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SULF2 (sulfatase 2)

Written2013-04Lewis Roberts, Chunling Hu
Division of Gastroenterology, Hepatology, Mayo Clinic, Mayo Clinic Cancer Center, Rochester, MN 55905, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)KIAA1247
HSULF-2
SULF-2
Other alias
HGNC (Hugo) SULF2
LocusID (NCBI) 55959
Atlas_Id 43735
Location 20q13.12  [Link to chromosome band 20q13]
Location_base_pair Starts at 47657406 and ends at 47786616 bp from pter ( according to hg19-Feb_2009)  [Mapping SULF2.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)
ARFGEF2 (20q13.13) / SULF2 (20q13.12)DDX21 (10q22.1) / SULF2 (20q13.12)SULF2 (20q13.12) / PRICKLE2 (3p14.1)
SULF2 (20q13.12) / ZNF217 (20q13.2)UBE2V1 (20q13.13) / SULF2 (20q13.12)ZMYND8 (20q13.12) / SULF2 (20q13.12)

DNA/RNA

Description SULF2 55959 chr 20: 46286150-46415360. The gene encompasses 130 kb of DNA; 21 exons.
Transcription 3 transcripts: transcript variant 1, 3909 bp linear mRNA, 21 exons (NM_018837); transcript variant 2, 4239 bp linear mRNA, 21 exons (NM_198596); transcript variant 3, 4248 bp linear mRNA, 21 exons (NM_001161841).

Protein

 
  Schematic diagram of SULF2 with domains.
Description 870 amino acid; 100 kDa protein; post translational modification: 11 N-glycosylation sites; contains from N-term to C-term, a signal peptide (1-24), a enzymatic domain (25-400) which contains a conserved cysteine (88) essential for the catalytic activity, a hydrophilic domain (401-739) which contains four lysines and arginies rich domains suited for interactions with sulfated HSGAGs that fit the heparin-binding motif, and a glucosamine-6-sulfatase domain (740-870).
Expression Widely expressed, especially in ovary, skeletal muscle, stomach, brain, uterus, heart, kidney, and placenta.
Localisation Extracellular space, cell surface, plasma membrane, endoplasmic reticulum, and Golgi stack.
Function SULF2 is a member of a novel family of extracellular HS 6-O endosulfatases with heparin-degrading endosulfatase activity. SULF2 desulfates HS and increases the local concentration of growth factors in the extracellular matrix. The released growth factors then bind to their cell surface receptors, with the consequent activation of cell growth and survival pathways in HCC. SULF2 up-regulated GPC3 expression and FGF2 ligand-receptor binding and signaling. It has been shown that SULF2 liberates growth factors such as Wnt3a from HSPGs such as GPC3 on the cell surface and in the extracellular matrix by desulfating heparan sulfate (HS). It has been reported that SULF2 mRNA is up-regulated in human breast cancers, and suppression of SULF2 expression decreases tumorigenesis of pancreatic cancer cell lines. SULF2 regulates PDGFRα signaling and growth in malignant glioma.
Homology Conserved in Rhesus monkey, dog, cow, mouse, rat, chicken, and zebrafish.

Mutations

 
Somatic Identified mutations in various cancers.

Implicated in

Note
  
Entity Hepatocellular carcinoma (HCC)
Prognosis In a microarray experiment performed on paired benign and tumor tissues from HCC patients, SULF2 expression was higher in the tumors than in the benign tissues in 79 (57%) of 139 HCCs. Patients with tumors expressing high SULF2 levels had a significantly poorer prognosis than those with tumor expressing low SULF2 levels (Lai et al., 2008a).
Oncogenesis Expression of SULF2 promotes HCC cell proliferation and migration. Knockdown of SULF2 decreases HCC cell proliferation and migration. SULF2 promotes tumorigenesis in nude mice and up-regulates GPC3 in vivo (Lai et al., 2008a).
  
