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LRIG3 (Leucine-Rich Repeats And Immunoglobulin-Like Domains 3)

Written2014-05Dongsheng Guo, Feng Mao, Ting Lei
Dept of Neurosurgery,Tongji Hospital, Huazhong University of Sciences, Technology, Wuhan, Hubei, 430030, People's Republic of China

Abstract LRIG3 is a member of mammalian LRIG family and less is known about the functions of LRIG3. Accumulating evidences showed that LRIG3 may also function as a tumor suppressor like LRIG1. LRIG3 can inhibit tumor cell proliferation, survival, adhesion and invasion in many types of human cancer cells based on cell experiments. Perinuclear staining of LRIG3 correlated with better survival in astrocytic tumors. Decreased LRIG3 was identified as one of 12 promising serum biomarkers for early stage non-small-cell lung cancer. LRIG3 may play a role in inner ear morphogenesis and neural crest formation.

Keywords LRIG3, glioma, ependymoma, NSCLC, pituitary adenoma, cervical adenocarcinoma, psoriasis

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)FLJ90440
KIAA3016
Other aliasLIG3
HGNC (Hugo) LRIG3
LocusID (NCBI) 121227
Atlas_Id 47529
Location 12q14.1  [Link to chromosome band 12q14]
Location_base_pair Starts at 59265937 and ends at 59313327 bp from pter ( according to hg19-Feb_2009)  [Mapping LRIG3.png]
Fusion genes
(updated 2016)
LRIG3 (12q14.1) / MDM2 (12q15)LRIG3 (12q14.1) / PIP4K2C (12q13.3)LRIG3 (12q14.1) / ROS1 (6q22.1)
ROCK1 (18q11.1) / LRIG3 (12q14.1)ROS1 (6q22.1) / LRIG3 (12q14.1)

DNA/RNA

Description According to Entrez-Gene, LRIG3 gene maps to NC_000012.12 in the region between 58872155 and 58920538 and spans across 48.3 kilobases. LRIG3 gene is encoded on the reverse strand.
Transcription Homo sapiens leucine-rich repeats and immunoglobulin-like domains 3 has at least two transcript variants. The pre-mRNAs comprise 19 exons. The coding sequence of transcript variant 1 (NM_001136051.2) and 2 (NM_153377.4) is 3691bp and 4110bp respectively.

Protein

 
  LRIG3 protein. SP: signal peptide; NF: N-terminal cysteine-rich flanking domain; LRRs: 15 leucine-rich repeats; CF: C-terminal cysteinerich flanking domain; Ig C2: C2-type immunoglobulin-like domains; TM: transmembrane domain; Cyto: cytoplasmic domain.
Description LRIG3 is a transmembrane cell-surface protein consisting of 1059 or 1119 amino acids. LRIG3 contains a signal peptide, 15 tandem LRR with cysteine rich N- and C-flanking domains, three immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic tail.
Expression LRIG3 is ubiquitously expressed in human organs. The highest expression of LRIG3 is in stomach, thyroid, and skin.
Localisation Differential subcellular expression in a cell type-sepcific manner.
Function LRIG3 may function as a tumor suppressor.

Mutations

Note Mutations in LRIG3 are rare, according to the TCGA data set.

Implicated in

Note
  
Entity Ependymoma
Note Perinuclear staining of LRIG3 was significantly lower in posterior fossa ependymomas than in supratentorial ependymomas (Yi et al., 2009).
  
  
Entity Pituitary adenoma
Note The expression of LRIG 3 in HP75 cell line was lower compared to normal pituitary glands (Guo et al., 2007).
  
  
Entity Astrocytic tumors
Note Perinuclear expression of LRIG3 in astrocytic tumors has been associated with better patient survival (Guo et al., 2006). Down-regulation of LRIG3 expression in glioblastoma cell lines resulted in increased proliferation and invasion, decreased apoptosis, and increased EGFR expression (Cai et al., 2009).
  
  
Entity Cervical adenocarcinoma
Note High fraction of LRIG3-positive cells were significantly associated with patient survival, and LRIG3 staining intensity was positively correlated with HPV status (Muller et al., 2013).
  
