrez)NM_014400
RefSeq genomic (Entrez)NC_000019 NC_018930 NT_011109 NW_004929415
Consensus coding sequences : CCDS (NCBI)LYPD3
Cluster EST : UnigeneHs.631594 [ NCBI ]
CGAP (NCI)Hs.631594
Alternative Splicing GalleryENSG00000124466
Gene ExpressionLYPD3 [ NCBI-GEO ]   LYPD3 [ EBI - ARRAY_EXPRESS ]   LYPD3 [ SEEK ]   LYPD3 [ MEM ]
Gene Expression Viewer (FireBrowse)LYPD3 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)27076
GTEX Portal (Tissue expression)LYPD3
Protein : pattern, domain, 3D structure
UniProt/SwissProtO95274   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO95274  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO95274
Splice isoforms : SwissVarO95274
PhosPhoSitePlusO95274
Domains : Interpro (EBI)LY6_UPA_recep-like    LY6_UPAR   
Domain families : Pfam (Sanger)UPAR_LY6 (PF00021)   
Domain families : Pfam (NCBI)pfam00021   
Domain families : Smart (EMBL)LU (SM00134)  
Conserved Domain (NCBI)LYPD3
DMDM Disease mutations27076
Blocks (Seattle)LYPD3
SuperfamilyO95274
Human Protein AtlasENSG00000124466
Peptide AtlasO95274
HPRD10783
IPIIPI00004310   IPI00643788   
Protein Interaction databases
DIP (DOE-UCLA)O95274
IntAct (EBI)O95274
FunCoupENSG00000124466
BioGRIDLYPD3
STRING (EMBL)LYPD3
ZODIACLYPD3
Ontologies - Pathways
QuickGOO95274
Ontology : AmiGOextracellular space  cell-matrix adhesion  integral component of membrane  laminin binding  anchored component of plasma membrane  
Ontology : EGO-EBIextracellular space  cell-matrix adhesion  integral component of membrane  laminin binding  anchored component of plasma membrane  
REACTOMEO95274 [protein]
REACTOME Pathways163125 [pathway]   
NDEx NetworkLYPD3
Atlas of Cancer Signalling NetworkLYPD3
Wikipedia pathwaysLYPD3
Orthology - Evolution
OrthoDB27076
GeneTree (enSembl)ENSG00000124466
Phylogenetic Trees/Animal Genes : TreeFamLYPD3
HOVERGENO95274
HOGENOMO95274
Homologs : HomoloGeneLYPD3
Homology/Alignments : Family Browser (UCSC)LYPD3
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerLYPD3 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)LYPD3
dbVarLYPD3
ClinVarLYPD3
1000_GenomesLYPD3 
Exome Variant ServerLYPD3
ExAC (Exome Aggregation Consortium)LYPD3 (select the gene name)
Genetic variants : HAPMAP27076
Genomic Variants (DGV)LYPD3 [DGVbeta]
DECIPHER (Syndromes)19:43964946-43969831  ENSG00000124466
CONAN: Copy Number AnalysisLYPD3 
Mutations
ICGC Data PortalLYPD3 
TCGA Data PortalLYPD3 
Broad Tumor PortalLYPD3
OASIS PortalLYPD3 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICLYPD3  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDLYPD3
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 LYPD3
DgiDB (Drug Gene Interaction Database)LYPD3
DoCM (Curated mutations)LYPD3 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)LYPD3 (select a term)
intoGenLYPD3
NCG5 (London)LYPD3
Cancer3DLYPD3(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM609484   
Orphanet
MedgenLYPD3
Genetic Testing Registry LYPD3
NextProtO95274 [Medical]
TSGene27076
GENETestsLYPD3
Huge Navigator LYPD3 [HugePedia]
snp3D : Map Gene to Disease27076
BioCentury BCIQLYPD3
ClinGenLYPD3
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD27076
Chemical/Pharm GKB GenePA142671490
Clinical trialLYPD3
Miscellaneous
canSAR (ICR)LYPD3 (select the gene name)
Probes
Litterature
PubMed28 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineLYPD3
EVEXLYPD3
GoPubMedLYPD3
iHOPLYPD3
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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