Affinage

SPINT2

Kunitz-type protease inhibitor 2 · UniProt O43291

Length
252 aa
Mass
28.2 kDa
Annotated
2026-06-10
84 papers in source corpus 39 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 10/10 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SPINT2 encodes HAI-2, a Kunitz-type serine protease inhibitor that governs pericellular proteolysis in epithelia and during development by restraining a network of membrane-anchored and soluble serine proteases (PMID:15792801, PMID:19592578, PMID:22952456). Its prototypic activity is inhibition of pro-HGF activation, blocking conversion to active HGF via Kunitz domain 1 (KD1) (PMID:15792801), and KD1 is the principal determinant of its anti-invasive, tumor-suppressive function (PMID:19107935). In vivo, HAI-2 is essential for placental and neural tube development, and its core function is inhibition of matriptase: genetic loss of matriptase rescues the lethality of Spint2-null mice (PMID:19592578). HAI-2 sits in a proteolytic cascade with prostasin acting downstream of matriptase and upstream of HAI-2 (PMID:22952456), and it regulates prostasin-driven matriptase zymogen activation, controlling matriptase stability, maturation/secretory transport, and catalytic activity as separable activities (PMID:24962579, PMID:28371047, PMID:32338287). HAI-2 inhibits a broad protease panel including matriptase-2 (elevating hepcidin via the hemojuvelin axis) (PMID:23293962), TMPRSS2 (PMID:32778768), prostasin and TMPRSS13 (PMID:24722141), and plasmin (PMID:30765871), with KD1 and KD2 contributing distinct specificities and prostasin requiring an exosite on KD2 in addition to the KD1 binding loop (PMID:24722141, PMID:30445423). Cell-type-selective function is set by subcellular localization: complex-type N-glycosylation at Asn-57 and intracellular targeting motifs determine whether HAI-2 is ER-retained, granule-resident, or cell-surface, dictating whether it engages active proteases (PMID:26171609, PMID:29438412, PMID:34643933, PMID:36637420). In intestinal epithelium, HAI-2 loss causes excessive prostasin proteolysis, disrupting barrier junctional proteins (EpCAM, E-cadherin, claudins) and producing tufting enteropathy through a matriptase/prostasin-dependent, EpCAM-cleavage-independent route (PMID:29617460, PMID:34089062, PMID:37539662). Loss-of-function SPINT2 mutations cause syndromic congenital sodium diarrhea, acting through loss of protease inhibition; KD2 missense mutations inactivate HAI-2 by inducing disulfide-linked oligomerization and trapping immature protein, selectively abolishing prostasin inhibition (PMID:19185281, PMID:30445423, PMID:38271183). SPINT2 is epigenetically silenced by promoter hypermethylation across cancers, derepressing HGF-MET signaling and promoting invasion (PMID:25910030, PMID:30838489). HAI-2 additionally restricts viral entry by blocking host-protease cleavage of influenza hemagglutinin and limiting SARS-CoV-2 infection through TMPRSS2 inhibition (PMID:24978308, PMID:32056846, PMID:34181691).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 2005 High

    Established that HAI-2 is a potent serine protease inhibitor whose anti-HGF-activation function maps to Kunitz domain 1, defining its core biochemical mechanism.

    Evidence In vitro enzymatic assay with recombinant hepsin and Kunitz-domain mutagenesis

    PMID:15792801

    Open questions at the time
    • Did not establish the in vivo relevance of hepsin as a target
    • KD2 contribution not addressed
  2. 2005 Medium

    Linked HAI-2 inhibitory function to tumor suppression, showing re-expression suppresses colony formation while a patient-derived missense mutant is inactive.

    Evidence Wild-type vs P111S re-expression in RCC cells with colony/motility assays and pathway inhibitors

    PMID:15930277

    Open questions at the time
    • Specific protease target driving the phenotype not identified
    • ERK/PLC-gamma dependence shown pharmacologically only
  3. 2009 High

    Demonstrated in vivo that the essential developmental function of HAI-2 is matriptase inhibition, via double-knockout rescue of lethality.

    Evidence Spint2/St14 double-knockout genetic epistasis in mice with placental and neural tube phenotyping

    PMID:19592578

    Open questions at the time
    • Identity of the additional protease driving residual neural tube defects unresolved
  4. 2009 High

    Established SPINT2 as the causative gene for syndromic congenital sodium diarrhea and tied disease to loss of protease-inhibitory activity.

    Evidence Human genetic linkage in families plus in vitro trypsin inhibition assays with mutant proteins

    PMID:19185281

    Open questions at the time
    • Physiological protease responsible for sodium homeostasis not pinpointed at the time
  5. 2012 High

    Placed HAI-2 within an ordered proteolytic cascade, showing prostasin acts downstream of matriptase and upstream of HAI-2, with prostasin paradoxically required for matriptase activation.

    Evidence Compound knockout mice (HAI-2/Prss8, c-Met, PAR-2, ENaC) and biochemical activation analysis in placenta

    PMID:22952456

    Open questions at the time
    • Molecular basis of prostasin-dependent matriptase activation not fully resolved
  6. 2013 Medium

    Expanded the target repertoire to matriptase-2 and connected HAI-2 to iron homeostasis through hepcidin regulation.

    Evidence Co-IP complex isolation and HAMP mRNA measurement after co-expression

    PMID:23293962

    Open questions at the time
    • Hemojuvelin cleavage step inferred, not directly demonstrated
    • Single Co-IP without in vivo confirmation
  7. 2014 High

    Defined HAI-2 as the selective regulator of prostasin-dependent matriptase zymogen activation in intestine, distinguishing it functionally from HAI-1.

    Evidence HAI-1/HAI-2 knockout mice and Caco-2 silencing with biochemical fractionation of matriptase

    PMID:24962579

    Open questions at the time
    • Why HAI-1 cannot substitute in intestine not fully explained at this stage
  8. 2014 Medium

    Mapped domain-specific protease specificity, showing KD1 and KD2 inhibit distinct protease subsets and that a free cysteine thiol drives mutant loss of function.

