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

2007-11-01   Thomas 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

Identity

HGNC
LOCATION
13q13.1
LOCUSID
ALIAS
ARHGAP37,DLC2,GT650,LINC00464
FUSION GENES

DNA/RNA

Note

GeneLoc location for GC13M032575: Start: 32,575,307bp from pter; End: 32,757,892; Size: 182,585; Orientation: minus strand
Atlas Image
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.

Proteins

Atlas Image
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

Entity name
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

Pubmed IDLast YearTitleAuthors
125318872003Deleted in liver cancer (DLC) 2 encodes a RhoGAP protein with growth suppressor function and is underexpressed in hepatocellular carcinoma.Ching YP et al
179798932007DLC-1:a Rho GTPase-activating protein and tumour suppressor.Durkin ME et al
175190082007The NMR structure of the murine DLC2 SAM domain reveals a variant fold that is similar to a four-helix bundle.Kwan JJ et al
162170262005Deleted in liver cancer 2 (DLC2) suppresses cell transformation by means of inhibition of RhoA activity.Leung TH et al
173805102007Solution structures, dynamics, and lipid-binding of the sterile alpha-motif domain of the deleted in liver cancer 2.Li H et al
146972422004Chromosome 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 et al
163643082006Mitochondrial targeting of growth suppressor protein DLC2 through the START domain.Ng DC et al
149850792004Rho GTPase activating protein cDNA on chromosome 13q12 is the deleted in liver cancer (DLC2) gene.Popescu NC et al
175176302007Oncogenic inhibition by a deleted in liver cancer gene requires cooperation between tensin binding and Rho-specific GTPase-activating protein activities.Qian X et al
170166432006Expression profile of the tumor suppressor genes DLC-1 and DLC-2 in solid tumors.Ullmannova V et al

Other Information

Locus ID:

NCBI: 90627
MIM: 609866
HGNC: 19164
Ensembl: ENSG00000133121

Variants:

dbSNP: 90627
ClinVar: 90627
TCGA: ENSG00000133121
COSMIC: STARD13

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000133121ENST00000255486Q9Y3M8
ENSG00000133121ENST00000336934Q9Y3M8
ENSG00000133121ENST00000336934A0A024RDV4
ENSG00000133121ENST00000399365Q9Y3M8
ENSG00000133121ENST00000399365B2R789
ENSG00000133121ENST00000439831H3BUW7
ENSG00000133121ENST00000567873H3BRG5

Expression (GTEx)

0
10
20
30
40
50
60
70

Pathways

PathwaySourceExternal ID
Signal TransductionREACTOMER-HSA-162582
Signaling by Rho GTPasesREACTOMER-HSA-194315
Rho GTPase cycleREACTOMER-HSA-194840

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
203641372010Genome-wide association study of intracranial aneurysm identifies three new risk loci.90
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
125318872003Deleted in liver cancer (DLC) 2 encodes a RhoGAP protein with growth suppressor function and is underexpressed in hepatocellular carcinoma.52
226935472012MicroRNA-125b induces metastasis by targeting STARD13 in MCF-7 and MDA-MB-231 breast cancer cells.44
298483462018STARD13-correlated ceRNA network-directed inhibition on YAP/TAZ activity suppresses stemness of breast cancer via co-regulating Hippo and Rho-GTPase/F-actin signaling.27
269857702016STARD13-correlated ceRNA network inhibits EMT and metastasis of breast cancer.20
231756282013Rho signalling restriction by the RhoGAP Stard13 integrates growth and morphogenesis in the pancreas.16
272203202016MicroRNA-125b promotes invasion and metastasis of gastric cancer by targeting STARD13 and NEU1.16
243335062014The regulation of RhoA at focal adhesions by StarD13 is important for astrocytoma cell motility.13

Citation

Thomas Ho-Yin Leung ; Judy Wai Ping Yam ; Irene Oi-Lin Ng

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

Atlas Genet Cytogenet Oncol Haematol. 2007-11-01

Online version: http://atlasgeneticsoncology.org/gene/44051/stard13