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STARD13 (StAR-related lipid transfer (START) domain containing 13)

Written2007-11Thomas Ho-Yin Leung, Judy Wai Ping Yam, Irene Oi-lin Ng
Departments of Pathology, Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong

(Note : for Links provided by Atlas : click)

Identity

Alias_namesLINC00464
START domain containing 13
long intergenic non-protein coding RNA 464
Alias_symbol (synonym)GT650
DLC2
ARHGAP37
Other aliasDLC2 (Deleted in Liver Cancer 2)
FLJ37385
HGNC (Hugo) STARD13
LocusID (NCBI) 90627
Atlas_Id 44051
Location 13q13.1  [Link to chromosome band 13q13]
Location_base_pair Starts at 33691685 and ends at 33760216 bp from pter ( according to hg19-Feb_2009)  [Mapping STARD13.png]
Fusion genes
(updated 2016)
BICC1 (10q21.1) / STARD13 (13q13.1)DDX46 (5q31.1) / STARD13 (13q13.1)POLR2J (7q22.1) / STARD13 (13q13.1)
STARD13 (13q13.1) / PPP1R14C (6q25.1)STARD13 (13q13.1) / STARD13 (13q13.1)STARD13 (13q13.1) / TNFRSF8 (1p36.22)
STARD13 (13q13.1) / TSR2 (Xp11.22)

DNA/RNA

Note GeneLoc location for GC13M032575: Start: 32,575,307bp from pter; End: 32,757,892; Size: 182,585; Orientation: minus strand
 
  Genomic characterization of human DLC2. (A) chromosomal map location of human DLC2 at 13q 12.3. Arrows underneath the gene symbols indicate the orientation of transcription. RFC3, replication factor C subunit 3; KL, Klotho; AS3, androgen shutoff 3; BRCA2, breast cancer 2, early onset; Tel, telomeric; Cen, centromeric. (B) genomic organization of human DLC2 locus. Non-coding (open boxes) and coding (filled boxes) are shown. (Ching YP,et al. J Biol Chem 2003)
Description DLC2 was identified due to striking sequence homology to DLC1. It localizes to a small region of 13q12.3, which is a locus frequently deleted in hepatocellular carcinoma (HCC) as well as in other cancers. Physical mapping of DLC2 in human genome revealed that it is in close proximity to the BRCA2 locus and flanked by microsatellite markers D13S171 and D13S267. The human DLC2 gene spans a region of 182 kb and contains 14 coding exons.
Transcription The mRNA of DLC2 is 5886 bp long with an open reading frame of 3342 bp. Using bioinformatic analysis, 4 isoforms of DLC2, namely, DLC2alpha (5886 bp), DLC2beta (5810 bp), DLC2gamma (5784 bp), and DLC2delta (943 bp) have been identified. These 4 isoforms are generated by alternative splicing of the 5' end of the transcript. Northern blot analysis detected 7.2- and 4.2-kb DLC2 transcripts in all tissues examined, with the highest expression in heart, skeletal muscle, kidney, and pancreas.