    Evidence Xenopus oocyte expression with KD1/KD2 mutagenesis against nine GI serine proteases

    PMID:24722141

    Open questions at the time
    • Structural basis of KD2-specific recognition not defined
    • Heterologous oocyte system
  9. 2015 Medium

    Established that HAI-2 function is gated by subcellular localization and N-glycan maturation, explaining cell-type-selective activity.

    Evidence Immunofluorescence, surface biotinylation, glycan characterization, and matriptase-HAI-2 complex detection in mammary vs breast cancer cells

    PMID:25786220 PMID:26171609

    Open questions at the time
    • Trigger for surface translocation in cancer cells unknown
    • Single-lab observations
  10. 2015 Medium

    Connected SPINT2 epigenetic silencing to aberrant HGF-MET-AKT signaling in cancer, providing a mechanism for its tumor-suppressive loss.

    Evidence Ectopic expression and decitabine reactivation in melanoma with MET/AKT phosphorylation readouts

    PMID:25910030

    Open questions at the time
    • Protease intermediary between HAI-2 loss and MET activation not specified here
  11. 2017 Medium

    Resolved that HAI-2 KD1 separately stabilizes matriptase, regulates its secretory transport via SEA-domain maturation, and inhibits its proteolytic activity.

    Evidence KD1 binding-loop mutagenesis with immunoblot of SEA cleavage and immunofluorescence localization

    PMID:28371047

    Open questions at the time
    • Mechanism coupling KD1 binding to SEA-domain processing not defined
  12. 2019 Medium

    Identified plasmin as a novel HAI-2 target and linked HAI-2 loss to plasmin-driven EMT, HGF/TGF-beta1 activation, and metastasis.

    Evidence Pulldown/LC-MS/MS identification with knockdown/overexpression and xenograft validation in lung cancer

    PMID:30765871

    Open questions at the time
    • Kunitz domain mediating plasmin inhibition not mapped
  13. 2019 Medium

    Showed that SCSD-associated KD2 mutations selectively impair prostasin inhibition, implying prostasin engages a KD2 exosite beyond the KD1 active-site loop.

    Evidence Functional inhibition assays of mutants against prostasin and matriptase with homology modeling

    PMID:30445423

    Open questions at the time
    • Exosite inferred from modeling, not structurally determined
  14. 2020 High

    Established HAI-2 as a TMPRSS2 inhibitor and stabilizing partner with anti-tumor consequences in prostate cancer.

    Evidence Co-IP/LC-MS/MS, recombinant inhibition assays, co-localization, and orthotopic xenografts

    PMID:32778768

    Open questions at the time
    • Relative in vivo importance of TMPRSS2 vs matriptase targeting not quantified
  15. 2020 Medium

    Demonstrated that HAI-2 inhibits matriptase zymogen as well as activated matriptase, indicating active-site engagement of the zymogen form.

    Evidence Purified-protein in vitro inhibition assays with zymogen vs activated matriptase

    PMID:32338287

    Open questions at the time
    • Structural basis of zymogen active-site accessibility not resolved
  16. 2020 Medium

    Extended HAI-2 antiviral function across multiple respiratory viruses by blocking host-protease cleavage of viral fusion proteins.

    Evidence Cleavage/fusion inhibition assays and cell-culture viral growth assays across influenza strains and HMPV

    PMID:24978308 PMID:32056846

    Open questions at the time
    • In vivo efficacy beyond influenza mouse model not established
  17. 2021 High

    Established that intestinal barrier failure from HAI-2 loss proceeds through a prostasin-dependent pathway with disruption of junctional proteins.

    Evidence Spint2-/-;Prss8R44Q mouse model with histology and junctional protein immunoblots

    PMID:29617460

    Open questions at the time
    • Direct prostasin substrate(s) responsible for junction loss not identified
  18. 2021 Medium

    Explained organ-selective disease through cell-type-selective excessive prostasin proteolysis, present in intestinal but not keratinocyte cells.

    Evidence Comparative HAI-2 deletion in Caco-2 vs HaCaT with prostasin/matriptase activation and half-life biochemistry

    PMID:34089062

    Open questions at the time
    • Molecular determinant of intestinal vs epidermal selectivity not pinpointed
  19. 2021 Medium

    Identified the intracellular targeting motifs (Arg/Lys-rich, EHLVY) distinguishing HAI-2 granule retention from HAI-1 surface distribution.

    Evidence Domain-swap and point mutagenesis with immunocytochemistry and surface biotinylation

    PMID:34643933

    Open questions at the time
    • Trafficking machinery recognizing these motifs not identified
  20. 2021 Medium

    Revealed a protease-independent developmental role in zebrafish, with HAI-2 promoting epithelial cohesion via genetic interaction with E-cadherin.

    Evidence Zebrafish spint2 mutant, chimera, and double-mutant epistasis analyses

    PMID:33826923

    Open questions at the time
    • Mechanism of E-cadherin-dependent cohesion not defined
    • Ortholog system may differ from mammals
  21. 2021 Medium

    Connected SPINT2 to cell-cycle control of tetraploid cells through CDKN1A transcription regulation via histone acetylation, distinct from its protease-inhibitor role.

    Evidence Genome-wide RNAi screen in HCT116 with IP/MS and histone acetylation analysis

    PMID:34962618

    Open questions at the time
    • Mechanism linking a secreted Kunitz inhibitor to nuclear chromatin regulation unclear
  22. 2023 Medium

    Defined that N-glycosylation at Asn-57 is required for correct folding and inhibitory activity, with non-glycosylated HAI-2 forming misfolded oligomers.

    Evidence Asn-57/Asn-94 mutagenesis with oligomerization, glycosylation, and inhibition assays in Caco-2 KO cells

    PMID:36637420

    Open questions at the time
    • Folding pathway requirement for the glycan not structurally characterized
  23. 2023 High

    Showed that matriptase-driven intestinal disease in HAI-2 deficiency proceeds through substrates other than EpCAM, refining the disease mechanism.

    Evidence Spint2-deficient mice with cleavage-resistant EpCAM knockin and intestinal matriptase inactivation

    PMID:37539662

    Open questions at the time
    • Identity of the relevant matriptase substrate(s) remains unknown
  24. 2024 High

    Established the molecular basis by which SCSD KD2 mutations inactivate HAI-2 through disulfide-linked oligomerization and immature glycoform trapping.

