Affinage

SULF1

Extracellular sulfatase Sulf-1 · UniProt Q8IWU6

Length
871 aa
Mass
101.0 kDa
Annotated
2026-04-28
99 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SULF1 is a cell-surface and secreted heparan sulfate 6-O-endosulfatase that selectively removes 6-O-sulfate groups from trisulfated disaccharide units within heparan sulfate proteoglycan (HSPG) chains, thereby remodeling the sulfation code that governs growth factor–HSPG co-receptor interactions and downstream signaling. Its catalytic activity requires SUMF1-mediated conversion of the active-site cysteine to Cα-formylglycine, Ca²⁺, and N-linked glycosylation, while a unique positively charged hydrophilic domain mediates high-affinity, catch-bond-dependent engagement with HS substrate (PMID:41025518, PMID:25863062, PMID:17855356, PMID:19666466). By desulfating HSPGs, SULF1 diminishes HS-dependent co-receptor function for FGF-2, HGF, HB-EGF, VEGF165, and Wnt ligands, attenuating RTK, ERK, AKT, and Wnt/β-catenin signaling cascades; conversely, it can enhance GDNF signaling by releasing HS-sequestered ligand and restricts Shh morphogen gradient diffusion (PMID:12686563, PMID:14973553, PMID:16778174, PMID:17720696, PMID:24768893, PMID:21722266). Beyond development—where Sulf1/Sulf2 double knockouts exhibit neonatal lethality with skeletal and renal defects—SULF1 regulates glutamatergic transmission and dopamine-pathway-specific reward and aversion behaviors in the adult brain, and its epigenetic silencing or cancer-associated fibroblast-restricted expression modulates tumor growth, angiogenesis, metabolic reprogramming, and chemoresistance (PMID:17593974, PMID:41381361, PMID:41486756, PMID:17310998, PMID:26378042, PMID:41549062).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2003 High

    The key question of how HSPG sulfation is enzymatically regulated at the cell surface was answered by identifying HSulf-1 as a 6-O-endosulfatase that desulfates HSPGs and thereby attenuates RTK/ERK signaling downstream of FGF-2 and HB-EGF.

    Evidence Re-expression in ovarian cancer cells with measurement of HSPG sulfation, RTK phosphorylation, and ERK activation

    PMID:12686563

    Open questions at the time
    • Enzymatic specificity for particular HS disaccharide motifs not yet defined
    • In vivo relevance not established
  2. 2004 High

    The generality of HSulf-1's signaling suppression was extended beyond FGF/EGFR to HGF/c-Met, establishing that HSPG desulfation broadly dampens HS-dependent growth factor axes including AKT signaling and cell invasion.

    Evidence Stable HSulf-1 transfection in SCCHN cells; Western blot for phospho-c-Met, phospho-ERK, phospho-AKT; transwell invasion

    PMID:14973553

    Open questions at the time
    • Direct evidence for HSPG structural changes mediating c-Met attenuation not shown
    • Endogenous regulation of SULF1 expression unknown
  3. 2005 High

    In vivo tumor growth suppression by SULF1/SULF2 was demonstrated, establishing their functional equivalence and anti-tumorigenic role through cell-surface sulfatase activity.

    Evidence Stable transfection in myeloma cells; SCID mouse xenograft

    PMID:16192265

    Open questions at the time
    • Contribution of each sulfatase individually in vivo not resolved
    • Mechanism of ECM deposition promotion unclear
  4. 2006 High

    HSulf-1 was shown to regulate angiogenesis by disrupting the ternary FGF-2/FGFR1c/HS complex on endothelial cells, extending its function to the tumor microvasculature and HS-dependent growth factors VEGF165 and HGF.

    Evidence shRNA knockdown in HUVECs; co-IP of FGF-2/FGFR1c/HS; Matrigel plug and xenograft assays

    PMID:16778174

    Open questions at the time
    • Whether anti-angiogenic activity operates through endothelial-autonomous or paracrine mechanisms in vivo not fully distinguished
  5. 2007 High

    Several foundational questions were resolved simultaneously: Sulf1/Sulf2 double-knockout mice revealed neonatal lethality proving developmental essentiality and functional redundancy; Sulf1 was shown to enhance rather than inhibit GDNF signaling by releasing HS-sequestered ligand; N-glycosylation was identified as essential for enzymatic activity and membrane targeting; SULF1 silencing was attributed to promoter DNA methylation and histone methylation; and HSulf-1 loss was linked to autocrine EGFR-ERK activation via amphiregulin/HB-EGF.

    Evidence Double KO mice with phenotyping; GDNF binding and neurite sprouting in KO tissues; glycosylation mutants and heparin-binding assays; bisulfite sequencing and ChIP; shRNA with neutralizing antibodies in breast cancer cells

    PMID:17310998 PMID:17363371 PMID:17593974 PMID:17720696 PMID:17855356

    Open questions at the time
    • Whether single Sulf1 KO has subtle phenotypes masked by Sulf2 compensation remains unclear
    • Structural basis of N-glycosylation requirement not defined
  6. 2009 High

    The hydrophilic domain (HD) was established as the HS-binding module with nanomolar affinity essential for enzymatic function; substrate specificity was defined as selective for trisulfated UA2S-GlcNS6S disaccharides; and transcriptional regulation by HNF1β was identified.

    Evidence SPR with HD constructs; disaccharide HPLC analysis; PI-88 inhibitor studies; ChIP and reporter assays for HNF1β binding to SULF1 promoter

    PMID:19487294 PMID:19666466 PMID:19822709

    Open questions at the time
    • Structural model of HD–HS interaction lacking
    • Whether PI-88 inhibition is therapeutically relevant in vivo unknown
  7. 2011 High

    HIF-1α/HIF-2α were identified as direct transcriptional repressors of SULF1 under hypoxia, linking tumor microenvironment oxygen tension to HSPG sulfation state, and SULF1 was shown to inhibit Wnt/β-catenin signaling at the HSPG level upstream of intracellular pathway components.

