SULF2 (sulfatase 2)

2013-04-01   Lewis Roberts , Chunling Hu 

Division of Gastroenterology, Hepatology, Mayo Clinic, Mayo Clinic Cancer Center, Rochester, MN 55905, USA

Identity

HGNC
LOCATION
20q13.12
LOCUSID
ALIAS
HSULF-2
FUSION GENES

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).

Proteins

Atlas Image
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

Atlas Image

Somatic

Identified mutations in various cancers.

Implicated in

Entity name
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 name
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 name
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

Atlas Image

Note

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

Bibliography

Pubmed IDLast YearTitleAuthors
215999972011SULFs in human neoplasia: implication as progression and prognosis factors.Bret C et al
191903382009Identification of SULF2 as a novel transcriptional target of p53 by use of integrated genomic analyses.Chau BN et al
161922652005HSulf-1 and HSulf-2 are potent inhibitors of myeloma tumor growth in vivo.Dai Y et al
219680182011Sulf2 gene is alternatively spliced in mammalian developing and tumour tissues with functional implications.Gill RB et al
207259052010The oncogenic effect of sulfatase 2 in human hepatocellular carcinoma is mediated in part by glypican 3-dependent Wnt activation.Lai JP et al
210404062010Sulfatase 2 protects hepatocellular carcinoma cells against apoptosis induced by the PI3K inhibitor LY294002 and ERK and JNK kinase inhibitors.Lai JP et al
190868472008Heparin-degrading sulfatases in hepatocellular carcinoma: roles in pathogenesis and therapy targets.Lai JP et al
186876752008Sulf loss influences N-, 2-O-, and 6-O-sulfation of multiple heparan sulfate proteoglycans and modulates fibroblast growth factor signaling.Lamanna WC et al
198554362010Sulf-2, a heparan sulfate endosulfatase, promotes human lung carcinogenesis.Lemjabbar-Alaoui H et al
163318862005Sulf-2, a proangiogenic heparan sulfate endosulfatase, is upregulated in breast cancer.Morimoto-Tomita M et al
185078592008Expression of novel extracellular sulfatases Sulf-1 and Sulf-2 in normal and osteoarthritic articular cartilage.Otsuki S et al
207079132010Human Sulfatase 2 inhibits in vivo tumor growth of MDA-MB-231 human breast cancer xenografts.Peterson SM et al
222931782012Heparan sulfate sulfatase SULF2 regulates PDGFRα signaling and growth in human and mouse malignant glioma.Phillips JJ et al
213474312011Glycomics analysis of mammalian heparan sulfates modified by the human extracellular sulfatase HSulf2.Staples GO et al
195208662009Functional consequences of the subdomain organization of the sulfs.Tang R et al
164176322006HSulf-2, an extracellular endoglucosamine-6-sulfatase, selectively mobilizes heparin-bound growth factors and chemokines: effects on VEGF, FGF-1, and SDF-1.Uchimura K et al
211047852011Sulfatase 1 and sulfatase 2 in hepatocellular carcinoma: associated signaling pathways, tumor phenotypes, and survival.Yang JD et al

Other Information

Locus ID:

NCBI: 55959
MIM: 610013
HGNC: 20392
Ensembl: ENSG00000196562

Variants:

dbSNP: 55959
ClinVar: 55959
TCGA: ENSG00000196562
COSMIC: SULF2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000196562ENST00000359930Q8IWU5
ENSG00000196562ENST00000437955B1AMP9
ENSG00000196562ENST00000467815Q8IWU5
ENSG00000196562ENST00000484875Q8IWU5
ENSG00000196562ENST00000495544H0Y872

Expression (GTEx)

0
50
100
150
200
250

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
123682952002Cloning and characterization of two extracellular heparin-degrading endosulfatases in mice and humans.134
164176322006HSulf-2, an extracellular endoglucosamine-6-sulfatase, selectively mobilizes heparin-bound growth factors and chemokines: effects on VEGF, FGF-1, and SDF-1.85
163318862005Sulf-2, a proangiogenic heparan sulfate endosulfatase, is upregulated in breast cancer.72
161922652005HSulf-1 and HSulf-2 are potent inhibitors of myeloma tumor growth in vivo.65
161922652005HSulf-1 and HSulf-2 are potent inhibitors of myeloma tumor growth in vivo.65
186876752008Sulf loss influences N-, 2-O-, and 6-O-sulfation of multiple heparan sulfate proteoglycans and modulates fibroblast growth factor signaling.58
198554362010Sulf-2, a heparan sulfate endosulfatase, promotes human lung carcinogenesis.56
207259052010The oncogenic effect of sulfatase 2 in human hepatocellular carcinoma is mediated in part by glypican 3-dependent Wnt activation.45
222931782012Heparan sulfate sulfatase SULF2 regulates PDGFRα signaling and growth in human and mouse malignant glioma.36
191903382009Identification of SULF2 as a novel transcriptional target of p53 by use of integrated genomic analyses.32

Citation

Lewis Roberts ; Chunling Hu

SULF2 (sulfatase 2)

Atlas Genet Cytogenet Oncol Haematol. 2013-04-01

Online version: http://atlasgeneticsoncology.org/gene/43735/sulf2