    Evidence Inducible KD2-mutant expression in HAI-2-KO Caco-2 cells with non-reducing PAGE, glycan, and prostasin inhibition assays

    PMID:38271183

    Open questions at the time
    • Whether oligomers exert dominant-negative effects in patients not addressed
  25. 2025 Medium

    Uncovered a non-protease mechanism in which SPINT2 stabilizes ACSL4 by blocking NEDD4L-mediated ubiquitination, promoting ferroptosis in cancer.

    Evidence Co-IP, ubiquitination assays, E3-ligase identification, and tumor suppression/metabolomic profiling

    PMID:41067336

    Open questions at the time
    • Single-lab Co-IP-based mechanism without independent replication
    • How a Kunitz inhibitor competes with an E3 ligase unclear
  26. 2025 Medium

    Linked SPINT2 to cellular senescence, where promoter hypomethylation upregulates SPINT2 to drive senescence via c-Met inhibition.

    Evidence DNMT1 knockdown/inhibition, SPINT2 knockdown/overexpression, methylation sequencing, and transcriptomics

    PMID:40838961

    Open questions at the time
    • Causal role of named downstream targets (COL27A1, STAM2, CBL) not functionally validated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of HAI-2 substrate selectivity (KD1 vs KD2 specificity and the proposed prostasin KD2 exosite) and how a secreted Kunitz inhibitor mediates intracellular roles (CDKN1A chromatin regulation, ACSL4 stabilization) remain unresolved.
  • No experimental structure of HAI-2 bound to a target protease
  • Mechanistic basis of non-protease intracellular functions unverified
  • Identity of matriptase substrate driving intestinal disease unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0140096 catalytic activity, acting on a protein 5 GO:0140313 molecular sequestering activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 3 GO:0031410 cytoplasmic vesicle 3
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3
Partners
ACSL4NEDD4LPLGPRSS8ST14TMPRSS13TMPRSS2TMPRSS6