  
Entity Non-small-cell lung cancer
Note LRIG3 downregulation was identified as one of 12 promising serum biomarkers for early stage non-small-cell lung cancer (Ostroff et al., 2010).
Abnormal Protein The LRIG3-ROS1 fusion has been identified in non-small-cell lung cancer (Cai et al., 2013).
  
  
Entity Psoriasis
Note The expression pattern of LRIG3 protein was altered in psoriatic lesions compared to normal skin (Karlsson et al., 2008).
  
  
Entity Inner ear morphogenesis
Note During inner ear development, Lrig3 acts to repress Netrin transcription and Lrig3 loss led to defects in inner ear morphogenesis (Abraira et al., 2008).
  
  
Entity Neural crest formation
Note LRIG3 is required for neural crest formation in developing Xenopus embryos by regulating the Wnt and Fgf signaling pathways (Zhao et al., 2008).
  

To be noted

Recently, Colleen Sweeney and Lisa V Goodrich reported that overexpression of LRIG3 in HEK293T cells increased the ERBB receptor expression (Rafidi et al., 2013). However, downregulation of LRIG3 in a human glioblastoma cell line, GL15, resulted in upregulation of total EGFR and phospho-EGFR, and enchanced glioma cell proliferation, adhesion and invasion (Cai et al., 2009). Therefore, the precise function of LRIG3 in regard to ERBB receptor signalling modulation may be context-dependent and the role of LRIG3 needs to be further studied.

Bibliography

Vertebrate Lrig3-ErbB interactions occur in vitro but are unlikely to play a role in Lrig3-dependent inner ear morphogenesis.
Abraira VE, Satoh T, Fekete DM, Goodrich LV.
PLoS One. 2010 Feb 1;5(2):e8981. doi: 10.1371/journal.pone.0008981.
PMID 20126551
 
Inhibition of LRIG3 gene expression via RNA interference modulates the proliferation, cell cycle, cell apoptosis, adhesion and invasion of glioblastoma cell (GL15).
Cai M, Han L, Chen R, Ye F, Wang B, Han F, Lei T, Guo D.
Cancer Lett. 2009b Jun 8;278(1):104-12. doi: 10.1016/j.canlet.2009.01.001. Epub 2009 Feb 5.
PMID 19200647
 
Effects of RNAi-mediated gene silencing of LRIG3 expression on cell cycle and survival of glioma cells.
Cai M, Xie R, Han L, Chen R, Wang B, Ye F, Guo D, Lei T.
J Huazhong Univ Sci Technolog Med Sci. 2009a Feb;29(1):88-93. doi: 10.1007/s11596-009-0119-z. Epub 2009 Feb 18.
PMID 19224171
 
ROS1 fusions in Chinese patients with non-small-cell lung cancer.
Cai W, Li X, Su C, Fan L, Zheng L, Fei K, Zhou C, Manegold C, Schmid-Bindert G.
Ann Oncol. 2013 Jul;24(7):1822-7. doi: 10.1093/annonc/mdt071. Epub 2013 Mar 20.
PMID 23514723
 
In vivo analysis of Lrig genes reveals redundant and independent functions in the inner ear.
Del Rio T, Nishitani AM, Yu WM, Goodrich LV.
PLoS Genet. 2013;9(9):e1003824. doi: 10.1371/journal.pgen.1003824. Epub 2013 Sep 26.
PMID 24086156
 
Immunohistochemical analysis of LRIG proteins in meningiomas: correlation between estrogen receptor status and LRIG expression.
Ghasimi S, Haapasalo H, Eray M, Korhonen K, Brannstrom T, Hedman H, Andersson U.
J Neurooncol. 2012 Jul;108(3):435-41. doi: 10.1007/s11060-012-0856-x. Epub 2012 Apr 8.
PMID 22484910
 
Down-regulation of leucine-rich repeats and immunoglobulin-like domain proteins (LRIG1-3) in HP75 pituitary adenoma cell line.
Guo D, Han L, Shu K, Chen J, Lei T.
J Huazhong Univ Sci Technolog Med Sci. 2007 Feb;27(1):91-4.
PMID 17393120
 
The LRIG gene family has three vertebrate paralogs widely expressed in human and mouse tissues and a homolog in Ascidiacea.
Guo D, Holmlund C, Henriksson R, Hedman H.
Genomics. 2004 Jul;84(1):157-65.
PMID 15203213
 