    Evidence ChIP for HIF binding to SULF1 promoter HREs; Wnt reporter epistasis with Wnt3a rescue and β-catenin knockdown in gastric cancer cells

    PMID:21266348 PMID:21722266

    Open questions at the time
    • Whether hypoxic silencing of SULF1 is reversible upon reoxygenation not tested
    • Wnt ligand specificity of SULF1 inhibition not addressed
  8. 2012 High

    Organ-specific HS sulfation patterns were shown to be generated by differential Sulf1/Sulf2 activity in vivo, with Sulf1 mRNA levels correlating with tissue-specific HS desulfation.

    Evidence HPLC disaccharide analysis across organs from Sulf1 and Sulf2 KO mice

    PMID:22298771

    Open questions at the time
    • Whether organ-specific sulfation differences translate to differential growth factor responsiveness not tested
  9. 2013 High

    Sulf1's action on Wnt ligands was shown to be context-dependent: it facilitates Wingless/Wnt degradation by reducing HS binding in Drosophila, and the HD was found to use multiple cooperative HS-binding sites for processive chain editing.

    Evidence Drosophila wing disc Wg stability assays; AFM single-molecule force spectroscopy of HD subdomains

    PMID:23300081 PMID:23891937

    Open questions at the time
    • Whether processivity is required in vivo not demonstrated
    • Crystal structure of HD still unavailable
  10. 2014 High

    Sulf1 was placed in developmental morphogen gradient control (restricting Shh diffusion in neural tube) and vascular specification (promoting VEGFA165/Notch signaling in arterial fate), while in cancer its loss was shown to suppress Bim expression specifically through ERK pathway activation.

    Evidence Shh gradient imaging in Xenopus morphants; zebrafish morpholino with vegfa165 rescue; ERK/PI3K inhibitor epistasis in ovarian cancer cells

    PMID:23959107 PMID:24596063 PMID:24768893

    Open questions at the time
    • Whether Sulf1 acts on Shh directly or indirectly through HS-bound intermediates not resolved
    • In vivo relevance of Bim regulation not confirmed in patient samples
  11. 2015 High

    The biophysical mechanism of HD–HS interaction was defined as a catch bond dependent on 6-O-sulfation, providing a molecular explanation for how Sulf1 maintains productive engagement with its substrate; Sulf1 was also shown to have ligand-specific effects on Wnt signaling (inhibiting Wnt8a, enhancing Wnt11b) and to regulate cerebellar neuron survival and migration.

    Evidence AFM force-clamp spectroscopy; Wnt8a/Wnt11b signaling and imaging in Xenopus; primary cerebellar granule cells from Sulf1 KO mice

    PMID:25681501 PMID:25863062 PMID:26448642

    Open questions at the time
    • Whether catch bond mechanism applies to full-length enzyme on cell surfaces not confirmed
    • Wnt ligand selectivity mechanism not structurally explained
  12. 2015 High

    SULF1 loss was linked to metabolic reprogramming (Warburg effect) in ovarian cancer through HB-EGF/ERK/c-Myc–driven upregulation of glycolytic enzymes and inhibition of pyruvate dehydrogenase.

    Evidence Isotope tracer metabolomics; oxygen consumption; c-Myc inhibitor epistasis; PG545 treatment

    PMID:26378042

    Open questions at the time
    • Whether metabolic phenotype is reversible upon SULF1 restoration in vivo not tested
  13. 2017 High

    Sulf1/2-mediated HS desulfation was shown to be required for corticospinal tract axon guidance by controlling Slit2 protein distribution on brain surfaces, with rescue by in utero electroporation.

    Evidence Sulf1/2 double KO mice; Slit2 immunostaining; in utero electroporation rescue

    PMID:29062064

    Open questions at the time
    • Individual contribution of Sulf1 versus Sulf2 to CST guidance not separated
  14. 2019 Medium

    Unbiased genome-scale CRISPR screening independently confirmed SULF1 loss as a contributor to cisplatin resistance in ovarian cancer.

    Evidence GeCKO library screen with CCK-8 validation

    PMID:31218106

    Open questions at the time
    • Mechanism of resistance beyond prior ERK/Bim findings not defined
    • Single cell line used
  15. 2020 Medium

    SULF1 produced by bone marrow fibroblasts was shown to suppress Wnt3A-driven prostate cancer growth in a 3D biomimetic microenvironment, establishing its paracrine tumor-suppressive function in the stromal compartment.

    Evidence SULF1 KO fibroblasts in 3D perlecan-modified hydrogel triculture; Wnt3A stimulation

    PMID:32413029

    Open questions at the time
    • In vivo validation of fibroblast-derived SULF1 tumor suppression lacking
    • Whether SULF1 acts on perlecan HS specifically not tested
  16. 2024 Medium

    A new non-enzymatic function was proposed: CAF-secreted SULF1 physically binds TGFBR3 on cancer cells, interfering with TGF-β1/TGFBR3 interaction and activating TGF-β/SMAD signaling to promote metastasis, with a positive feedback loop identified in pulmonary fibrosis.

    Evidence Co-IP of SULF1–TGFBR3; CAF conditioned medium; SMAD pathway Western blots; in vivo xenograft; fibroblast functional assays

    PMID:38438372 PMID:39354547

    Open questions at the time
    • Whether the TGFBR3 interaction requires SULF1 enzymatic activity or is independent not tested
    • Reciprocal IP validation lacking for TGFBR3 interaction
    • Positive feedback loop not validated in vivo
  17. 2025 High

    Recombinant human SULF1 was fully reconstituted, confirming SUMF1-dependent Cα-formylglycine formation and Ca²⁺ as catalytic requirements, and a potent marine fucosylated chondroitin sulfate inhibitor was characterized; separately, SULF1–THBS2 interaction was linked to TGF-β1/SMAD2/3 signaling in colon cancer, with MARCHF1 identified as an E3 ligase targeting SULF1 for degradation.