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 HAI-2 (SPINT2) potently inhibits hepsin-mediated activation of pro-HGF into biologically active HGF, with IC50 of 1.3 nM; inhibition is due to Kunitz domain-1, as shown by HAI-1B Kunitz domain mutants (R260A, K401A) losing inhibitory activity. In vitro enzymatic assay with soluble recombinant hepsin and soluble HAI-2; Kunitz domain mutagenesis FEBS letters High 15792801
2005 Restoration of HAI-2/SPINT2 expression in a RCC cell line reduced in vitro colony formation, whereas a missense mutant (P111S) had no significant effect, placing HAI-2 as a functional tumor suppressor in RCC. Increased cell motility from HAI-2 inactivation was abrogated by ERK/MAPK and PLC-γ inhibitors. Re-expression of wild-type vs. P111S mutant SPINT2 in RCC cell line; pharmacological inhibitor treatment; colony formation assay; cell motility assay Cancer research Medium 15930277
2009 Genetic inactivation of Spint2 in mice causes defects in neural tube closure and placental labyrinth development with loss of epithelial polarity, leading to embryonic death. Simultaneous inactivation of matriptase (St14) fully restores placental development and embryonic survival, establishing matriptase inhibition as an essential HAI-2 function. Neural tube defects persisted at lower frequency even without matriptase, indicating HAI-2 also inhibits additional serine proteases required for neural development. Genetic knockout (Spint2-/- mice); genetic epistasis (Spint2/St14 double knockout); phenotypic analysis of placentation and neural tube Development (Cambridge, England) High 19592578
2009 Loss-of-function mutations in SPINT2 cause syndromic congenital sodium diarrhea. SPINT2 mutations (splice, missense, nonsense) were associated with loss of protein synthesis or failure to inhibit the serine protease trypsin in vitro, demonstrating that HAI-2 protease inhibitory activity is required for normal intestinal sodium homeostasis. Genetic linkage/SNP scan identifying SPINT2 mutations in families with syndromic CSD; in vitro trypsin inhibition assay with patient-derived mutant proteins American journal of human genetics High 19185281
2009 HAI-2/PB Kunitz domain 1 (KD-1) is critical for anti-invasive and anti-tumorigenic function in hepatocellular carcinoma cells: KD-1 inactivating mutant abolished anti-invasion activity in vitro and tumor suppression in vivo, while KD-2 inactivating mutant did not. Ectopic expression of wild-type and KD-1 vs. KD-2 mutant HAI-2 in HCC cell lines; Matrigel invasion assay; in vivo tumorigenicity assay International journal of cancer Medium 19107935
2012 Genetic epistasis establishes that prostasin (PRSS8) acts downstream of matriptase and upstream of HAI-2 in a proteolytic cascade: hypomorphic Prss8 mutations rescue early embryonic lethality, mid-gestation placental failure, and neural tube defects in HAI-2-deficient mice. Biochemical analysis revealed prostasin is required for conversion of matriptase zymogen to active matriptase (paradoxically upstream), while prostasin zymogen activation is matriptase-independent. Inactivation of c-Met, PAR-2, or ENaC alpha did not rescue lethality. In vivo genetic epistasis (compound knockout mice: HAI-2/Prss8, HAI-2/c-Met, HAI-2/PAR-2, HAI-2/ENaC-α); biochemical analysis of matriptase and prostasin activation in placental tissue PLoS genetics High 22952456
2013 HAI-2 inhibits matriptase-2 at the cell surface and in conditioned medium, forming a stable complex with matriptase-2 (demonstrated by co-immunoprecipitation). HAI-2 thereby indirectly elevates hepcidin expression (HAMP) by blocking matriptase-2-mediated suppression of hepcidin, likely through preventing matriptase-2 from cleaving membrane-bound hemojuvelin. Co-expression of matriptase-2 and HAI-2; complex isolation by immunoprecipitation from cell lysates and conditioned medium; HAMP mRNA measurement The Biochemical journal Medium 23293962
2013 HAI-2 suppresses prostate cancer cell migration, invasion, tumorigenicity and metastasis primarily through regulation of matriptase: HAI-2 knockdown increases matriptase activation, and matriptase knockdown rescues the invasion induced by HAI-2 loss. HAI-2 overexpression in N2 cells reduced tumor growth and metastasis in orthotopic xenografts. HAI-2 knockdown and overexpression in human PCa cell lines (103E, N1, N2); matriptase knockdown rescue experiment; orthotopic xenograft mouse model; immunohistochemistry Oncogene Medium 24121274
2014 HAI-2, but not HAI-1, regulates prostasin-dependent matriptase zymogen activation. In HAI-2-deficient intestinal epithelial cells, matriptase is lost due to accelerated prostasin-driven activation and subsequent shedding. HAI-1 ablation did not affect matriptase in intestinal cells. Gene silencing in Caco-2 monolayers confirmed that HAI-2 loss causes accelerated matriptase shedding mechanistically through loss of prostasin regulation. Genetically engineered HAI-1 and HAI-2 knockout mice; gene silencing in Caco-2 intestinal epithelial cell monolayers; immunofluorescence and biochemical fractionation of matriptase localization/activation The Journal of biological chemistry High 24962579
2014 Y163C mutation in Kunitz domain 2 (KD2) of HAI-2 causes complete loss of inhibitory activity on two intestinal serine proteases, prostasin and TMPRSS13, but mutations in KD1 (Y68C) affect a different subset of proteases. HAI-2 wild-type inhibits nine gastrointestinal serine proteases. The thiol group of the introduced cysteine (not loss of Tyr) is responsible for HAI-2 loss of function. Xenopus laevis oocyte expression system cellular assay; site-directed mutagenesis of KD1 and KD2; functional assay against nine GI serine proteases PloS one Medium 24722141
2015 HAI-2 inhibition of matriptase depends on subcellular co-localization: in mammary epithelial cells, HAI-2 resides in intracellular vesicle/granule structures and does not form matriptase-HAI-2 complexes upon matriptase activation. In breast cancer cells, a proportion of HAI-2 translocates to the cell surface where it inhibits matriptase, forming three distinct matriptase-HAI-2 complexes. Induction of matriptase zymogen activation in human mammary epithelial vs. breast cancer cells; immunofluorescent staining of HAI-2 localization; immunoprecipitation of matriptase-HAI-2 complexes; cell surface biotinylation PloS one Medium 25786220
2015 HAI-2 (SPINT2) inhibits HGF-induced MET-AKT signaling in melanoma cells and decreases cell motility and invasive growth. Epigenetic silencing of SPINT2 by DNA methylation activates the HGF-MET pathway. Ectopic SPINT2 expression in melanoma cells; MET/AKT phosphorylation assay; cell motility and invasion assay; decitabine-induced reactivation The Journal of investigative dermatology Medium 25910030
2015 The N-glycan on Asn-57 of HAI-2 determines subcellular distribution: oligomannose-type N-glycan (25-kDa form) is largely ER-retained, while complex-type N-glycan (30–40-kDa form) is targeted to vesicles/granules and the cell surface where it can inhibit matriptase. In breast cancer cells, the mature 30–40-kDa HAI-2 translocates to the cell surface to form matriptase-HAI-2 complexes. Biochemical characterization of two HAI-2 species by size and N-glycan type; subcellular fractionation; immunofluorescence; matriptase-HAI-2 complex detection PloS one Medium 26171609