Protein

 
  A. DLC2 is a multifunctional protein. Diagram of protein domains in DLC2. SAM, sterile alpha motif; ATP/GTP binding, ATP/GTP-binding site motif A; GAP, RhoGAP domain; START, StAR-related lipid transfer domain. (Ching YP,et al. J Biol Chem 2003)
B. Functional domains of the DLC2 isoforms. DLC2alpha and DLC2beta each contains a SAM, a RhoGAP, and a START domain, but they differ in their N-terminal sequence. The difference in the amino acid sequence was located at the first 60 aa in DLC2alpha and the first 52 aa in DLC2beta. DLC2gamma contains a RhoGAP and a START domain. DLC2delta only contains a SAM domain. (Leung TH, et al. Proc Nat Acad Sci USA. 2005)
Description DLC2alpha encodes a 1113-amino acid protein which has a calculated molecular mass of 125 kD. DLC2 contains an N-terminal sterile alpha motif (SAM) domain for protein-protein interactions, followed by an ATP/GTP-binding motif, a GTPase-activating protein (GAP) domain, and a C-terminal STAR-related lipid transfer (START) domain. The 4 isoforms of DLC2, DLC2alpha, DLC2beta, DLC2gamma, and DLC2delta, encode proteins of 1113, 1105, 995, and 135 amino acids, respectively. DLC2alpha and DLC2beta encode a protein containing three functional domains, SAM, RhoGAP and START domains. DLC2alpha and DLC2beta differ by only a few N-terminal amino acids. DLC2gamma contains the RhoGAP and START domains, but lacks the N-terminal SAM domain, whereas DLC2delta contains only the SAM domain.
Co-immunoprecipitation assay of ectopically expressed DLC2 in cells revealed that DLC1 forms homodimers in vivo and the region 160-672 residues is responsible for the interaction.
Expression DLC2 is ubiquitously expressed in human tissues and is more abundant in heart, skeletal muscle, kidney and pancreas.
Localisation DLC2alpha, DLC2beta and DLC2gamma are predominantly localized in the cytoplasm in mouse fibroblast and human HCC cells. Cellular fractionation and immunofluorescence microscopy revealed that DLC2 localizes to cytoplasmic speckles overlapping with mitochondria and in structures in close proximity to lipid droplets. The START domain of DLC2 has been demonstrated to be responsible for mitochondria targeting of DLC2.
Function DLC2 has been implicated to be a tumor suppressor protein. DLC2 has growth suppressive and anti-metastatic effects on HCC cell line, HepG2 and breast cancer cell line, MCF7. The RhoGAP domain has been demonstrated to be responsible for its biological functions and the RhoGAP activity has been demonstrated in vitro and in vivo. Recombinant DLC2 showed GAP activity specific for small GTPases, RhoA and Cdc42. Using GST-Rhoteckin pull down assay, in vivo RhoA activity has been shown to be negatively regulated by DLC2. However, in cells transfected with DLC2 RhoGAP mutant, the in vivo RhoA activity remained unchanged. Moreover, DLC2 inactivates RhoA activity via its RhoGAP domain and leads to the inhibition of actin stress fiber formation. Ectopic expression of DLC2 changed mouse fibroblast morphology from angular and spindle-shaped to round-shaped with dendritic cellular protrusions. Cells express DLC2 RhoGAP mutants did not exhibit morphological change and the actin stress fiber formation in these cells is unaffected. Introduction of human DLC2 into mouse fibroblasts suppressed Ras signaling and Ras-induced cellular transformation in a GAP-dependent manner. Overexpression of DLC2 also suppressed cell proliferation, motility and anchorage-independent growth in human hepatoma cells.
Collectively, down regulation of RhoA activity in HCC cell line by DLC2 resulted in change of cell morphology, migration rate, proliferation rate and transforming ability.
Several proteins were identified as interacting partners of DLC2 by yeast two-hybrid screening. These proteins include SWI/SNF, alpha-tubulin, HMG CoA reductase, and TAX1 binding protein (TAX1BP1).
Homology DLC family members: DLC1 is located at chromosome 8p22; DLC3 is located at chromosome Xq13; DLC2 shares 51% and 52% amino acid identities with DLC1 and DLC3, respectively.

