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RARRES3 (retinoic acid receptor responder (tazarotene induced) 3)

Written2012-01Tiffany Scharadin, Richard L Eckert
Department of Biochemistry, Molecular Biology, University of Maryland, School of Medicine, Baltimore, Maryland 21201, USA

(Note : for Links provided by Atlas : click)


Alias_namesretinoic acid receptor responder (tazarotene induced) 3
Alias_symbol (synonym)TIG3
Other aliasMGC8906
LocusID (NCBI) 5920
Atlas_Id 42051
Location 11q12.3  [Link to chromosome band 11q12]
Location_base_pair Starts at 63536801 and ends at 63546458 bp from pter ( according to hg19-Feb_2009)  [Mapping RARRES3.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
MRPL28 (16p13.3) / RARRES3 (11q12.3)RARRES3 (11q12.3) / CDC42SE1 (1q21.3)RARRES3 (11q12.3) / MYC (8q24.21)
RARRES3 (11q12.3) / SSU72 (1p36.33)
Note Reported at 11q23 (DiSepio et al., 1998) but more recent results suggest TIG3 is at 11q12 (Auer et al., 2002).


  Schematic of the TIG3 gene. Thick red boxes indicate exons.
Description DNA size: 9658 bp with 4 exons.
Transcription mRNA size: 779 bp, processed: 495 bp.


Note The C-terminus of TIG3 is believed to be a membrane-anchoring domain which is involved in driving membrane localization and is also required for centrosome localization. Removal of this domain from TIG3 causes it to distribute diffusely throughout the cytoplasm and reduces its ability to decrease cell survival (Deucher et al., 2000; Sturniolo et al., 2003; Sturniolo et al., 2005; Jans et al., 2008; Tsai et al., 2009).
  Schematic of the TIG3 protein. The purple indicates the hydrophilic N-terminus (amino acids 1-134) and green indicates the hydrophobic C-terminus (amino acids 134-164). The orange regions represent conserved elements with the H-rev107 family. Highly conserved regions are labeled.
Description 164 amino acids; 18 kDa protein; contains a hydrophilic N-terminus (1-134) and hydrophobic, membrane-anchoring domain (134-164).
Expression Ubiquitously expressed; expression is reduced in hyperproliferative diseases including cancer.
Localisation Cell membrane, centrosome (Scharadin et al., 2011).
Function TIG3 is a type II tumor suppressor gene which regulates cell proliferation and survival (DiSepio et al., 1998). Loss of TIG3 expression leads to hyperproliferative diseases including psoriasis and cancer. Restoration of TIG3 expression to cancer cell lines decreases cell cycle progression and induces apoptosis causing an overall decrease in viable cells (DiSepio et al., 1998; Huang et al., 2002; Higuchi et al., 2003; Tsai et al., 2009; Scharadin et al., 2011). Localization of TIG3 to the centrosome is believed to be responsible for this decrease in cell survival, which leads to an increase in p21 level, a G1/S phase block, an activation of the caspase cascade, and a reorganization of the microtubule network (Scharadin et al., 2011).
In contrast, expression of TIG3 in normal keratinocytes induces a process of terminal differentiation through the binding to and activation of type I transglutaminase and increase in cornified envelope formation to decrease cell survival (Sturniolo et al., 2003; Sturniolo et al., 2005; Jans et al., 2008). Localization of TIG3 to the cell membrane in keratinocytes is necessary for it to bind type I transglutaminase.
Homology TIG3 shares homology with the H-rev107 family of class II tumor suppressors and the NlpC/P60 superfamily (Hajnal et al., 1994; DiSepio et al., 1998; Husmann et al., 1998; Anantharaman and Aravind, 2003; Jahng et al., 2003).


Note No known mutations.