2016 HAI-2 inhibits influenza virus H1N1 and H3N2 hemagglutinin cleavage and reduces viral infection in cell culture; HAI-2 administration in a mouse influenza model confers protection, acting by inhibiting host proteases (matriptase, TMPRSS2) that cleave HA. In vitro HA cleavage inhibition assay; cell culture infection assay; mouse influenza model Biochemical and biophysical research communications Medium 24978308
2016 HAI-2 forms complexes with prostasin in human milk in addition to matriptase-HAI-2 complexes, providing in vivo evidence that both matriptase and prostasin are HAI-2 target proteases during lactation. Purification of protease-inhibitor complexes from human milk; immunoaffinity and ion-exchange chromatography; mass spectrometry identification PloS one Medium 27043831
2017 HAI-2 Kunitz domain 1 mutations (K42N, C47F, R48L) delay SEA domain cleavage of matriptase, causing accumulation of non-SEA-cleaved matriptase in the ER, thereby regulating matriptase secretory transport and cell-surface localization. Two of the mutants (C47F, R48L) also show reduced ability to inhibit matriptase proteolytic activity. HAI-2 thus separately: (1) stabilizes matriptase, (2) regulates its secretory transport via maturation/oligomerization, and (3) inhibits its proteolytic activity. Site-directed mutagenesis of HAI-2 KD1 binding loop; expression in cells; analysis of matriptase SEA domain cleavage by immunoblot; subcellular localization by immunofluorescence Traffic (Copenhagen, Denmark) Medium 28371047
2018 In human skin, HAI-2 is primarily intracellularly localized in basal and spinous layer keratinocytes, preventing its interaction with active prostasin or matriptase; consequently HAI-1 (not HAI-2) is the prominent inhibitor of prostasin and matriptase in skin. Subcellular localization thus determines tissue-specific protease inhibitor function. Immunohistochemistry of human foreskin; immunoblot analysis of foreskin lysates; comparison of protease activation status across tissues PloS one Medium 29438412
2018 HAI-2 loss in oral squamous cell carcinoma (OSCC) cells causes a pro-invasive phenotype via excess prostasin activity: SPINT2 knockout suppresses OSCC proliferation and invasion, and this is rescued by HAI-2 re-expression or prostasin knockdown. Prostasin protein levels increase markedly in HAI-2-deficient OSCC cells. Homozygous SPINT2 CRISPR knockout in OSCC lines; prostasin knockdown rescue; Matrigel invasion assay; western blot Oncotarget Medium 29545930
2018 HAI-2 loss in mice with HAI-2-deficient intestinal epithelial cells causes excessive prostasin proteolysis with prolonged active prostasin and depletion of HAI-1 monomer, but this phenotype is not observed in epidermal (HaCaT) cells, identifying tissue-selective functional relationship between HAI-2 and prostasin in intestinal epithelium. Targeted HAI-2 deletion in Caco-2 and HaCaT cells; biochemical analysis of prostasin activation, matriptase activation, and HAI-1 levels PLoS one Medium 29617460
2019 SPINT2 missense mutations in KD2 (p.Phe161Val, p.Tyr163Cys, p.Gly168Ser) found in SCSD patients selectively impair inhibition of prostasin-catalyzed cleavage but do not affect matriptase inhibition. Homology modeling suggests these mutations induce KD2 misfolding. This implies prostasin needs to engage an exosite on KD2 in addition to the KD1 binding loop for inhibition. Functional inhibition assays with wild-type and mutant HAI-2 against prostasin and matriptase; homology modeling Human molecular genetics Medium 30445423
2019 HAI-2 functions as a novel inhibitor of plasmin in lung cancer: HAI-2 downregulation increases cell-surface plasmin activity, EMT, and invasion; HAI-2 suppresses plasmin-mediated activations of HGF and TGF-β1. Plasmin was identified as a novel HAI-2 target by pulldown and LC/MS/MS. In xenograft models, HAI-2 loss increased lung cancer metastasis via elevated plasmin activity. Pulldown and LC/MS/MS identification of plasmin as HAI-2 target; HAI-2 knockdown/overexpression; plasmin activity assay; transwell invasion; in vivo xenograft British journal of cancer Medium 30765871
2020 HAI-2 forms a stable complex with TMPRSS2 (identified by co-immunoprecipitation and LC/MS/MS) and potently inhibits TMPRSS2 proteolytic activity, with both KD1 and KD2 showing comparable inhibitory effects. HAI-2 suppresses TMPRSS2-induced pro-HGF activation, ECM degradation, and prostate cancer invasion and metastasis in orthotopic xenograft models. Co-IP and LC/MS/MS; recombinant protein inhibition assay; immunofluorescence co-localization; HAI-2 overexpression in xenograft model Oncogene High 32778768
2020 HAI-2 and HAI-1 inhibit the catalytic activity of the matriptase zymogen toward peptide substrates and natural protein substrates (pro-HGF, pro-prostasin) at comparable concentrations to their inhibition of activated matriptase, indicating that the Kunitz inhibitors interact with the active sites of both zymogen and activated matriptase similarly. Purified protein in vitro inhibition assay; cell-based assay with HAI-1/HAI-2 and zymogen vs. activated matriptase The Biochemical journal Medium 32338287
2020 SPINT2 inhibits proteolytic cleavage-activation of influenza A (H1N1, H3N2, H7N9) hemagglutinin and HMPV F protein by trypsin, recombinant matriptase, or KLK5, and reduces viral growth in cell culture by inhibiting matriptase or TMPRSS2. Inhibition is effective whether added at infection or 24 h post-infection. Cleavage and fusion inhibition assays with recombinant SPINT2; cell culture viral growth assay Virology Medium 32056846
2021 SPINT2 acts as a general regulator of CDKN1A transcription via histone acetylation. Loss of SPINT2 improves survival of tetraploid cells (identified by genome-wide RNAi screen) by reducing CDKN1A expression, linking SPINT2 to cell cycle arrest after genome doubling. Genome-wide RNAi screen in HCT116 colorectal cancer cells; mass spectrometry and immunoprecipitation; chromatin/histone acetylation analysis Cellular oncology (Dordrecht, Netherlands) Medium 34962618
2021 In HAI-2-deficient mice expressing only zymogen-locked prostasin (Prss8 R44Q), which does not bind HAI-2, postnatal intestinal failure develops (villous atrophy, tufted villi, loss of goblet cells, loss of colonic crypt structure) with reduced EpCAM, E-cadherin, occludin, and claudins-1/-7, and elevated claudin-4, demonstrating that HAI-2 regulates intestinal epithelial barrier integrity through a prostasin-dependent pathway. Genetic mouse model (Spint2-/-;Prss8R44Q/R44Q); histology; immunoblot of junctional proteins PloS one High 29617460