    Evidence Recombinant expression in HEK293 with SUMF1 co-expression; kinetic analysis; Co-IP of SULF1–THBS2; MARCHF1 overexpression/knockdown

    PMID:41025518 PMID:41550717

    Open questions at the time
    • No crystal or cryo-EM structure of SULF1 available
    • MARCHF1-mediated degradation not validated in vivo
    • Whether fCS inhibitor has therapeutic utility untested
  18. 2026 High

    Cell-type-specific roles of Sulf1 in the adult brain were established: Sulf1 regulates neuronal excitability and AMPA/NMDA ratios in striatal MSNs, and conditional deletion in D1- versus D2-MSNs produces a double dissociation of reward versus aversion learning; CAF-derived SULF1 was also shown to non-redundantly promote HNSCC invasion.

    Evidence Whole-cell patch clamp in D1/D2-MSNs of Sulf1 KO mice; conditional KO with behavioral testing; CRISPR KO in primary CAFs with 3D spheroid coculture

    PMID:41381361 PMID:41486756 PMID:41549062

    Open questions at the time
    • Whether Sulf1 acts on synaptic HS to regulate glutamate receptor clustering or on growth factor signaling in neurons not distinguished
    • Molecular targets of Sulf1 in striatal circuits unidentified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Despite extensive functional characterization, no atomic-resolution structure of SULF1 exists, the precise mechanism by which HD-mediated catch-bond processivity operates on native cell-surface HS remains unresolved, and whether the newly described protein–protein interactions (TGFBR3, THBS2) are enzymatic-activity-dependent or represent independent binding functions is unknown.
  • No crystal or cryo-EM structure
  • Catch-bond processivity not demonstrated on native cell surfaces
  • Enzymatic versus non-enzymatic contributions to TGFBR3/THBS2 interactions unresolved
  • Neuronal substrates and HS-binding partners in brain circuits unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 4 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005576 extracellular region 3 GO:0005886 plasma membrane 3 GO:0031012 extracellular matrix 2
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-1266738 Developmental Biology 5 R-HSA-112316 Neuronal System 3 R-HSA-1430728 Metabolism 3
Partners
MARCHF1SUMF1TGFBR3THBS2