  
Entity Lung cancer
Prognosis Paired samples of lung squamous carcinoma and non malignant neighboring tissue were obtained from 10 patients undergoing surgical resection. SULF2 increased in 8/10 pairs with a mean increase of 3 ± 0.3-fold. qPCR analysis of SULF2 in archived cases of lung carcinoma verified it. SULF2 increased 4 ± 0.3 fold in squamous carcinomas and 3 ± 0.4 fold in adenocarcinomas (Lemjabbar-Alaoui et al., 2010).
Oncogenesis Knockdown of SULF2 or expression of dominant-negative SULF2 reduces growth of lung cancer cells. SULF2 over-expression in non-malignant bronchial epithelial cells induces a transformed phenotype in culture. SULF2 knockdown reduces growth of tumors arising from lung cancer cells (Lemjabbar-Alaoui et al., 2010).
  
  
Entity Glioblastoma (GBM)
Prognosis SULF2 expression is elevated in GBM. Unsing a stringent cutoff of a 10-fold increase in SULF2 SAGE tags over levels in normal brain to define high SULF2 levels, 7 of 16 GBMs has increased SULF2 expression. Strikingly, in an independent set of 424 primary human GBM tumors, SULF2 expression was increased in 46% (197/424) of tumors related to normal brain. Immunohistochemistry on an independent set of 57 primary human GBM tumors demonstrated SULF2 protein in tumor cells in 50% of tumors. SULF2 expression is associated with the proneural subtype of GBM characterized by abnormalities in the PDGFRα-signaling pathway and SULF2 expression is associated with the proneural GBM subtype (Phillips et al., 2012).
Oncogenesis SULF2 confers a growth advantage to human GBM cells, SULF2 knockdown resulted in a significant decrease in cell viability. SULF2 also confers a growth advantage to human GBM cells in vivo. SULF2 confers increased tumorigenicity and proliferation. Prolonged survival confered by ablation of SULF2 in tumorigenic neurospheres. And absence of SULF2 resulted in decreased tumor cell proliferation in vivo (Phillips et al., 2012).
  

Breakpoints

 
Note Fusion of ARFGEF2 exon 1 to SULF2 exons 3-21.

Bibliography

SULFs in human neoplasia: implication as progression and prognosis factors.
Bret C, Moreaux J, Schved JF, Hose D, Klein B.
J Transl Med. 2011 May 21;9:72. doi: 10.1186/1479-5876-9-72.
PMID 21599997
 
Identification of SULF2 as a novel transcriptional target of p53 by use of integrated genomic analyses.
Chau BN, Diaz RL, Saunders MA, Cheng C, Chang AN, Warrener P, Bradshaw J, Linsley PS, Cleary MA.
Cancer Res. 2009 Feb 15;69(4):1368-74. doi: 10.1158/0008-5472.CAN-08-2742. Epub 2009 Feb 3.
PMID 19190338
 
HSulf-1 and HSulf-2 are potent inhibitors of myeloma tumor growth in vivo.
Dai Y, Yang Y, MacLeod V, Yue X, Rapraeger AC, Shriver Z, Venkataraman G, Sasisekharan R, Sanderson RD.
J Biol Chem. 2005 Dec 2;280(48):40066-73. Epub 2005 Sep 27.
PMID 16192265
 
Sulf2 gene is alternatively spliced in mammalian developing and tumour tissues with functional implications.
Gill RB, Day A, Barstow A, Liu H, Zaman G, Dhoot GK.
Biochem Biophys Res Commun. 2011 Oct 28;414(3):468-73. doi: 10.1016/j.bbrc.2011.09.088. Epub 2011 Sep 24.
PMID 21968018
 
The oncogenic effect of sulfatase 2 in human hepatocellular carcinoma is mediated in part by glypican 3-dependent Wnt activation.
Lai JP, Oseini AM, Moser CD, Yu C, Elsawa SF, Hu C, Nakamura I, Han T, Aderca I, Isomoto H, Garrity-Park MM, Shire AM, Li J, Sanderson SO, Adjei AA, Fernandez-Zapico ME, Roberts LR.
Hepatology. 2010a Nov;52(5):1680-9. doi: 10.1002/hep.23848.
PMID 20725905
 
Sulfatase 2 protects hepatocellular carcinoma cells against apoptosis induced by the PI3K inhibitor LY294002 and ERK and JNK kinase inhibitors.
Lai JP, Sandhu DS, Yu C, Moser CD, Hu C, Shire AM, Aderca I, Murphy LM, Adjei AA, Sanderson S, Roberts LR.
Liver Int. 2010b Nov;30(10):1522-8. doi: 10.1111/j.1478-3231.2010.02336.x. Epub 2010 Sep 8.
PMID 21040406
 