2021 In Caco-2 colorectal cells (but not HaCaT keratinocytes), HAI-2 deletion causes constitutive high-level prostasin zymogen activation, prolonged active prostasin half-life, depletion of HAI-1 monomer, and secondary increase in matriptase activation. This cell-type-selective excessive proteolysis explains organ-selective intestinal damage from SPINT2 mutations. Targeted HAI-2 deletion in Caco-2 vs. HaCaT cells; biochemical assays for prostasin and matriptase activation/inhibition status; half-life measurements Human molecular genetics Medium 34089062
2021 Differences in intracellular Arg/Lys-rich and EHLVY motifs between HAI-1 and HAI-2 account for their distinct subcellular distributions (HAI-1 on cell surface and inside; HAI-2 predominantly in intracellular granules). Domain swap and point mutation experiments confirmed these motifs as the key targeting signals. Domain swap mutagenesis; point mutations; immunocytochemistry; cell surface biotinylation/avidin depletion Human cell Medium 34643933
2021 In zebrafish, Spint2 is required for hatching gland cell cohesion, collective intra-epidermal migration, and survival prior to degranulation. Spint2 acts independently of tested matriptases and prostasins, but displays tight genetic interaction with E-cadherin, promoting hatching gland cell cohesiveness and survival. No genetic interaction with EpCAM was observed. Zebrafish spint2 mutant analysis; chimera analysis; genetic epistasis with matriptase, prostasin, E-cadherin, EpCAM mutants Developmental biology Medium 33826923
2021 SPINT2 knockdown in lung cancer (Calu-3) cells leads to a strong increase in SARS-CoV-2 viral load, while SPINT2 overexpression drastically reduces viral load, demonstrating that SPINT2 restricts SARS-CoV-2 infection, likely through inhibition of TMPRSS2. SPINT2 siRNA knockdown and overexpression in Calu-3 cells; viral load quantification PLoS pathogens Medium 34181691
2023 N-glycosylation at Asn-57 (not Asn-94) is required for correct HAI-2 protein folding and protease inhibitory activity. Non-glycosylated HAI-2 (Asn-57 mutant) is synthesized as disulfide-linked oligomers with distorted conformations and lacks protease inhibitory function. The oligomannose-type N-glycan is the precursor of the complex-type N-glycan form. Point mutations of Asn-57 and Asn-94 in HAI-2; biochemical characterization of oligomerization, glycosylation state, and protease inhibitory activity in HAI-2 knockout Caco-2 cells Glycobiology Medium 36637420
2023 Early-onset tufting enteropathy and postnatal lethality in Spint2-deficient mice are driven by matriptase activity but NOT through excessive proteolysis of EpCAM: expression of cleavage-resistant EpCAM failed to rescue intestinal failure. Matriptase inactivation counteracted Spint2 deficiency even with cleavage-resistant EpCAM, indicating matriptase-driven intestinal dysfunction proceeds via substrates other than EpCAM. Genetic mouse models combining Spint2 deficiency with cleavage-resistant EpCAM knockin and intestinal St14 (matriptase) inactivation; in vitro and in vivo EpCAM cleavage assays Development (Cambridge, England) High 37539662
2024 SCSD-associated SPINT2 missense mutations in KD2 (e.g., p.Phe161Val, p.Tyr163Cys, p.Gly168Ser) inactivate HAI-2 through two mechanisms: (1) ~50% of protein forms disulfide-linked oligomers due to disarrayed disulfide bonding, losing protease inhibitory activity; (2) remaining monomeric protein is trapped in an immature, lightly glycosylated form and cannot suppress prostasin proteolysis. These mutants cannot rescue excessive prostasin proteolysis caused by HAI-2 knockout in Caco-2 cells. Doxycycline-inducible expression of HAI-2 KD2 mutants in HAI-2-knockout Caco-2 cells; non-reducing SDS-PAGE for oligomer detection; glycosylation state analysis; prostasin inhibition functional assay Human molecular genetics High 38271183
2025 SPINT2 interacts with ACSL4 and prevents its ubiquitination by the E3 ligase NEDD4L, thereby stabilizing ACSL4 protein and promoting ferroptotic cell death in gallbladder cancer. SPINT2 deficiency alters lipid metabolism and reduces ferroptosis susceptibility. Co-immunoprecipitation demonstrating SPINT2-ACSL4 interaction; ubiquitination assay; NEDD4L identification as E3 ligase; in vitro and in vivo tumor suppression assays; metabolomic profiling International journal of biological macromolecules Medium 41067336
2025 DNMT1 downregulation during senescence causes hypomethylation of SPINT2 promoter CpG sites, leading to SPINT2 upregulation. SPINT2 overexpression alone induces senescence, and SPINT2 knockdown mitigates DNMT1 inhibition-induced senescence. SPINT2 drives senescence by inhibiting c-Met signaling; downstream targets include COL27A1, STAM2, and CBL. DNMT1 knockdown and pharmacological inhibition; SPINT2 siRNA knockdown and overexpression; methylation-specific sequencing; transcriptomic profiling; senescence marker assays Aging Medium 40838961
2019 STYK1 overexpression significantly decreases SPINT2 protein levels in NSCLC cells, and SPINT2 overexpression reverses STYK1-mediated NSCLC proliferation, migration, invasion, and EMT both in vitro and in vivo, placing SPINT2 downstream of STYK1 in a lung cancer progression pathway. RNA-seq, qRT-PCR, western blot after STYK1 overexpression; SPINT2 overexpression rescue; in vivo tumor model Cell death & disease Medium 31164631
2019 SPINT2 loss in glioma promotes cell growth and invasion partly via increased MMP2 expression and activity, as demonstrated by SPINT2 knockdown and knock-in functional assays in adult and pediatric HGG cell lines. SPINT2 knockdown and knock-in in HGG cell lines; MMP2 activity assay; invasion and viability assays Cellular oncology (Dordrecht, Netherlands) Medium 31701492
2019 SPINT2 restores expression reduces c-Met activation in GBM cells and suppresses tumorigenic properties in vitro and in vivo, with SPINT2 downregulation resulting from promoter hypermethylation (confirmed by targeted bisulfite sequencing, 5-aza treatment, DNMT1 knockdown, and luciferase reporter assay). 5-aza treatment, DNMT1 knockdown, luciferase reporter for methylation-mediated regulation; SPINT2 re-expression; c-Met phosphorylation assay; in vivo GBM model Journal of neuro-oncology Medium 30838489
2018 SPINT2 promotes SMC proliferation and migration inhibition in aortic smooth muscle cells: SPINT2 overexpression reduces active MMP-2 and MMP-9 expression, suppresses SMC switching from contractile to synthetic phenotype, and inhibits ERK activation. A specific ERK agonist reverses SPINT2-mediated inhibition of SMC migration and phenotypic switching. SPINT2 overexpression via adenoviral vector in primary mouse aortic SMCs; PDGF-BB induction model; MTT, Ki-67, wound healing, ELISA, western blot; ERK agonist rescue Experimental and therapeutic medicine Medium 37928510
2025 Co-expression of HAI-2 (SPINT2) with TMPRSS2 ectodomain enables efficient production of active wildtype TMPRSS2 in mammalian cells, demonstrating that HAI-2 stabilizes TMPRSS2 zymogen during expression. Purified TMPRSS2 cleaves synthetic and protein substrates efficiently (kcat/KM 10^4–10^6 M-1s-1). Mammalian cell co-expression of TMPRSS2 ectodomain with HAI-2; purification and kinetic characterization of recombinant TMPRSS2 The Biochemical journal Medium 41408854