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 HSulf-1 is a cell surface-associated heparan sulfate 6-O-endosulfatase that removes 6-O-sulfate groups from cell surface HSPGs, thereby diminishing phosphorylation of receptor tyrosine kinases (including FGFR and EGFR family members) that require sulfated HSPGs as co-receptors, and attenuating downstream ERK signaling in response to FGF-2 and HB-EGF. Re-expression of HSulf-1 in ovarian cancer cell lines; measurement of HSPG sulfation, RTK phosphorylation, and ERK pathway activation The Journal of biological chemistry High 12686563
2004 HSulf-1 re-expression attenuates HGF-mediated phosphorylation of c-Met and downstream ERK/MAPK and Akt signaling, and reduces HGF-mediated cell motility and invasion in head and neck squamous carcinoma cells. Stable transfection of HSulf-1 in SCCHN cell lines; transwell invasion assay; Western blot for phospho-c-Met, phospho-ERK, phospho-Akt Oncogene High 14973553
2005 HSulf-1 and HSulf-2 have similar in vivo functions; their extracellular sulfatase activity is restricted to the local tumor cell surface, and their expression promotes extracellular matrix deposition within tumors while dramatically reducing myeloma tumor growth in SCID mice. Stable transfection of myeloma cells with HSulf-1 or HSulf-2 cDNA; in vivo SCID mouse xenograft model The Journal of biological chemistry High 16192265
2006 HSulf-1 expression in breast carcinoma cells inhibits angiogenesis in vivo by reducing the ability of vascular endothelial cell heparan sulfate to form a complex with FGF-2 and its receptor FGFR1c; shRNA knockdown of HSulf-1 in HUVECs enhances proliferation mediated by HS-dependent growth factors (FGF-2, HGF, VEGF165) but not HS-independent VEGF121. shRNA knockdown; Matrigel plug assay; CD31 staining; co-immunoprecipitation of FGF-2/FGFR1c/heparan sulfate complex; xenograft model Cancer research High 16778174
2007 SULF1 and SULF2 act as major regulators of heparan sulfate 6-O-desulfation in vivo; they reduce GDNF binding to HS and enhance GDNF signaling and neurite sprouting, functioning as essential regulators of GDNF-dependent neural innervation in the embryonic esophagus. Sulf1/Sulf2 double-knockout mice; biochemical HS sulfation analysis; GDNF binding assays; neurite sprouting assays; genetic epistasis Development (Cambridge, England) High 17720696
2007 Sulf1 and Sulf2 play overlapping yet critical roles in mouse development; neither single knockout showed significant flaws, but Sulf1/Sulf2 double knockout mice exhibited highly penetrant neonatal lethality with skeletal and renal abnormalities, demonstrating functional redundancy. Genetic knockout mice (Sulf1-/-, Sulf2-/-, double KO); phenotypic analysis of development and survival PloS one High 17593974
2007 Quail Sulf1 is an asparagine-linked glycosylated protein; N-linked glycosylation at sites in the enzymatic and C-terminal domains is essential for its enzymatic activity, membrane targeting, secretion, heparin binding, and 6-O-desulfation activity. Domain mapping with deletion mutants; glycosylation inhibitor studies; N-glycanase cleavage; heparin binding assays The Journal of biological chemistry High 17855356
2007 HSulf-1 loss in breast cancer cells triggers autocrine activation of the EGFR-ERK pathway through heparin-binding growth factors amphiregulin and HB-EGF; HSulf-1 inhibits this autocrine loop, reducing cyclin D1 levels and altering cell cycle distribution. shRNA-mediated HSulf-1 knockdown; neutralizing antibodies against amphiregulin and HB-EGF; Western blot for phospho-ERK, cyclin D1; cell cycle analysis The Journal of biological chemistry High 17363371
2007 HSulf-1 expression is epigenetically silenced in ovarian cancer through DNA methylation of CpG sites in exon 1A and histone H3 methylation at the promoter; 5-aza-2'-deoxycytidine treatment restores HSulf-1 transcription. Bisulfite sequencing; chromatin immunoprecipitation (ChIP) for histone H3 methylation; 5-aza-2'-deoxycytidine treatment Oncogene High 17310998
2009 The unique hydrophilic domain (HD) of Sulf1 (~320 amino acids, positively charged) is required for enzymatic activity and functions as a high-affinity heparin/heparan sulfate interaction domain with nanomolar affinity; the outer regions of the HD mediate HS binding, and substrate 6-O-sulfate groups are required for association, suggesting that substrate turnover facilitates enzyme release. HD deletion mutants; GST-HD fusion proteins; surface plasmon resonance; heparinase treatment; FGF-2 signaling assay The Journal of biological chemistry High 19666466
2009 HSulf-1 and HSulf-2 selectively remove 6-O-sulfate groups from N,6-O,2-O trisulfated disaccharides in intact heparan sulfate on the cell surface; both Sulf activities are potently inhibited by the sulfated heparin mimetic PI-88. Flow cytometry with anti-HS antibody RB4CD12; disaccharide analysis by HPLC; ELISA with purified recombinant enzymes; in vivo activity on brain microvessels Glycobiology High 19822709
2009 Variant hepatic nuclear factor 1 (vHNF1/HNF1β) is a transcriptional repressor of HSulf-1 in ovarian cancer; vHNF1 binds to two responsive elements in the HSulf-1 promoter and suppresses its expression, reducing sensitivity to cisplatin. shRNA knockdown of vHNF1; reporter assay; chromatin immunoprecipitation (ChIP); xenograft model with cisplatin treatment Cancer research High 19487294
2009 Promoter hypermethylation of the HSulf-1 gene's 5' regulatory region (approximately 400 bp) correlates with HSulf-1 silencing in human breast and gastric cancer cell lines and tissue samples. Cloning of 5' promoter region; bisulfite sequencing; correlation of methylation with expression International journal of cancer Medium 19006069