Heparin-degrading sulfatases in hepatocellular carcinoma: roles in pathogenesis and therapy targets.
Lai JP, Thompson JR, Sandhu DS, Roberts LR.
Future Oncol. 2008b Dec;4(6):803-14. doi: 10.2217/14796694.4.6.803. (REVIEW)
PMID 19086847
 
Sulf loss influences N-, 2-O-, and 6-O-sulfation of multiple heparan sulfate proteoglycans and modulates fibroblast growth factor signaling.
Lamanna WC, Frese MA, Balleininger M, Dierks T.
J Biol Chem. 2008 Oct 10;283(41):27724-35. doi: 10.1074/jbc.M802130200. Epub 2008 Aug 6.
PMID 18687675
 
Sulf-2, a heparan sulfate endosulfatase, promotes human lung carcinogenesis.
Lemjabbar-Alaoui H, van Zante A, Singer MS, Xue Q, Wang YQ, Tsay D, He B, Jablons DM, Rosen SD.
Oncogene. 2010 Feb 4;29(5):635-46. doi: 10.1038/onc.2009.365. Epub 2009 Oct 26.
PMID 19855436
 
Sulf-2, a proangiogenic heparan sulfate endosulfatase, is upregulated in breast cancer.
Morimoto-Tomita M, Uchimura K, Bistrup A, Lum DH, Egeblad M, Boudreau N, Werb Z, Rosen SD.
Neoplasia. 2005 Nov;7(11):1001-10.
PMID 16331886
 
Expression of novel extracellular sulfatases Sulf-1 and Sulf-2 in normal and osteoarthritic articular cartilage.
Otsuki S, Taniguchi N, Grogan SP, D'Lima D, Kinoshita M, Lotz M.
Arthritis Res Ther. 2008;10(3):R61. doi: 10.1186/ar2432. Epub 2008 May 28.
PMID 18507859
 
Human Sulfatase 2 inhibits in vivo tumor growth of MDA-MB-231 human breast cancer xenografts.
Peterson SM, Iskenderian A, Cook L, Romashko A, Tobin K, Jones M, Norton A, Gomez-Yafal A, Heartlein MW, Concino MF, Liaw L, Martini PG.
BMC Cancer. 2010 Aug 13;10:427. doi: 10.1186/1471-2407-10-427.
PMID 20707913
 
Heparan sulfate sulfatase SULF2 regulates PDGFRa signaling and growth in human and mouse malignant glioma.
Phillips JJ, Huillard E, Robinson AE, Ward A, Lum DH, Polley MY, Rosen SD, Rowitch DH, Werb Z.
J Clin Invest. 2012 Mar 1;122(3):911-22. doi: 10.1172/JCI58215. Epub 2012 Feb 1.
PMID 22293178
 
Glycomics analysis of mammalian heparan sulfates modified by the human extracellular sulfatase HSulf2.
Staples GO, Shi X, Zaia J.
PLoS One. 2011 Feb 8;6(2):e16689. doi: 10.1371/journal.pone.0016689.
PMID 21347431
 
Functional consequences of the subdomain organization of the sulfs.
Tang R, Rosen SD.
J Biol Chem. 2009 Aug 7;284(32):21505-14. doi: 10.1074/jbc.M109.028472. Epub 2009 Jun 11.
PMID 19520866
 
HSulf-2, an extracellular endoglucosamine-6-sulfatase, selectively mobilizes heparin-bound growth factors and chemokines: effects on VEGF, FGF-1, and SDF-1.
Uchimura K, Morimoto-Tomita M, Bistrup A, Li J, Lyon M, Gallagher J, Werb Z, Rosen SD.
BMC Biochem. 2006 Jan 17;7:2.
PMID 16417632
 
Sulfatase 1 and sulfatase 2 in hepatocellular carcinoma: associated signaling pathways, tumor phenotypes, and survival.
Yang JD, Sun Z, Hu C, Lai J, Dove R, Nakamura I, Lee JS, Thorgeirsson SS, Kang KJ, Chu IS, Roberts LR.
Genes Chromosomes Cancer. 2011 Feb;50(2):122-35. doi: 10.1002/gcc.20838.
PMID 21104785
 