Perinuclear leucine-rich repeats and immunoglobulin-like domain proteins (LRIG1-3) as prognostic indicators in astrocytic tumors.
Guo D, Nilsson J, Haapasalo H, Raheem O, Bergenheim T, Hedman H, Henriksson R.
Acta Neuropathol. 2006 Mar;111(3):238-46. Epub 2006 Mar 11.
PMID 16532360
 
Redistribution of LRIG proteins in psoriasis.
Karlsson T, Mark EB, Henriksson R, Hedman H.
J Invest Dermatol. 2008 May;128(5):1192-5. Epub 2007 Nov 22.
PMID 18037903
 
Expression of LRIG1 and LRIG3 correlates with human papillomavirus status and patient survival in cervical adenocarcinoma.
Muller S, Lindquist D, Kanter L, Flores-Staino C, Henriksson R, Hedman H, Andersson S.
Int J Oncol. 2013 Jan;42(1):247-52. doi: 10.3892/ijo.2012.1702. Epub 2012 Nov 16.
PMID 23165628
 
Unlocking biomarker discovery: large scale application of aptamer proteomic technology for early detection of lung cancer.
Ostroff RM, Bigbee WL, Franklin W, Gold L, Mehan M, Miller YE, Pass HI, Rom WN, Siegfried JM, Stewart A, Walker JJ, Weissfeld JL, Williams S, Zichi D, Brody EN.
PLoS One. 2010 Dec 7;5(12):e15003. doi: 10.1371/journal.pone.0015003.
PMID 21170350
 
Over-expression of LRIG3 suppresses growth and invasion of bladder cancer cells.
Qi Y, Chang L, Li H, Yu G, Xiao W, Xia D, Guan W, Yang Y, Lang B, Deng KL, Yao WM, Ye ZQ, Zhuang QY.
J Huazhong Univ Sci Technolog Med Sci. 2013 Feb;33(1):111-6. doi: 10.1007/s11596-013-1081-3. Epub 2013 Feb 8.
PMID 23392718
 
Leucine-rich repeat and immunoglobulin domain-containing protein-1 (Lrig1) negative regulatory action toward ErbB receptor tyrosine kinases is opposed by leucine-rich repeat and immunoglobulin domain-containing protein 3 (Lrig3).
Rafidi H, Mercado F 3rd, Astudillo M, Fry WH, Saldana M, Carraway KL 3rd, Sweeney C.
J Biol Chem. 2013 Jul 26;288(30):21593-605. doi: 10.1074/jbc.M113.486050. Epub 2013 May 30.
PMID 23723069
 
Activin and BMP4 synergistically promote formation of definitive endoderm in human embryonic stem cells.
Teo AK, Ali Y, Wong KY, Chipperfield H, Sadasivam A, Poobalan Y, Tan EK, Wang ST, Abraham S, Tsuneyoshi N, Stanton LW, Dunn NR.
Stem Cells. 2012 Apr;30(4):631-42. doi: 10.1002/stem.1022.
PMID 22893457
 
LRIG1 is a triple threat: ERBB negative regulator, intestinal stem cell marker and tumour suppressor.
Wang Y, Poulin EJ, Coffey RJ.
Br J Cancer. 2013 May 14;108(9):1765-70. doi: 10.1038/bjc.2013.138. Epub 2013 Apr 4. (REVIEW)
PMID 23558895
 
Expression of EGFR and LRIG proteins in oesophageal carcinoma with emphasis on patient survival and cellular chemosensitivity.
Wu X, Hedman H, Bergqvist M, Bergstrom S, Henriksson R, Gullbo J, Lennartsson J, Hesselius P, Ekman S.
Acta Oncol. 2012 Jan;51(1):69-76. doi: 10.3109/0284186X.2011.562239. Epub 2011 Mar 18.
PMID 21417672
 
Effect of over-expressed LRIG3 on cell cycle and survival of glioma cells.
Yang H, Mao F, Zhang H, Wang B, Wan F, Guo D, Lei T.
J Huazhong Univ Sci Technolog Med Sci. 2011 Oct;31(5):667-72. doi: 10.1007/s11596-011-0579-9. Epub 2011 Oct 25.
PMID 22038358
 