Implicated in

Note
  
Entity Cancer
Note DLC2, with its RhoGAP domain, is able to inhibit the activity of RhoA, which is believed to play a significant role in cell transformation in many cancer types. Down regulation of DLC2 mRNA expression has been reported in various types of cancer including liver, breast, lung, ovarian, renal, uterine, gastric, colon and rectal tumors.
DLC2 localizes to a small region of 13q12.3 commonly deleted in HCC. DLC2 is flanked by microsatellite markers D13S171 and D13S267. Loss of heterozygosity on these two markers is frequently found in HCC. Allelic losses at markers D13S171 and D13S267 are detected in 33.3% and 40.7% of the informative cases, respectively. RT-PCR analysis of DLC2 mRNA in 45 HCC samples revealed that 17.8% of the cases showed significant underexpression (more than 2-fold) of DLC2 mRNA when compared with the corresponding non-tumorous liver tissues from the same patients.
Studies in human cancers have suggested that small GTPases of the Rho family are critically involved tumorigenesis. Suppression of RhoA activity may be able to reverse the transformation phenotype in cancers. RhoGAP activity of DLC2 has been demonstrated both in vitro and in vivo. Anchorage-independent growth of cancer cells is a hallmark of cellular transformation. Stable expression of DLC2 in liver cancer cell line effectively abolished the anchorage-independent growth ability of the cells. This indicated that DLC2 is capable of reducing the transforming phenotype and supports the view that DLC2 is a functional tumor suppressor.
  

Bibliography

Deleted in liver cancer (DLC) 2 encodes a RhoGAP protein with growth suppressor function and is underexpressed in hepatocellular carcinoma.
Ching YP, Wong CM, Chan SF, Leung TH, Ng DC, Jin DY, Ng IO
The Journal of biological chemistry. 2003 ; 278 (12) : 10824-10830.
PMID 12531887
 
DLC-1:a Rho GTPase-activating protein and tumour suppressor.
Durkin ME, Yuan BZ, Zhou X, Zimonjic DB, Lowy DR, Thorgeirsson SS, Popescu NC
Journal of cellular and molecular medicine. 2007 ; 11 (5) : 1185-1207.
PMID 17979893
 
The NMR structure of the murine DLC2 SAM domain reveals a variant fold that is similar to a four-helix bundle.
Kwan JJ, Donaldson LW
BMC structural biology. 2007 ; 7 : page 34.
PMID 17519008
 
Deleted in liver cancer 2 (DLC2) suppresses cell transformation by means of inhibition of RhoA activity.
Leung TH, Ching YP, Yam JW, Wong CM, Yau TO, Jin DY, Ng IO
Proceedings of the National Academy of Sciences of the United States of America. 2005 ; 102 (42) : 15207-15212.
PMID 16217026
 
Solution structures, dynamics, and lipid-binding of the sterile alpha-motif domain of the deleted in liver cancer 2.
Li H, Fung KL, Jin DY, Chung SS, Ching YP, Ng IO, Sze KH, Ko BC, Sun H
Proteins. 2007 ; 67 (4) : 1154-1166.
PMID 17380510
 
Chromosome 13q12 encoded Rho GTPase activating protein suppresses growth of breast carcinoma cells, and yeast two-hybrid screen shows its interaction with several proteins.
Nagaraja GM, Kandpal RP
Biochemical and biophysical research communications. 2004 ; 313 (3) : 654-665.
PMID 14697242
 
Mitochondrial targeting of growth suppressor protein DLC2 through the START domain.
Ng DC, Chan SF, Kok KH, Yam JW, Ching YP, Ng IO, Jin DY
FEBS letters. 2006 ; 580 (1) : 191-198.
PMID 16364308
 
Rho GTPase activating protein cDNA on chromosome 13q12 is the deleted in liver cancer (DLC2) gene.
Popescu NC, Durkin ME
Biochemical and biophysical research communications. 2004 ; 315 (4) : page 781.
PMID 14985079
 
Oncogenic inhibition by a deleted in liver cancer gene requires cooperation between tensin binding and Rho-specific GTPase-activating protein activities.
Qian X, Li G, Asmussen HK, Asnaghi L, Vass WC, Braverman R, Yamada KM, Popescu NC, Papageorge AG, Lowy DR
Proceedings of the National Academy of Sciences of the United States of America. 2007 ; 104 (21) : 9012-9017.
PMID 17517630
 
Expression profile of the tumor suppressor genes DLC-1 and DLC-2 in solid tumors.
Ullmannova V, Popescu NC
International journal of oncology. 2006 ; 29 (5) : 1127-1132.
PMID 17016643
 