Citation

This paper should be referenced as such :
Roberts, L ; Hu, C
SULF2 (sulfatase 2)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(10):713-715.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/SULF2ID43735ch20q13.html


External links

Nomenclature
HGNC (Hugo)SULF2   20392
Cards
AtlasSULF2ID43735ch20q13
Entrez_Gene (NCBI)SULF2  55959  sulfatase 2
AliasesHSULF-2
GeneCards (Weizmann)SULF2
Ensembl hg19 (Hinxton)ENSG00000196562 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000196562 [Gene_View]  chr20:47657406-47786616 [Contig_View]  SULF2 [Vega]
ICGC DataPortalENSG00000196562
TCGA cBioPortalSULF2
AceView (NCBI)SULF2
Genatlas (Paris)SULF2
WikiGenes55959
SOURCE (Princeton)SULF2
Genetics Home Reference (NIH)SULF2
Genomic and cartography
GoldenPath hg38 (UCSC)SULF2  -     chr20:47657406-47786616 -  20q13.12   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)SULF2  -     20q13.12   [Description]    (hg19-Feb_2009)
EnsemblSULF2 - 20q13.12 [CytoView hg19]  SULF2 - 20q13.12 [CytoView hg38]
Mapping of homologs : NCBISULF2 [Mapview hg19]  SULF2 [Mapview hg38]
OMIM610013   
Gene and transcription
Genbank (Entrez)AB033073 AI824415 AK074483 AK075035 AK126452
RefSeq transcript (Entrez)NM_001161841 NM_018837 NM_198596
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)SULF2
Cluster EST : UnigeneHs.162016 [ NCBI ]
CGAP (NCI)Hs.162016
Alternative Splicing GalleryENSG00000196562
Gene ExpressionSULF2 [ NCBI-GEO ]   SULF2 [ EBI - ARRAY_EXPRESS ]   SULF2 [ SEEK ]   SULF2 [ MEM ]
Gene Expression Viewer (FireBrowse)SULF2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)55959
GTEX Portal (Tissue expression)SULF2
Human Protein AtlasENSG00000196562-SULF2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8IWU5   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ8IWU5  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ8IWU5
Splice isoforms : SwissVarQ8IWU5
Catalytic activity : Enzyme3.1.6.- [ Enzyme-Expasy ]   3.1.6.-3.1.6.- [ IntEnz-EBI ]   3.1.6.- [ BRENDA ]   3.1.6.- [ KEGG ]   
PhosPhoSitePlusQ8IWU5
Domaine pattern : Prosite (Expaxy)SULFATASE_1 (QS0023-   
Domains : Interpro (EBI)Alkaline_Pase-like_a/b/a    Alkaline_phosphatase_core    Extracellular_sulfatase    Extracellular_sulfatase_C    Sulfatase_CS    Sulfatase_N   
Domain families : Pfam (Sanger)DUF3740 (PF12548)    Sulfatase (PF00884)   
Domain families : Pfam (NCBI)pfam12548    pfam00884   
Conserved Domain (NCBI)SULF2
DMDM Disease mutations55959
Blocks (Seattle)SULF2
SuperfamilyQ8IWU5
Human Protein Atlas [tissue]ENSG00000196562-SULF2 [tissue]
Peptide AtlasQ8IWU5
HPRD18130
IPIIPI00297252   IPI00555879   IPI00744879   IPI00941316   IPI01012043   
Protein Interaction databases
DIP (DOE-UCLA)Q8IWU5
IntAct (EBI)Q8IWU5
FunCoupENSG00000196562
BioGRIDSULF2
STRING (EMBL)SULF2
ZODIACSULF2
Ontologies - Pathways
QuickGOQ8IWU5
Ontology : AmiGOkidney development  chondrocyte development  glomerular filtration  arylsulfatase activity  arylsulfatase activity  calcium ion binding  extracellular space  endoplasmic reticulum  Golgi stack  plasma membrane  N-acetylglucosamine-6-sulfatase activity  N-acetylglucosamine-6-sulfatase activity  response to wounding  cell surface  positive regulation of vascular endothelial growth factor production  esophagus smooth muscle contraction  positive regulation of Wnt signaling pathway  heparan sulfate proteoglycan metabolic process  heparan sulfate proteoglycan metabolic process  glomerular basement membrane development  positive regulation of catenin import into nucleus  glial cell-derived neurotrophic factor receptor signaling pathway  negative regulation of fibroblast growth factor receptor signaling pathway  embryonic skeletal system development  cartilage development  bone development  innervation  positive regulation of canonical Wnt signaling pathway  liver regeneration  regulation of hepatocyte proliferation  