Expression of leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins in human ependymoma relates to tumor location, WHO grade, and patient age.
Yi W, Haapasalo H, Holmlund C, Jarvela S, Raheem O, Bergenheim AT, Hedman H, Henriksson R.
Clin Neuropathol. 2009 Jan-Feb;28(1):21-7.
PMID 19216216
 
Effect of silencing LRIG3 gene on the proliferation and apoptosis of bladder cancer T24 cells.
Yuan X, Bao S, Yang W, Ye Z.
J Huazhong Univ Sci Technolog Med Sci. 2011 Apr;31(2):220-5. doi: 10.1007/s11596-011-0256-z. Epub 2011 Apr 20.
PMID 21505989
 
Lrig3 regulates neural crest formation in Xenopus by modulating Fgf and Wnt signaling pathways.
Zhao H, Tanegashima K, Ro H, Dawid IB.
Development. 2008 Apr;135(7):1283-93. doi: 10.1242/dev.015073. Epub 2008 Feb 20.
PMID 18287203
 

Citation

This paper should be referenced as such :
D Guo, F Mao, T Lei
LRIG3 (Leucine-Rich Repeats And Immunoglobulin-Like Domains 3)
Atlas Genet Cytogenet Oncol Haematol. 2015;19(2):102-104.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/LRIG3ID47529ch12q14.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  Lung: Adenocarcinoma with t(6;12)(q22;q14.1) LRIG3/ROS1
Lung: Translocations in Adenocarcinoma