Source papers

Stage 0 corpus · 84 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Hepsin activates pro-hepatocyte growth factor and is inhibited by hepatocyte growth factor activator inhibitor-1B (HAI-1B) and HAI-2. FEBS letters 128 15792801
2005 Tumor suppressor activity and epigenetic inactivation of hepatocyte growth factor activator inhibitor type 2/SPINT2 in papillary and clear cell renal cell carcinoma. Cancer research 101 15930277
2009 Regulation of cell surface protease matriptase by HAI2 is essential for placental development, neural tube closure and embryonic survival in mice. Development (Cambridge, England) 96 19592578
2009 Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea. American journal of human genetics 85 19185281
2006 Hepatocyte growth factor activation inhibitors (HAI-1 and HAI-2) regulate HGF-induced invasion of human breast cancer cells. International journal of cancer 80 16557597
2008 An epigenetic genome-wide screen identifies SPINT2 as a novel tumor suppressor gene in pediatric medulloblastoma. Cancer research 78 19047176
2013 Genetic characterization of congenital tufting enteropathy: epcam associated phenotype and involvement of SPINT2 in the syndromic form. Human genetics 71 24142340
2012 Reduced prostasin (CAP1/PRSS8) activity eliminates HAI-1 and HAI-2 deficiency-associated developmental defects by preventing matriptase activation. PLoS genetics 62 22952456
2018 Hepatocyte growth factor activator inhibitors (HAI-1 and HAI-2): Emerging key players in epithelial integrity and cancer. Pathology international 59 29431273
2013 HAI-2 suppresses the invasive growth and metastasis of prostate cancer through regulation of matriptase. Oncogene 52 24121274
2014 The protease inhibitor HAI-2, but not HAI-1, regulates matriptase activation and shedding through prostasin. The Journal of biological chemistry 50 24962579
2003 Hepatocyte growth factor activator inhibitor 2/placental bikunin (HAI-2/PB) gene is frequently hypermethylated in human hepatocellular carcinoma. Cancer research 50 14695180
2001 Reduced expression of hepatocyte growth factor activator inhibitor type-2/placental bikunin (HAI-2/PB) in human glioblastomas: implication for anti-invasive role of HAI-2/PB in glioblastoma cells. International journal of cancer 48 11433397
2017 Repeated Administration of Opra Kappa (LY2456302), a Novel, Short-Acting, Selective KOP-r Antagonist, in Persons with and without Cocaine Dependence. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 47 28857070
2010 Epigenetic inactivation and tumor suppressor activity of HAI-2/SPINT2 in gastric cancer. International journal of cancer 41 20063316
2020 Inhibition of TMPRSS2 by HAI-2 reduces prostate cancer cell invasion and metastasis. Oncogene 40 32778768
2010 The role of hepatocyte growth factor activator inhibitor (HAI)-1 and HAI-2 in endometrial cancer. International journal of cancer 40 20715109
2019 STYK1 promotes tumor growth and metastasis by reducing SPINT2/HAI-2 expression in non-small cell lung cancer. Cell death & disease 37 31164631
2018 Serine peptidase inhibitor Kunitz type 2 (SPINT2) in cancer development and progression. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 34 29499401
2009 Expression of hepatocyte growth factor activator inhibitors (HAI-1 and HAI-2) in ovarian cancer. International journal of oncology 33 19148468
2019 SPINT2 (HAI-2) missense variants identified in congenital sodium diarrhea/tufting enteropathy affect the ability of HAI-2 to inhibit prostasin but not matriptase. Human molecular genetics 32 30445423
2015 Epigenetic Silencing of SPINT2 Promotes Cancer Cell Motility via HGF-MET Pathway Activation in Melanoma. The Journal of investigative dermatology 32 25910030
2010 Loss of the matriptase inhibitor HAI-2 during prostate cancer progression. The Prostate 32 20687215
2013 Epigenetic inactivation of SPINT2 is associated with tumor suppressive function in esophageal squamous cell carcinoma. Experimental cell research 29 24269829
2016 Matriptase Complexes and Prostasin Complexes with HAI-1 and HAI-2 in Human Milk: Significant Proteolysis in Lactation. PloS one 28 27043831
2014 Functional analysis of a missense mutation in the serine protease inhibitor SPINT2 associated with congenital sodium diarrhea. PloS one 26 24722141
2013 Hepatocyte growth factor activator inhibitor type 2 (HAI-2) modulates hepcidin expression by inhibiting the cell surface protease matriptase-2. The Biochemical journal 26 23293962
2009 HAI-2 is epigenetically downregulated in human hepatocellular carcinoma, and its Kunitz domain type 1 is critical for anti-invasive functions. International journal of cancer 25 19107935
2016 Evidence for nociceptin/orphanin FQ (NOP) but not µ (MOP), δ (DOP) or κ (KOP) opioid receptor mRNA in whole human blood. British journal of anaesthesia 24 26865135
2017 HAI-2 stabilizes, inhibits and regulates SEA-cleavage-dependent secretory transport of matriptase. Traffic (Copenhagen, Denmark) 23 28371047
2015 N-Glycan Branching Affects the Subcellular Distribution of and Inhibition of Matriptase by HAI-2/Placental Bikunin. PloS one 23 26171609
2018 Tissue distribution and subcellular localizations determine in vivo functional relationship among prostasin, matriptase, HAI-1, and HAI-2 in human skin. PloS one 21 29438412
2015 Differential subcellular localization renders HAI-2 a matriptase inhibitor in breast cancer cells but not in mammary epithelial cells. PloS one 21 25786220
2020 SPINT2 inhibits proteases involved in activation of both influenza viruses and metapneumoviruses. Virology 20 32056846
2018 Hepatocyte growth factor activator inhibitor type-2 (HAI-2)/SPINT2 contributes to invasive growth of oral squamous cell carcinoma cells. Oncotarget 18 29545930
2018 Selectivity profiling of NOP, MOP, DOP and KOP receptor antagonists in the rat spinal nerve ligation model of mononeuropathic pain. European journal of pharmacology 17 29524385
2018 Loss of HAI-2 in mice with decreased prostasin activity leads to an early-onset intestinal failure resembling congenital tufting enteropathy. PloS one 16 29617460
2014 Inhibition of influenza virus infection and hemagglutinin cleavage by the protease inhibitor HAI-2. Biochemical and biophysical research communications 16 24978308
2021 Elevated Circulating and Placental SPINT2 Is Associated with Placental Dysfunction. International journal of molecular sciences 15 34299087
2018 Up-regulation of SPINT2/HAI-2 by Azacytidine in bone marrow mesenchymal stromal cells affects leukemic stem cell survival and adhesion. Journal of cellular and molecular medicine 15 30484958