Citation

This paper should be referenced as such :
Leung, THY ; Yam, JWP ; Ng, IOL
STARD13 (star-related lipid transfer (START) domain containing 13)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(4):292-294.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/STARD13ID44051ch13q13.html


External links

Nomenclature
HGNC (Hugo)STARD13   19164
Cards
AtlasSTARD13ID44051ch13q13
Entrez_Gene (NCBI)STARD13  90627  StAR related lipid transfer domain containing 13
AliasesARHGAP37; DLC2; GT650; LINC00464
GeneCards (Weizmann)STARD13
Ensembl hg19 (Hinxton)ENSG00000133121 [Gene_View]  chr13:33691685-33760216 [Contig_View]  STARD13 [Vega]
Ensembl hg38 (Hinxton)ENSG00000133121 [Gene_View]  chr13:33691685-33760216 [Contig_View]  STARD13 [Vega]
ICGC DataPortalENSG00000133121
TCGA cBioPortalSTARD13
AceView (NCBI)STARD13
Genatlas (Paris)STARD13
WikiGenes90627
SOURCE (Princeton)STARD13
Genetics Home Reference (NIH)STARD13
Genomic and cartography
GoldenPath hg19 (UCSC)STARD13  -     chr13:33691685-33760216 -  13q13.1   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)STARD13  -     13q13.1   [Description]    (hg38-Dec_2013)
EnsemblSTARD13 - 13q13.1 [CytoView hg19]  STARD13 - 13q13.1 [CytoView hg38]
Mapping of homologs : NCBISTARD13 [Mapview hg19]  STARD13 [Mapview hg38]
OMIM609866   
Gene and transcription
Genbank (Entrez)AA256386 AK091804 AK094704 AK095114 AK308430
RefSeq transcript (Entrez)NM_001243466 NM_001243474 NM_001243476 NM_052851 NM_178006 NM_178007 NM_178008
RefSeq genomic (Entrez)NC_000013 NC_018924 NG_029752 NT_024524 NW_004929388
Consensus coding sequences : CCDS (NCBI)STARD13
Cluster EST : UnigeneHs.721224 [ NCBI ]
CGAP (NCI)Hs.721224
Alternative Splicing GalleryENSG00000133121
Gene ExpressionSTARD13 [ NCBI-GEO ]   STARD13 [ EBI - ARRAY_EXPRESS ]   STARD13 [ SEEK ]   STARD13 [ MEM ]
Gene Expression Viewer (FireBrowse)STARD13 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)90627
GTEX Portal (Tissue expression)STARD13
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9Y3M8   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9Y3M8  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9Y3M8
Splice isoforms : SwissVarQ9Y3M8
PhosPhoSitePlusQ9Y3M8
Domaine pattern : Prosite (Expaxy)RHOGAP (PS50238)    START (PS50848)   
Domains : Interpro (EBI)Rho_GTPase_activation_prot    RhoGAP_dom    SAM    SAM/pointed    START-like_dom    START_lipid-bd_dom   
Domain families : Pfam (Sanger)RhoGAP (PF00620)    SAM_2 (PF07647)    START (PF01852)   
Domain families : Pfam (NCBI)pfam00620    pfam07647    pfam01852   
Domain families : Smart (EMBL)RhoGAP (SM00324)  START (SM00234)  
Conserved Domain (NCBI)STARD13
DMDM Disease mutations90627
Blocks (Seattle)STARD13
PDB (SRS)2H80    2JW2    2PSO   
PDB (PDBSum)2H80    2JW2    2PSO   
PDB (IMB)2H80    2JW2    2PSO   
PDB (RSDB)2H80    2JW2    2PSO   
Structural Biology KnowledgeBase2H80    2JW2    2PSO   
SCOP (Structural Classification of Proteins)2H80    2JW2    2PSO   
CATH (Classification of proteins structures)2H80    2JW2    2PSO   
SuperfamilyQ9Y3M8
Human Protein AtlasENSG00000133121
Peptide AtlasQ9Y3M8
HPRD11607
IPIIPI00419226   IPI00329291   IPI00395688   IPI00741772   IPI00739795   
Protein Interaction databases
DIP (DOE-UCLA)Q9Y3M8
IntAct (EBI)Q9Y3M8
FunCoupENSG00000133121
BioGRIDSTARD13
STRING (EMBL)STARD13