Implicated in

Entity Various cancers
Note TIG3 expression is reduced in several cancer including breast, skin, lymphoma, leukemia, kidney, ureter, colorectal, liver, biliary tract, ovary, and uterine.
Disease Cancer is a disease characterized by uncontrolled cell proliferation.
Prognosis Cancer prognosis is dependent upon several tumor-specific conditions, including location, size, and metastasis.
Oncogenesis Loss of TIG3 mRNA and protein expression is observed in several cancers and may be necessary for oncogenesis (DiSepio et al., 1998; Casanova et al., 2001; Duvic et al., 2003; Shyu et al., 2003; Jiang et al., 2005; Lotz et al., 2005; Shyu et al., 2005). Tazarotene treatment of skin cancers leads to increased TIG3 expression and reduced proliferation (Duvic et al., 2000; Duvic et al., 2003). The loss of TIG3 is associated with increased cell proliferation and TIG3 loss may be necessary for cancer progression.
Entity Hyperproliferative diseases
Note Loss of TIG3 expression is associated with hyperproliferative diseases including psoriasis and cancer.
TIG3 mRNA and protein levels are reduced in psoriatic lesions. Treatment with tazarotene leads to an increase in TIG3 levels and restoration of the normal epidermal condition (Duvic et al., 2000). Hypermethylation of the TIG3 promoter is a possible mechanism for reduced expression in psoriasis (Kwong et al., 2005).
Disease Psoriasis is a common disorder of the skin which is characterized by inflammation and hyperproliferation of the epidermis.
Prognosis Psoriasis is a non-fatal, chronic disorder that can be controlled with treatment.


Note No breakpoints known.


Evolutionary history, structural features and biochemical diversity of the NlpC/P60 superfamily of enzymes.
Anantharaman V, Aravind L.
Genome Biol. 2003;4(2):R11. Epub 2003 Feb 3.
PMID 12620121
The class II tumour suppressor gene RARRES3 maps to 11q12, not 11q23.
Auer RL, Bertoni F, Jones C, Cotter FE.
Leukemia. 2002 Jul;16(7):1396; author reply 1396-7.
PMID 12094268
The class II tumor-suppressor gene RARRES3 is expressed in B cell lymphocytic leukemias and down-regulated with disease progression.
Casanova B, de la Fuente MT, Garcia-Gila M, Sanz L, Silva A, Garcia-Marco JA, Garcia-Pardo A.
Leukemia. 2001 Oct;15(10):1521-6.
PMID 11587209
The carboxy-terminal hydrophobic domain of TIG3, a class II tumor suppressor protein, is required for appropriate cellular localization and optimal biological activity.
Deucher A, Nagpal S, Chandraratna RA, Di Sepio D, Robinson NA, Dashti SR, Eckert RL.
Int J Oncol. 2000 Dec;17(6):1195-203.
PMID 11078805
Identification and characterization of a retinoid-induced class II tumor suppressor/growth regulatory gene.
DiSepio D, Ghosn C, Eckert RL, Deucher A, Robinson N, Duvic M, Chandraratna RA, Nagpal S.
Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14811-5.
PMID 9843971
Expression of a retinoid-inducible tumor suppressor, Tazarotene-inducible gene-3, is decreased in psoriasis and skin cancer.
Duvic M, Helekar B, Schulz C, Cho M, DiSepio D, Hager C, DiMao D, Hazarika P, Jackson B, Breuer-McHam J, Young J, Clayman G, Lippman SM, Chandraratna RA, Robinson NA, Deucher A, Eckert RL, Nagpal S.
Clin Cancer Res. 2000 Aug;6(8):3249-59.
PMID 10955811
Tazarotene-induced gene 3 is suppressed in basal cell carcinomas and reversed in vivo by tazarotene application.