2009 A novel shorter SULF1 splice variant (SULF1B) antagonizes the canonical SULF1A: while SULF1A enhances Wnt signalling, SULF1B inhibits Wnt signalling and promotes angiogenesis, with both isoforms expressed in a developmental stage-specific manner. Cloning and expression of SULF1 splice variants; Wnt signaling reporter assays; angiogenesis assays; expression analysis in developing tissues Experimental cell research Medium 19577565
2011 HSulf-1 inhibits autocrine EGFR-ERK signaling through heparin-binding growth factors in breast cancer cells; HSulf-1 expression is transcriptionally repressed under hypoxia via HIF-1α and HIF-2α binding to two functional hypoxia-responsive elements on the native HSulf-1 promoter. HIF-1α knockdown; chromatin immunoprecipitation with HIF-1α and HIF-2α antibodies; shRNA depletion; bFGF2 signaling assays; invasion assays Cancer research High 21266348
2011 HSulf-1 re-expression downregulates VEGFR-2 phosphorylation in ovarian and hepatocellular cancer cells, suppressing angiogenesis; shRNA knockdown of HSulf-1 enhances phospho-VEGFR-2 recovery. HSulf-1 expression vectors and shRNA; Western blot for phospho-VEGFR-2; xenograft tumor model; microvessel density analysis PloS one Medium 21853101
2011 HSulf-1 inhibits Wnt/β-catenin signaling at the cell surface in gastric cancer cells that depend on extracellular Wnt signaling (MKN28), but has no effect in cells with constitutively active intracellular Wnt pathway (AGS), demonstrating that Sulf1 modulates Wnt signaling upstream at the HSPG level. HSulf-1 transfection; Wnt/β-catenin reporter assay; Wnt3a cDNA rescue; β-catenin shRNA; HSPG epitope analysis Cancer science High 21722266
2012 Sulf1 and Sulf2 differentially generate organ-specific sulfation patterns of heparan sulfate in vivo; Sulf1 predominantly acts on UA2S-GlcNS6S trisulfated disaccharides, and Sulf1 mRNA expression levels in different organs correlate with the degree of HS desulfation in those organs. Disaccharide analysis of heparan sulfate from Sulf1 and Sulf2 knockout mice by HPLC; organ-specific expression analysis The Journal of biological chemistry High 22298771
2013 Sulf1 (and human Sulf1 expressed in Drosophila) inhibits the binding of Wingless/Wnt to Dally (an HSPG), reduces extracellular Wg protein levels by facilitating Wg degradation, and negatively regulates Wg/Wnt signaling; the fate of Wnt ligands upon Sulf action is context-dependent. In vitro, in vivo, and ex vivo systems in Drosophila; HS-Wg interaction assays; Wg stability measurement; human Sulf1 expression in Drosophila wing disc The Journal of biological chemistry High 23300081
2013 The hydrophilic domain (HD) of Sulf1 contains at least two separate HS-binding sites (inner and C-terminal regions) that cooperate for processive enzymatic action along HS chains; full-length Sulf1 shows broader GAG interaction while HD alone is highly specific for HS/heparin containing 6-O-sulfate substrate groups. Affinity chromatography; AFM single-molecule force spectroscopy; immunofluorescence on living cells; HD subdomain constructs Biochimica et biophysica acta High 23891937
2013 TNF-α induces Sulf-1 expression in fibroblasts via NF-κB, ERK1/2, and p38 MAPK signaling, leading to 6-O-desulfation of cell surface HS and attenuation of FGF-1-mediated ERK1/2 activation and cell proliferation; siRNA silencing of Sulf-1 restores FGF-1 responsiveness. TNF-α treatment of MRC-5 fibroblasts; HS compositional analysis; siRNA knockdown; ERK1/2 activation assay; proliferation assay The international journal of biochemistry & cell biology Medium 27693418
2014 Loss of HSulf-1 promotes tumorigenicity in ovarian cancer by decreasing Bim (pro-apoptotic) expression through increased p-ERK; ERK inhibition with PD98059 restores Bim levels, while PI3K/AKT inhibition does not, placing HSulf-1's effect on Bim specifically in the ERK pathway. shRNA knockdown; re-expression constructs; pharmacological inhibitors (PD98059, LY294002); Western blot for Bim; soft agar colony assay; xenograft model International journal of cancer High 24596063
2014 Sulf1 modulates BMP and FGF signaling during zebrafish trunk development: sulf1 knockdown decreases Pax7-expressing dermomyotome cells and sdf1/cxcl12 expression, both of which are restored by BMP signaling inhibition, while FGF signaling activation rescues neuromast deposition. Antisense morpholino knockdown in zebrafish; pharmacological inhibition/activation of BMP and FGF; in situ hybridization for pathway markers Developmental biology High 23583585
2014 Sulf1 restricts Shh ligand diffusion in the Xenopus neural tube by promoting ventral accumulation of Shh protein; Sulf1 knockdown leads to a less steep Shh gradient and altered ventral neural progenitor specification. Single-cell mRNA injection of GFP-tagged Shh; morpholino knockdown; in situ hybridization for Shh protein distribution and neural progenitor markers Developmental biology High 24768893
2014 Sulf1 plays an essential role in arterial specification in zebrafish by promoting VegfA165-mediated signaling; sulf1 morphants show reduced Notch and ephrinB2 expression in the dorsal aorta with increased venous marker flt4, rescued by vegfa165 mRNA co-injection. Antisense morpholino knockdown in zebrafish; vegfa165 mRNA rescue; in situ hybridization for arterial/venous markers; in vitro VEGFA-mediated signaling assays Angiogenesis High 23959107
2015 The HD of Sulf1 exhibits catch bond behavior with heparan sulfate; the catch bond character is attributed specifically to the 6-O-sulfation site on GAGs (slip bond only without 6-O-sulfation), characterized by two coupled slip-bond states with an energy difference of ~9 kBT. AFM-based force clamp spectroscopy; dynamic force spectroscopy; two-state two-path model analysis Biophysical journal High 25863062
2015 Sulf1 has ligand-specific effects on Wnt signaling: it inhibits canonical Wnt8a signaling while enhancing non-canonical Wnt11b activity, and differentially affects membrane accumulation and extracellular levels of Wnt8a versus Wnt11b ligands. Wnt signaling assays in Xenopus; fluorescently tagged Wnt ligand imaging in ectodermal explants; Sulf1 overexpression Journal of cell science Medium 25681501