External links

Nomenclature
HGNC (Hugo)LRIG3   30991
Cards
AtlasLRIG3ID47529ch12q14
Entrez_Gene (NCBI)LRIG3  121227  leucine-rich repeats and immunoglobulin like domains 3
AliasesLIG3
GeneCards (Weizmann)LRIG3
Ensembl hg19 (Hinxton)ENSG00000139263 [Gene_View]  chr12:59265937-59313327 [Contig_View]  LRIG3 [Vega]
Ensembl hg38 (Hinxton)ENSG00000139263 [Gene_View]  chr12:59265937-59313327 [Contig_View]  LRIG3 [Vega]
ICGC DataPortalENSG00000139263
TCGA cBioPortalLRIG3
AceView (NCBI)LRIG3
Genatlas (Paris)LRIG3
WikiGenes121227
SOURCE (Princeton)LRIG3
Genetics Home Reference (NIH)LRIG3
Genomic and cartography
GoldenPath hg19 (UCSC)LRIG3  -     chr12:59265937-59313327 -  12q14.1   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)LRIG3  -     12q14.1   [Description]    (hg38-Dec_2013)
EnsemblLRIG3 - 12q14.1 [CytoView hg19]  LRIG3 - 12q14.1 [CytoView hg38]
Mapping of homologs : NCBILRIG3 [Mapview hg19]  LRIG3 [Mapview hg38]
OMIM608870   
Gene and transcription
Genbank (Entrez)AK074921 AK130083 AK292857 AK301162 AL833710
RefSeq transcript (Entrez)NM_001136051 NM_153377
RefSeq genomic (Entrez)NC_000012 NC_018923 NT_029419 NW_004929384
Consensus coding sequences : CCDS (NCBI)LRIG3
Cluster EST : UnigeneHs.253736 [ NCBI ]
CGAP (NCI)Hs.253736
Alternative Splicing GalleryENSG00000139263
Gene ExpressionLRIG3 [ NCBI-GEO ]   LRIG3 [ EBI - ARRAY_EXPRESS ]   LRIG3 [ SEEK ]   LRIG3 [ MEM ]
Gene Expression Viewer (FireBrowse)LRIG3 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)121227
GTEX Portal (Tissue expression)LRIG3
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ6UXM1   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ6UXM1  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ6UXM1
Splice isoforms : SwissVarQ6UXM1
PhosPhoSitePlusQ6UXM1
Domaine pattern : Prosite (Expaxy)IG_LIKE (PS50835)    LRR (PS51450)   
Domains : Interpro (EBI)Cys-rich_flank_reg_C    Ig-like_dom    Ig-like_fold    Ig_I-set    Ig_sub    Ig_sub2    L_dom-like    Leu-rich_rpt    Leu-rich_rpt_typical-subtyp    LRRNT   
Domain families : Pfam (Sanger)I-set (PF07679)    LRR_8 (PF13855)   
Domain families : Pfam (NCBI)pfam07679    pfam13855   
Domain families : Smart (EMBL)IG (SM00409)  IGc2 (SM00408)  LRR_TYP (SM00369)  LRRCT (SM00082)  LRRNT (SM00013)  
Conserved Domain (NCBI)LRIG3
DMDM Disease mutations121227
Blocks (Seattle)LRIG3
SuperfamilyQ6UXM1
Human Protein AtlasENSG00000139263
Peptide AtlasQ6UXM1
HPRD08317
IPIIPI00184265   IPI00640455   IPI00942627   IPI01020988   IPI01023010   
Protein Interaction databases
DIP (DOE-UCLA)Q6UXM1
IntAct (EBI)Q6UXM1
FunCoupENSG00000139263
BioGRIDLRIG3
STRING (EMBL)LRIG3
ZODIACLRIG3
Ontologies - Pathways
QuickGOQ6UXM1
Ontology : AmiGOextracellular space  plasma membrane  integral component of membrane  cytoplasmic vesicle membrane  otolith morphogenesis  
Ontology : EGO-EBIextracellular space  plasma membrane  integral component of membrane  cytoplasmic vesicle membrane  otolith morphogenesis  
NDEx NetworkLRIG3
Atlas of Cancer Signalling NetworkLRIG3
Wikipedia pathwaysLRIG3
Orthology - Evolution
OrthoDB121227
GeneTree (enSembl)ENSG00000139263
Phylogenetic Trees/Animal Genes : TreeFamLRIG3
HOVERGENQ6UXM1
HOGENOMQ6UXM1
Homologs : HomoloGeneLRIG3
Homology/Alignments : Family Browser (UCSC)LRIG3
Gene fusions - Rearrangements
Fusion : MitelmanLRIG3/PIP4K2C [12q14.1/12q13.3]  
Fusion : MitelmanLRIG3/ROS1 [12q14.1/6q22.1]  [t(6;12)(q22;q14)]  
Fusion : MitelmanROCK1/LRIG3 [18q11.1/12q14.1]  [t(12;18)(q14;q11)]  
Fusion : COSMICLRIG3 [12q14.1]  -  ROS1 [6q22.1]  [fusion_1269]  [fusion_1270]  
Fusion: TCGALRIG3 12q14.1 PIP4K2C 12q13.3 BRCA
Fusion: TCGAROCK1 18q11.1 LRIG3 12q14.1 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerLRIG3 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)LRIG3
dbVarLRIG3
ClinVarLRIG3
1000_GenomesLRIG3 
Exome Variant ServerLRIG3
ExAC (Exome Aggregation Consortium)LRIG3 (select the gene name)
Genetic variants : HAPMAP121227
Genomic Variants (DGV)LRIG3 [DGVbeta]
DECIPHER (Syndromes)12:59265937-59313327  ENSG00000139263
CONAN: Copy Number AnalysisLRIG3 
Mutations
ICGC Data PortalLRIG3 
TCGA Data PortalLRIG3 
Broad Tumor PortalLRIG3
OASIS PortalLRIG3 [ Somatic mutations - Copy number]
Cancer Gene: CensusLRIG3 
Somatic Mutations in Cancer : COSMICLRIG3  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDLRIG3
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
BioMutasearch LRIG3
DgiDB (Drug Gene Interaction Database)LRIG3
DoCM (Curated mutations)LRIG3 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)LRIG3 (select a term)
intoGenLRIG3
NCG5 (London)LRIG3
Cancer3DLRIG3(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM608870   
Orphanet
MedgenLRIG3
Genetic Testing Registry LRIG3
NextProtQ6UXM1 [Medical]
TSGene121227
GENETestsLRIG3
Huge Navigator LRIG3 [HugePedia]
snp3D : Map Gene to Disease121227
BioCentury BCIQLRIG3
ClinGenLRIG3
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD121227
Chemical/Pharm GKB GenePA134864136
Clinical trialLRIG3
Miscellaneous
canSAR (ICR)LRIG3 (select the gene name)
Probes
Litterature
PubMed26 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineLRIG3
EVEXLRIG3
GoPubMedLRIG3
iHOPLRIG3
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

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indexed on : Wed Apr 12 11:34:30 CEST 2017

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