Duvic M, Ni X, Talpur R, Herne K, Schulz C, Sui D, Ward S, Joseph A, Hazarika P.
J Invest Dermatol. 2003 Oct;121(4):902-9.
PMID 14632211
Subtraction cloning of H-rev107, a gene specifically expressed in H-ras resistant fibroblasts.
Hajnal A, Klemenz R, Schafer R.
Oncogene. 1994 Feb;9(2):479-90.
PMID 8290259
Induction of TIG3, a putative class II tumor suppressor gene, by retinoic acid in head and neck and lung carcinoma cells and its association with suppression of the transformed phenotype.
Higuchi E, Chandraratna RA, Hong WK, Lotan R.
Oncogene. 2003 Jul 24;22(30):4627-35.
PMID 12879006
The retinoid-inducible gene I: effect on apoptosis and mitogen-activated kinase signal pathways.
Huang SL, Shyu RY, Yeh MY, Jiang SY.
Anticancer Res. 2002 Mar-Apr;22(2A):799-804.
PMID 12014653
Transcriptional and translational downregulation of H-REV107, a class II tumour suppressor gene located on human chromosome 11q11-12.
Husmann K, Sers C, Fietze E, Mincheva A, Lichter P, Schafer R.
Oncogene. 1998 Sep 10;17(10):1305-12.
PMID 9771974
Lecithin retinol acyltransferase is a founder member of a novel family of enzymes.
Jahng WJ, Xue L, Rando RR.
Biochemistry. 2003 Nov 11;42(44):12805-12.
PMID 14596594
Localization of the TIG3 transglutaminase interaction domain and demonstration that the amino-terminal region is required for TIG3 function as a keratinocyte differentiation regulator.
Jans R, Sturniolo MT, Eckert RL.
J Invest Dermatol. 2008 Mar;128(3):517-29. Epub 2007 Aug 30.
PMID 17762858
Decreased expression of type II tumor suppressor gene RARRES3 in tissues of hepatocellular carcinoma and cholangiocarcinoma.
Jiang SY, Chou JM, Leu FJ, Hsu YY, Shih YL, Yu JC, Lee MS, Shyu RY.
World J Gastroenterol. 2005 Feb 21;11(7):948-53.
PMID 15742394
Silencing of the retinoid response gene TIG1 by promoter hypermethylation in nasopharyngeal carcinoma.
Kwong J, Lo KW, Chow LS, Chan FL, To KF, Huang DP.
Int J Cancer. 2005 Jan 20;113(3):386-92.
PMID 15455391
Suppression of the TIG3 tumor suppressor gene in human ovarian carcinomas is mediated via mitogen-activated kinase-dependent and -independent mechanisms.
Lotz K, Kellner T, Heitmann M, Nazarenko I, Noske A, Malek A, Gontarewicz A, Schafer R, Sers C.
Int J Cancer. 2005 Oct 10;116(6):894-902.
PMID 15856468
TIG3 tumor suppressor-dependent organelle redistribution and apoptosis in skin cancer cells.
Scharadin TM, Jiang H, Jans R, Rorke EA, Eckert RL.
PLoS One. 2011;6(8):e23230. Epub 2011 Aug 17.
PMID 21858038
Expression and regulation of retinoid-inducible gene 1 (RIG1) in breast cancer.
Shyu RY, Chang SC, Yu JC, Hsu SJ, Chou JM, Lee MS, Jiang SY.
Anticancer Res. 2005 May-Jun;25(3c):2453-60.
PMID 16080475
RARRES3 expression positively correlated to tumour differentiation in tissues of colorectal adenocarcinoma.
Shyu RY, Jiang SY, Chou JM, Shih YL, Lee MS, Yu JC, Chao PC, Hsu YJ, Jao SW.
Br J Cancer. 2003 Jul 7;89(1):146-51.
PMID 12838316
A novel transglutaminase activator forms a complex with type 1 transglutaminase.
Sturniolo MT, Chandraratna RA, Eckert RL.
Oncogene. 2005 Apr 21;24(18):2963-72.
PMID 15846304
Induction of apoptosis by the retinoid inducible growth regulator RIG1 depends on the NC motif in HtTA cervical cancer cells.
Tsai FM, Shyu RY, Lin SC, Wu CC, Jiang SY.
BMC Cell Biol. 2009 Feb 26;10:15.
PMID 19245694