2015 Sulf1 deficiency in cerebellar granule cells results in reduced neurite length, reduced cell survival, and reduced migration capacity, correlated with Sulf-specific interference with FGF2, GDNF, and NGF signaling pathways; Sulf2 deficiency alters a specific HS epitope on cerebellar neuron surfaces. Primary cerebellar granule cells from Sulf1/Sulf2 knockout mice; neurite length measurement; survival assays; migration assays; biochemical HS analysis; HS epitope detection PloS one High 26448642
2015 HSulf-1 loss promotes aerobic glycolysis (Warburg effect) in ovarian cancer by upregulating glycolytic genes (Glut1, HKII, LDHA) and blocking glucose entry into the TCA cycle via increased inhibitory phosphorylation of pyruvate dehydrogenase; mechanistically, HSulf-1 loss promotes c-Myc induction through HB-EGF-mediated p-ERK activation. shRNA silencing; HSulf-1 overexpression; metabolomic profiling; isotope tracer analysis; oxygen consumption rate measurement; pharmacological c-Myc inhibition; PG545 treatment Oncotarget High 26378042
2017 Desulfation of heparan sulfate by Sulf1 and Sulf2 is required for corticospinal tract axon guidance; in Sulf1/2 double KO mice, increased 6-O-sulfated HS causes abnormal accumulation of Slit2 protein on brain surfaces, leading to dorsal repulsion of CST axons; in utero electroporation of Sulf1/2 into radial glial cells rescues the CST defects. Sulf1/2 double KO mice; in utero electroporation rescue; proteomic analysis; Slit2 protein localization by immunostaining; HS sulfation analysis Scientific reports High 29062064
2019 CRISPR/Cas9 genome-scale knockout screening confirmed SULF1 loss as contributing to cisplatin resistance in ovarian cancer cell lines, validated by CCK-8 and RT-PCR analysis. Genome-scale CRISPR/Cas9 knockout (GeCKO) screening; CCK-8 viability assay; RT-PCR American journal of cancer research Medium 31218106
2020 SULF1, produced primarily by bone marrow fibroblasts, suppresses Wnt3A-driven growth of prostate cancer cells in a 3D perlecan-modified triculture model; M2-like macrophages increase SULF1 and HSPG2 levels in fibroblasts, and SULF1 knockout fibroblasts fail to suppress Wnt3A-mediated PCa tumoroid growth. SULF1 knockout fibroblasts; 3D bone marrow biomimetic hydrogel triculture model; co-culture with macrophages; Wnt3A treatment; tumoroid growth measurement PloS one Medium 32413029
2024 Cancer-associated fibroblast-secreted SULF1 binds to TGFBR3 on gastric cancer cell membranes, interferes with the TGF-β1/TGFBR3 interaction, and subsequently activates TGF-β signaling to promote cancer cell metastasis and cisplatin resistance. Co-immunoprecipitation; CAF-derived conditioned medium experiments; SULF1 overexpression/knockdown; Western blot for TGF-β pathway components; in vivo xenograft Cell death discovery Medium 38438372
2024 SULF1 promotes pulmonary fibrosis by catalyzing the release of TGF-β1 bound to TGFβRIII (TGFBR3), thereby activating the TGF-β1/SMAD pathway; TGF-β1 in turn induces SULF1 expression through the TGF-β1/SMAD pathway, creating a positive feedback loop. Co-immunoprecipitation; SULF1 shRNA knockdown in HFL1 fibroblasts; Western blot for SMAD pathway; TGF-β1 ELISA; fibroblast functional assays (proliferation, migration, invasion) Journal of translational medicine Medium 39354547
2025 Active human SULF1 requires co-expression of sulfatase-modifying factor 1 (SUMF1) for full enzymatic activity, which depends on conversion of the active site cysteine to Cα-formylglycine and the presence of a Ca2+ ion; marine fucosylated chondroitin sulfate inhibits SULF1 with IC50 ~0.05 μg/mL in mixed-mode inhibition. Recombinant protein expression in HEK293 cells; co-expression with SUMF1; enzymatic activity assays; kinetic analysis; inhibitor characterization Glycobiology High 41025518
2025 SULF1 interacts with thrombospondin-2 (THBS2) to regulate the TGF-β1/SMAD2/3 pathway in colon cancer; MARCHF1 ubiquitin ligase accelerates SULF1 protein degradation, thereby suppressing SULF1-driven tumor progression and 5-FU resistance. Co-immunoprecipitation of SULF1 with THBS2; MARCHF1 overexpression/knockdown; Western blot for SMAD2/3; proliferation, migration, and invasion assays; 5-FU sensitivity assay iScience Medium 41550717
2026 Sulf1 disruption in D2-MSNs of the nucleus accumbens shell alters neural firing (smaller rheobase but blunted response to larger current), and in D1-MSNs leads to more depolarized resting membrane potentials and increased AMPA/NMDA ratio, demonstrating that Sulf1 is required for regulation of neuronal excitability and glutamatergic transmission in the adult brain. Sulf1 knockout mice; whole-cell patch-clamp recording in D1-MSNs and D2-MSNs labeled with Cre-dependent AAV-mCherry eNeuro High 41381361
2026 Sulf1 conditional knockout in D1 receptor-expressing cells impairs cocaine-induced conditioned place preference (reward learning), while Sulf1 conditional knockout in D2 receptor-expressing cells impairs inhibitory avoidance (aversion learning), demonstrating pathway-specific roles of Sulf1 in reward and aversion circuits. Sulf1 floxed mice generated by CRISPR-Cas9; Cre-mediated conditional KO in D1-Cre and D2-Cre mice; conditioned place preference and inhibitory avoidance behavioral tests Journal of neurochemistry High 41486756
2026 SULF1 derived from cancer-associated fibroblasts promotes invasion of head and neck squamous cell carcinoma cells; CRISPR/Cas9-mediated SULF1 knockout in primary HNSCC CAFs reduces fibroblast proliferation and markedly impairs cancer cell migration and invasion in 2D and 3D spheroid coculture models; SULF2 expressed in tumor cells does not compensate for SULF1 loss. CRISPR/Cas9 SULF1 knockout in primary CAFs; 2D migration/invasion assays; 3D spheroid coculture with two-photon microscopy; proteomic analysis Cancer medicine Medium 41549062