ZODIACSTARD13
Ontologies - Pathways
QuickGOQ9Y3M8
Ontology : AmiGOGTPase activator activity  protein binding  lipid particle  cytosol  signal transduction  lipid binding  mitochondrial membrane  endothelial cell migration  endothelial cell migration  positive regulation of GTPase activity  positive regulation of GTPase activity  regulation of small GTPase mediated signal transduction  negative regulation of cell migration involved in sprouting angiogenesis  negative regulation of cell migration involved in sprouting angiogenesis  endothelial tube lumen extension  endothelial tube lumen extension  
Ontology : EGO-EBIGTPase activator activity  protein binding  lipid particle  cytosol  signal transduction  lipid binding  mitochondrial membrane  endothelial cell migration  endothelial cell migration  positive regulation of GTPase activity  positive regulation of GTPase activity  regulation of small GTPase mediated signal transduction  negative regulation of cell migration involved in sprouting angiogenesis  negative regulation of cell migration involved in sprouting angiogenesis  endothelial tube lumen extension  endothelial tube lumen extension  
REACTOMEQ9Y3M8 [protein]
REACTOME Pathways194840 [pathway]   
NDEx NetworkSTARD13
Atlas of Cancer Signalling NetworkSTARD13
Wikipedia pathwaysSTARD13
Orthology - Evolution
OrthoDB90627
GeneTree (enSembl)ENSG00000133121
Phylogenetic Trees/Animal Genes : TreeFamSTARD13
HOVERGENQ9Y3M8
HOGENOMQ9Y3M8
Homologs : HomoloGeneSTARD13
Homology/Alignments : Family Browser (UCSC)STARD13
Gene fusions - Rearrangements
Fusion : MitelmanSTARD13/TNFRSF8 [13q13.1/1p36.22]  
Fusion: TCGASTARD13 13q13.1 TNFRSF8 1p36.22 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSTARD13 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)STARD13
dbVarSTARD13
ClinVarSTARD13
1000_GenomesSTARD13 
Exome Variant ServerSTARD13
ExAC (Exome Aggregation Consortium)STARD13 (select the gene name)
Genetic variants : HAPMAP90627
Genomic Variants (DGV)STARD13 [DGVbeta]
DECIPHER (Syndromes)13:33691685-33760216  ENSG00000133121
CONAN: Copy Number AnalysisSTARD13 
Mutations
ICGC Data PortalSTARD13 
TCGA Data PortalSTARD13 
Broad Tumor PortalSTARD13
OASIS PortalSTARD13 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICSTARD13  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDSTARD13
intOGen PortalSTARD13
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 STARD13
DgiDB (Drug Gene Interaction Database)STARD13
DoCM (Curated mutations)STARD13 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)STARD13 (select a term)
intoGenSTARD13
NCG5 (London)STARD13
Cancer3DSTARD13(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM609866   
Orphanet
MedgenSTARD13
Genetic Testing Registry STARD13
NextProtQ9Y3M8 [Medical]
TSGene90627
GENETestsSTARD13
Huge Navigator STARD13 [HugePedia]
snp3D : Map Gene to Disease90627
BioCentury BCIQSTARD13
ClinGenSTARD13
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD90627
Chemical/Pharm GKB GenePA38806
Clinical trialSTARD13
Miscellaneous
canSAR (ICR)STARD13 (select the gene name)
Probes
Litterature
PubMed44 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineSTARD13
EVEXSTARD13
GoPubMedSTARD13
iHOPSTARD13
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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