This paper should be referenced as such :
Scharadin, T ; Eckert, RL
RARRES3 (retinoic acid receptor responder (tazarotene induced) 3)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(6):417-419.
Free journal version : [ pdf ]   [ DOI ]
On line version :

External links

HGNC (Hugo)RARRES3   9869
Entrez_Gene (NCBI)RARRES3  5920  retinoic acid receptor responder 3
AliasesHRASLS4; HRSL4; PLA1/2-3; RIG1; 
GeneCards (Weizmann)RARRES3
Ensembl hg19 (Hinxton)ENSG00000133321 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000133321 [Gene_View]  chr11:63536801-63546458 [Contig_View]  RARRES3 [Vega]
ICGC DataPortalENSG00000133321
Genatlas (Paris)RARRES3
Genetics Home Reference (NIH)RARRES3
Genomic and cartography
GoldenPath hg38 (UCSC)RARRES3  -     chr11:63536801-63546458 +  11q12.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)RARRES3  -     11q12.3   [Description]    (hg19-Feb_2009)
EnsemblRARRES3 - 11q12.3 [CytoView hg19]  RARRES3 - 11q12.3 [CytoView hg38]
Mapping of homologs : NCBIRARRES3 [Mapview hg19]  RARRES3 [Mapview hg38]
Gene and transcription
Genbank (Entrez)AB030815 AB453252 AF060228 AF092922 AK293357
RefSeq transcript (Entrez)NM_004585
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)RARRES3
Cluster EST : UnigeneHs.17466 [ NCBI ]
CGAP (NCI)Hs.17466
Alternative Splicing GalleryENSG00000133321
Gene Expression Viewer (FireBrowse)RARRES3 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5920
GTEX Portal (Tissue expression)RARRES3
Human Protein AtlasENSG00000133321-RARRES3 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9UL19   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9UL19  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9UL19
Splice isoforms : SwissVarQ9UL19
Catalytic activity : Enzyme3.1.1.- [ Enzyme-Expasy ]   3.1.1.-3.1.1.- [ IntEnz-EBI ]   3.1.1.- [ BRENDA ]   3.1.1.- [ KEGG ]   
Domains : Interpro (EBI)LRAT-like_dom    NLP_P60_dom    RARRES3   
Domain families : Pfam (Sanger)LRAT (PF04970)   
Domain families : Pfam (NCBI)pfam04970   
Conserved Domain (NCBI)RARRES3
DMDM Disease mutations5920
Blocks (Seattle)RARRES3
PDB (SRS)2LKT    2MY9   
PDB (PDBSum)2LKT    2MY9   
PDB (IMB)2LKT    2MY9   
PDB (RSDB)2LKT    2MY9   
Structural Biology KnowledgeBase2LKT    2MY9   
SCOP (Structural Classification of Proteins)2LKT    2MY9   
CATH (Classification of proteins structures)2LKT    2MY9   
Human Protein Atlas [tissue]ENSG00000133321-RARRES3 [tissue]
Peptide AtlasQ9UL19
IPIIPI00296991   IPI00909431   IPI00479609   
Protein Interaction databases
IntAct (EBI)Q9UL19
Ontologies - Pathways
Ontology : AmiGOphospholipase A2 activity  protein binding  cytosol  phospholipid metabolic process  negative regulation of cell proliferation  integral component of membrane  lipid catabolic process  transferase activity, transferring acyl groups  phosphatidylethanolamine acyl-chain remodeling  
Ontology : EGO-EBIphospholipase A2 activity  protein binding  cytosol  phospholipid metabolic process  negative regulation of cell proliferation  integral component of membrane  lipid catabolic process  transferase activity, transferring acyl groups  phosphatidylethanolamine acyl-chain remodeling  
REACTOMEQ9UL19 [protein]
REACTOME PathwaysR-HSA-1482839 [pathway]   
Atlas of Cancer Signalling NetworkRARRES3
Wikipedia pathwaysRARRES3
Orthology - Evolution
GeneTree (enSembl)ENSG00000133321
Phylogenetic Trees/Animal Genes : TreeFamRARRES3
Homologs : HomoloGeneRARRES3
Homology/Alignments : Family Browser (UCSC)RARRES3
Gene fusions - Rearrangements
Fusion : QuiverRARRES3
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerRARRES3 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)RARRES3
Exome Variant ServerRARRES3
ExAC (Exome Aggregation Consortium)ENSG00000133321
GNOMAD BrowserENSG00000133321
Genetic variants : HAPMAP5920
Genomic Variants (DGV)RARRES3 [DGVbeta]
DECIPHERRARRES3 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisRARRES3 
ICGC Data PortalRARRES3 
TCGA Data PortalRARRES3 
Broad Tumor PortalRARRES3
OASIS PortalRARRES3 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICRARRES3  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDRARRES3
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 RARRES3
DgiDB (Drug Gene Interaction Database)RARRES3
DoCM (Curated mutations)RARRES3 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)RARRES3 (select a term)
NCG5 (London)RARRES3
Cancer3DRARRES3(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry RARRES3
NextProtQ9UL19 [Medical]
Target ValidationRARRES3
Huge Navigator RARRES3 [HugePedia]
snp3D : Map Gene to Disease5920
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD5920
Chemical/Pharm GKB GenePA34230
Clinical trialRARRES3
canSAR (ICR)RARRES3 (select the gene name)
PubMed61 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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