Source papers

Stage 0 corpus · 99 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Loss of HSulf-1 up-regulates heparin-binding growth factor signaling in cancer. The Journal of biological chemistry 204 12686563
2013 MicroRNA-21 suppresses PTEN and hSulf-1 expression and promotes hepatocellular carcinoma progression through AKT/ERK pathways. Cancer letters 159 23684551
2007 SULF1 and SULF2 regulate heparan sulfate-mediated GDNF signaling for esophageal innervation. Development (Cambridge, England) 144 17720696
2006 HSulf-1 inhibits angiogenesis and tumorigenesis in vivo. Cancer research 121 16778174
2005 HSulf-1 and HSulf-2 are potent inhibitors of myeloma tumor growth in vivo. The Journal of biological chemistry 117 16192265
2004 HSulf-1 modulates HGF-mediated tumor cell invasion and signaling in head and neck squamous carcinoma. Oncogene 117 14973553
2007 Secreted sulfatases Sulf1 and Sulf2 have overlapping yet essential roles in mouse neonatal survival. PloS one 101 17593974
2007 Epigenetic silencing of HSulf-1 in ovarian cancer:implications in chemoresistance. Oncogene 93 17310998
2009 The tumor suppressor function of human sulfatase 1 (SULF1) in carcinogenesis. Journal of gastrointestinal cancer 80 19373441
2005 Enhanced levels of Hsulf-1 interfere with heparin-binding growth factor signaling in pancreatic cancer. Molecular cancer 78 15817123
2008 Redundant function of the heparan sulfate 6-O-endosulfatases Sulf1 and Sulf2 during skeletal development. Developmental dynamics : an official publication of the American Association of Anatomists 77 18213582
2009 Direct detection of HSulf-1 and HSulf-2 activities on extracellular heparan sulfate and their inhibition by PI-88. Glycobiology 75 19822709
2012 Organ-specific sulfation patterns of heparan sulfate generated by extracellular sulfatases Sulf1 and Sulf2 in mice. The Journal of biological chemistry 71 22298771
2009 Characterization of the human sulfatase Sulf1 and its high affinity heparin/heparan sulfate interaction domain. The Journal of biological chemistry 65 19666466
2007 Loss of HSulf-1 expression enhances autocrine signaling mediated by amphiregulin in breast cancer. The Journal of biological chemistry 64 17363371
2006 SULF1 inhibits tumor growth and potentiates the effects of histone deacetylase inhibitors in hepatocellular carcinoma. Gastroenterology 63 16762634
2011 Identification of MST1/STK4 and SULF1 proteins as autoantibody targets for the diagnosis of colorectal cancer by using phage microarrays. Molecular & cellular proteomics : MCP 59 21228115
2008 Expression of novel extracellular sulfatases Sulf-1 and Sulf-2 in normal and osteoarthritic articular cartilage. Arthritis research & therapy 54 18507859
2011 HSulf-1 modulates FGF2- and hypoxia-mediated migration and invasion of breast cancer cells. Cancer research 50 21266348
2009 Promoter hypermethylation correlates with the Hsulf-1 silencing in human breast and gastric cancer. International journal of cancer 43 19006069
2010 Mesomelia-synostoses syndrome results from deletion of SULF1 and SLCO5A1 genes at 8q13. American journal of human genetics 42 20602915
2015 Sulf1 and Sulf2 Differentially Modulate Heparan Sulfate Proteoglycan Sulfation during Postnatal Cerebellum Development: Evidence for Neuroprotective and Neurite Outgrowth Promoting Functions. PloS one 41 26448642
2009 Regulation of HSulf-1 expression by variant hepatic nuclear factor 1 in ovarian cancer. Cancer research 39 19487294
2019 Loss of ZNF587B and SULF1 contributed to cisplatin resistance in ovarian cancer cell lines based on Genome-scale CRISPR/Cas9 screening. American journal of cancer research 37 31218106
2009 A novel SULF1 splice variant inhibits Wnt signalling but enhances angiogenesis by opposing SULF1 activity. Experimental cell research 33 19577565
2012 HSULF-1 inhibits ERK and AKT signaling and decreases cell viability in vitro in human lung epithelial cells. Respiratory research 30 22873647
2006 Hsulf-1 regulates growth and invasion of pancreatic cancer cells. Journal of clinical pathology 30 16603650
2014 Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer. Cancer & metabolism 29 25225614
2007 Quail Sulf1 function requires asparagine-linked glycosylation. The Journal of biological chemistry 28 17855356
2020 LncRNA NEAT1 regulated cell proliferation, invasion, migration and apoptosis by targeting has-miR-376b-3p/SULF1 axis in non-small cell lung cancer. European review for medical and pharmacological sciences 26 32432744
2015 HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer. Oncotarget 26 26378042
2011 HSulf-1 inhibits cell proliferation and invasion in human gastric cancer. Cancer science 26 21722266
2006 Sulf1 expression pattern and its role in cartilage and joint development. Developmental dynamics : an official publication of the American Association of Anatomists 26 17061267
2013 Drosophila heparan sulfate 6-O-endosulfatase Sulf1 facilitates wingless (Wg) protein degradation. The Journal of biological chemistry 24 23300081
2011 hSulf-1 gene exhibits anticancer efficacy through negatively regulating VEGFR-2 signaling in human cancers. PloS one 24 21853101
2020 SULF1 suppresses Wnt3A-driven growth of bone metastatic prostate cancer in perlecan-modified 3D cancer-stroma-macrophage triculture models. PloS one 22 32413029
2016 Heparan sulfate 6-O-endosulfatases, Sulf1 and Sulf2, regulate glomerular integrity by modulating growth factor signaling. American journal of physiology. Renal physiology 22 26764203
2016 Drosophila Sulf1 is required for the termination of intestinal stem cell division during regeneration. Journal of cell science 22 27888216
2015 Sulf1 has ligand-dependent effects on canonical and non-canonical Wnt signalling. Journal of cell science 22 25681501
2014 Sulf1 influences the Shh morphogen gradient during the dorsal ventral patterning of the neural tube in Xenopus tropicalis. Developmental biology 22 24768893
2013 Sulf1 modulates BMP signaling and is required for somite morphogenesis and development of the horizontal myoseptum. Developmental biology 22 23583585
2012 Mammalian Sulf1 RNA alternative splicing and its significance to tumour growth regulation. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 22 22700218
2022 Extracellular Heparan 6-O-Endosulfatases SULF1 and SULF2 in Head and Neck Squamous Cell Carcinoma and Other Malignancies. Cancers 21 36428645
2015 Catch bond interaction between cell-surface sulfatase Sulf1 and glycosaminoglycans. Biophysical journal 21 25863062
2015 Expression of Sulf1 and Sulf2 in cartilage, bone and endochondral fracture healing. Histochemistry and cell biology 21 26464246
2012 The enhanced antitumor effects of biodegradable cationic heparin-polyethyleneimine nanogels delivering HSulf-1 gene combined with cisplatin on ovarian cancer. International journal of oncology 21 22825572
2011 Polymorphisms in the SULF1 gene are associated with early age of onset and survival of ovarian cancer. Journal of experimental & clinical cancer research : CR 21 21214932
2024 Cancer associated fibroblasts-derived SULF1 promotes gastric cancer metastasis and CDDP resistance through the TGFBR3-mediated TGF-β signaling pathway. Cell death discovery 20 38438372
2014 SULF1/SULF2 splice variants differentially regulate pancreatic tumour growth progression. Experimental cell research 18 24726914
2014 Sulf1 and Sulf2 expression in the nervous system and its role in limiting neurite outgrowth in vitro. Experimental neurology 18 25448158
2017 Desulfation of Heparan Sulfate by Sulf1 and Sulf2 Is Required for Corticospinal Tract Formation. Scientific reports 17 29062064
2024 CircNSD1 promotes cardiac fibrosis through targeting the miR-429-3p/SULF1/Wnt/β-catenin signaling pathway. Acta pharmacologica Sinica 16 38760544