Ontology : EGO-EBIkidney development  chondrocyte development  glomerular filtration  arylsulfatase activity  arylsulfatase activity  calcium ion binding  extracellular space  endoplasmic reticulum  Golgi stack  plasma membrane  N-acetylglucosamine-6-sulfatase activity  N-acetylglucosamine-6-sulfatase activity  response to wounding  cell surface  positive regulation of vascular endothelial growth factor production  esophagus smooth muscle contraction  positive regulation of Wnt signaling pathway  heparan sulfate proteoglycan metabolic process  heparan sulfate proteoglycan metabolic process  glomerular basement membrane development  positive regulation of catenin import into nucleus  glial cell-derived neurotrophic factor receptor signaling pathway  negative regulation of fibroblast growth factor receptor signaling pathway  embryonic skeletal system development  cartilage development  bone development  innervation  positive regulation of canonical Wnt signaling pathway  liver regeneration  regulation of hepatocyte proliferation  
NDEx NetworkSULF2
Atlas of Cancer Signalling NetworkSULF2
Wikipedia pathwaysSULF2
Orthology - Evolution
OrthoDB55959
GeneTree (enSembl)ENSG00000196562
Phylogenetic Trees/Animal Genes : TreeFamSULF2
HOVERGENQ8IWU5
HOGENOMQ8IWU5
Homologs : HomoloGeneSULF2
Homology/Alignments : Family Browser (UCSC)SULF2
Gene fusions - Rearrangements
Fusion : MitelmanARFGEF2/SULF2 [20q13.13/20q13.12]  [inv(20)(q13q13)]  [t(20;20)(q13;q13)]  
Fusion : MitelmanSULF2/PRICKLE2 [20q13.12/3p14.1]  [t(3;20)(p14;q13)]  
Fusion : MitelmanUBE2V1/SULF2 [20q13.13/20q13.12]  [t(20;20)(q13;q13)]  
Fusion : MitelmanZMYND8/SULF2 [20q13.12/20q13.12]  [t(20;20)(q13;q13)]  
Fusion: TCGAZMYND8 20q13.12 SULF2 20q13.12 OV
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSULF2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)SULF2
dbVarSULF2
ClinVarSULF2
1000_GenomesSULF2 
Exome Variant ServerSULF2
ExAC (Exome Aggregation Consortium)ENSG00000196562
GNOMAD BrowserENSG00000196562
Genetic variants : HAPMAP55959
Genomic Variants (DGV)SULF2 [DGVbeta]
DECIPHERSULF2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisSULF2 
Mutations
ICGC Data PortalSULF2 
TCGA Data PortalSULF2 
Broad Tumor PortalSULF2
OASIS PortalSULF2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICSULF2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDSULF2
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 SULF2
DgiDB (Drug Gene Interaction Database)SULF2
DoCM (Curated mutations)SULF2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)SULF2 (select a term)
intoGenSULF2
NCG5 (London)SULF2
Cancer3DSULF2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM610013   
Orphanet
MedgenSULF2
Genetic Testing Registry SULF2
NextProtQ8IWU5 [Medical]
TSGene55959
GENETestsSULF2
Target ValidationSULF2
Huge Navigator SULF2 [HugePedia]
snp3D : Map Gene to Disease55959
BioCentury BCIQSULF2
ClinGenSULF2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD55959
Chemical/Pharm GKB GenePA134902131
Clinical trialSULF2
Miscellaneous
canSAR (ICR)SULF2 (select the gene name)
Probes
Litterature
PubMed52 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineSULF2
EVEXSULF2
GoPubMedSULF2
iHOPSULF2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Thu Oct 12 16:34:44 CEST 2017

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