2016 SULF1/SULF2 reactivation during liver damage and tumour growth. Histochemistry and cell biology 16 27013228
2014 Loss of HSulf-1 expression enhances tumorigenicity by inhibiting Bim expression in ovarian cancer. International journal of cancer 16 24596063
2012 Distinct expression patterns of Sulf1 and Hs6st1 spatially regulate heparan sulfate sulfation during prostate development. Developmental dynamics : an official publication of the American Association of Anatomists 16 23074159
2017 Loss of HSulf-1: The Missing Link between Autophagy and Lipid Droplets in Ovarian Cancer. Scientific reports 15 28169314
2014 The heparan sulfate editing enzyme Sulf1 plays a novel role in zebrafish VegfA mediated arterial venous identity. Angiogenesis 15 23959107
2014 Sulfatase 1 (hSulf-1) reverses basic fibroblast growth factor-stimulated signaling and inhibits growth of hepatocellular carcinoma in animal model. Oncotarget 15 24970807
2016 Tumour-necrosis factor-α induces heparan sulfate 6-O-endosulfatase 1 (Sulf-1) expression in fibroblasts. The international journal of biochemistry & cell biology 13 27693418
2013 Cooperation of binding sites at the hydrophilic domain of cell-surface sulfatase Sulf1 allows for dynamic interaction of the enzyme with its substrate heparan sulfate. Biochimica et biophysica acta 13 23891937
2011 Efficient inhibition of an intraperitoneal xenograft model of human ovarian cancer by HSulf-1 gene delivered by biodegradable cationic heparin-polyethyleneimine nanogels. Oncology reports 13 22086394
2020 HSulf‑1 and palbociclib exert synergistic antitumor effects on RB‑positive triple‑negative breast cancer. International journal of oncology 12 32377705
2013 The association of arylendosulfatase 1 (SULF1) gene polymorphism with recurrent miscarriage. Journal of assisted reproduction and genetics 12 24322345
2018 Genetic variations in the SULF1 gene alter the risk of cervical cancer and precancerous lesions. Oncology letters 11 30127996
2016 Short SULF1/SULF2 splice variants predominate in mammary tumours with a potential to facilitate receptor tyrosine kinase-mediated cell signalling. Histochemistry and cell biology 11 27294358
2014 Expression of the heparan sulfate 6-O-endosulfatases, Sulf1 and Sulf2, in the avian and mammalian inner ear suggests a role for sulfation during inner ear development. Developmental dynamics : an official publication of the American Association of Anatomists 11 25370455
2012 SULF1 inhibits proliferation and invasion of esophageal squamous cell carcinoma cells by decreasing heparin-binding growth factor signaling. Digestive diseases and sciences 11 23053899
2011 HSulf-1 suppresses cell growth and down-regulates Hedgehog signaling in human gastric cancer cells. Oncology letters 10 22848304
2024 SULF1 expression is increased and promotes fibrosis through the TGF-β1/SMAD pathway in idiopathic pulmonary fibrosis. Journal of translational medicine 9 39354547
2020 Abnormal Pyramidal Decussation and Bilateral Projection of the Corticospinal Tract Axons in Mice Lacking the Heparan Sulfate Endosulfatases, Sulf1 and Sulf2. Frontiers in molecular neuroscience 9 32038163
2013 Endosulfatases SULF1 and SULF2 limit Chlamydia muridarum infection. Cellular microbiology 9 23480519
2024 SULF1 regulates malignant progression of colorectal cancer by modulating ARSH via FAK/PI3K/AKT/mTOR signaling. Cancer cell international 8 38844922
2015 Restoration of epigenetically silenced SULF1 expression by 5-aza-2-deoxycytidine sensitizes hepatocellular carcinoma cells to chemotherapy-induced apoptosis. Medical epigenetics 8 26236329
2020 Development of novel monoclonal antibodies and immunoassays for sensitive and specific detection of SULF1 endosulfatase. Biochimica et biophysica acta. General subjects 7 33276062
2016 Single-nucleotide polymorphism in microRNA-binding site of SULF1 target gene as a protective factor against the susceptibility to breast cancer: a case-control study. OncoTargets and therapy 7 27274271
2014 Association of the SNP rs2623047 in the HSPG modification enzyme SULF1 with an Australian Caucasian breast cancer cohort. Gene 7 24911625
2007 FGF mediated Sulf1 regulation. FEBS letters 7 17905233
2024 SULF1 Activates the VEGFR2/PI3K/AKT Pathway to Promote the Development of Cervical Cancer. Current cancer drug targets 6 37539927
2022 Context Dependent Sulf1/Sulf2 Functional Divergence in Endothelial Cell Activity. International journal of molecular sciences 6 35409127
2019 Sulfatases, in Particular Sulf1, Are Important for the Integrity of the Glomerular Filtration Barrier in Zebrafish. BioMed research international 5 31428635
2014 hSulf-1 inhibits cell proliferation and migration and promotes apoptosis by suppressing stat3 signaling in hepatocellular carcinoma. Oncology letters 5 24944651
2009 Expression analysis of Sulf1 in the chick forebrain at early and late stages of development. Developmental dynamics : an official publication of the American Association of Anatomists 5 19653319
2018 Multi-tasking Sulf1/Sulf2 enzymes do not only facilitate extracellular cell signalling but also participate in cell cycle related nuclear events. Experimental cell research 4 29360432
2023 [Identification of SULF1 as a Shared Gene in Idiopathic Pulmonary Fibrosis
and Lung Adenocarcinoma]. Zhongguo fei ai za zhi = Chinese journal of lung cancer 3 37985153
2021 Expression of Heparan Sulfate Endosulfatases in the Adult Mouse Brain: Co-expression of Sulf1 and Dopamine D1/D2 Receptors. Frontiers in neuroanatomy 3 34489650
2022 Role of Prosaposin and Extracellular Sulfatase Sulf-1 Detection in Pleural Effusions as Diagnostic Biomarkers of Malignant Mesothelioma. Biomedicines 2 36359323
2015 SULF 1 gene polymorphism, rs6990375 is in significant association with fetus failure in IVF technique. Iranian journal of reproductive medicine 2 26131010
2026 Altered Excitability and Glutamatergic Synaptic Transmission in the Medium Spiny Neurons of the Nucleus Accumbens in Mice Deficient in the Heparan Sulfate Endosulfatase Sulf1. eNeuro 1 41381361
2026 Essential Roles of Heparan Sulfate Endosulfatase Sulf1 in Reward and Aversion Learning Through Distinct Dopamine D1 and D2 Receptor Pathways in Male Mice. Journal of neurochemistry 1 41486756
2026 SULF1 in Cancer Associated Fibroblasts Promotes Invasion in Head and Neck Cancer Cell Lines. Cancer medicine 1 41549062
2026 SULF1 and EPB41L3: Potential Biomarkers of Acute Myocardial Infarction and the Vascular Inflammatory Milieu. Journal of inflammation research 0 41918590
2026 Secreted SULF1 protein modulates CD8 + T cell exhaustion by promoting TAM polarization in gastric cancer. Genes and immunity 0 41986482
2025 Production and inhibition of human Heparan 6-O-Endosulfatase SULF1. Glycobiology 0 41025518
2025 DCN, NPM3 and SULF1 are hub genes related to vasculogenic mimicry in lung adenocarcinoma. Journal of cancer research and clinical oncology 0 41205056
2025 Circulating miR-378a-3p Screens End-Stage Renal Disease Patients, Predicts the Occurrence of MACEs, and Regulates Vascular Calcification via Targeting SULF1. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 0 41376260
2025 SULF1's Role in Endothelial Senescence and Atherosclerosis: Insights from Single-Cell and Bulk Transcriptomics. Journal of inflammation research 0 41426245
2025 MARCHF1-mediated SULF1 degradation blocks THBS2/TGF-β/SMAD2/3 signaling to reverse colon cancer metastasis and 5-FU resistance. iScience 0 41550717
2024 Mesomelia-synostoses syndrome: contiguous deletion syndrome, SULF1 haploinsufficiency or enhancer adoption? Molecular cytogenetics 0 38992676
2024 Genetic variants of FER and SULF1 in the fibroblast-related genes are associated with non-small-cell lung cancer survival. International journal of cancer 0 39707607