2002 Expression of hepatocyte growth factor activator inhibitor type 2 (HAI-2) in human testis: identification of a distinct transcription start site for the HAI-2 gene in testis. Biological chemistry 15 12553733
2021 Loss of USP28 and SPINT2 expression promotes cancer cell survival after whole genome doubling. Cellular oncology (Dordrecht, Netherlands) 14 34962618
2019 Signaling characteristics and functional regulation of delta opioid-kappa opioid receptor (DOP-KOP) heteromers in peripheral sensory neurons. Neuropharmacology 14 30776373
2010 Hepatocyte growth factor activator inhibitors (HAI-1 and HAI-2) are potential targets in uterine leiomyosarcoma. International journal of oncology 14 20664929
2006 Serum hepatocyte growth factor activator inhibitor type I (HAI-I) and type 2 (HAI-2) in prostate cancer. The Prostate 14 16353247
2020 Inhibition of an active zymogen protease: the zymogen form of matriptase is regulated by HAI-1 and HAI-2. The Biochemical journal 13 32338287
2019 HAI-2 as a novel inhibitor of plasmin represses lung cancer cell invasion and metastasis. British journal of cancer 13 30765871
2018 Aberrant methylation and silencing of the SPINT2 gene in high-grade gliomas. Cancer science 13 29987920
2015 SPINT2 Deregulation in Prostate Carcinoma. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 13 26442953
2001 Mouse hepatocyte growth factor activator inhibitor type 1 (HAI-1) and type 2 (HAI-2)/placental bikunin genes and their promoters. Biochimica et biophysica acta 13 11406276
2019 Aberrant regulation favours matriptase proteolysis in neoplastic B-cells that co-express HAI-2. Journal of enzyme inhibition and medicinal chemistry 12 30777474
2003 Differential expression of bikunin (HAI-2/PB), a proposed mediator of glioma invasion, by demethylation treatment. Journal of neuro-oncology 12 14558597
2019 Loss of SPINT2 expression frequently occurs in glioma, leading to increased growth and invasion via MMP2. Cellular oncology (Dordrecht, Netherlands) 11 31701492
2012 Inactivation of PbTopo IIIβ causes hyper-excision of the Pathogenicity Island HAI2 resulting in reduced virulence of Pectobacterium atrosepticum. Molecular microbiology 11 22524709
2020 Differential subcellular distribution renders HAI-2 a less effective protease inhibitor than HAI-1 in the control of extracellular matriptase proteolytic activity. Genes & diseases 10 35685459
2019 SPINT2 is hypermethylated in both IDH1 mutated and wild-type glioblastomas, and exerts tumor suppression via reduction of c-Met activation. Journal of neuro-oncology 10 30838489
2020 Cyclic derivative of morphiceptin Dmt-cyclo-(D-Lys-Phe-D-Pro-Asp)-NH2(P-317), a mixed agonist of MOP and KOP opioid receptors, exerts anti-inflammatory and anti-tumor activity in colitis and colitis-associated colorectal cancer in mice. European journal of pharmacology 9 32835668
2018 Congenital sodium diarrhea and chorioretinal coloboma with optic disc coloboma in a patient with biallelic SPINT2 mutations, including p.(Tyr163Cys). American journal of medical genetics. Part A 9 29575628
2023 SPINT2 is involved in the proliferation, migration and phenotypic switching of aortic smooth muscle cells: Implications for the pathogenesis of thoracic aortic dissection. Experimental and therapeutic medicine 8 37928510
2021 The Kunitz-type serine protease inhibitor Spint2 is required for cellular cohesion, coordinated cell migration and cell survival during zebrafish hatching gland development. Developmental biology 8 33826923
2015 Aberrant methylation of promoter region of SPINT2/HAI-2 gene: an epigenetic mechanism in hepatitis C virus-induced hepatocarcinogenesis. Genetic testing and molecular biomarkers 8 26030814
2022 Chemical Composition, Antitumor Properties, and Mechanism of the Essential Oil from Plagiomnium acutum T. Kop. International journal of molecular sciences 7 36499119
2014 Knockout subtraction autoradiography: a novel ex vivo method to detect heteromers finds sparse KOP receptor/DOP receptor heterodimerization in the brain. European journal of pharmacology 7 24657279
2018 Study on the methylation status of SPINT2 gene and its expression in cervical carcinoma. Cancer biomarkers : section A of Disease markers 6 29843210
2018 Dysregulated HAI-2 Plays an Important Role in Renal Cell Carcinoma Bone Metastasis through Ligand-Dependent MET Phosphorylation. Cancers 6 29890660
2010 Lack of genotype effect on D1, D2 receptors and dopamine transporter binding in triple MOP-, DOP-, and KOP-opioid receptor knockout mice of three different genetic backgrounds. Synapse (New York, N.Y.) 6 20196137
2003 Characterization of transcripts generated from mouse hepatocyte growth factor activator inhibitor type 2 (HAI-2) and HAI-2-related small peptide (H2RSP) genes: chimeric mRNA transcribed from both HAI-2 and H2RSP genes is detected in human but not in mouse. Biochemical and biophysical research communications 6 12604353
2024 SPINT2 mutations in the Kunitz domain 2 found in SCSD patients inactivate HAI-2 as prostasin inhibitor via abnormal protein folding and N-glycosylation. Human molecular genetics 5 38271183
2007 New benzomorphan derivatives of MPCB as MOP and KOP receptor ligands. Die Pharmazie 5 18065096
2001 Identification of hepatocyte growth factor activator inhibitor type 2 (HAI-2)-related small peptide (H2RSP): its nuclear localization and generation of chimeric mRNA transcribed from both HAI-2 and H2RSP genes. Biochemical and biophysical research communications 5 11606055
2023 N-glycosylation on Asn-57 is required for the correct HAI-2 protein folding and protease inhibitory activity. Glycobiology 4 36637420
2021 Targeted HAI-2 deletion causes excessive proteolysis with prolonged active prostasin and depletion of HAI-1 monomer in intestinal but not epidermal epithelial cells. Human molecular genetics 4 34089062
2021 The endogenous cellular protease inhibitor SPINT2 controls SARS-CoV-2 viral infection and is associated to disease severity. PLoS pathogens 4 34181691
2021 The difference in the intracellular Arg/Lys-rich and EHLVY motifs contributes to distinct subcellular distribution of HAI-1 versus HAI-2. Human cell 4 34643933
2017 Syndromic congenital diarrhoea: new SPINT2 mutation identified in the UAE. BMJ case reports 4 28716867
2014 Serendipity or prepared mind? Recollections of the KOP translocation (1967) and of one form of Perrault syndrome. American journal of medical genetics. Part C, Seminars in medical genetics 3 25424868
2023 CYX-5, a G-protein biassed MOP receptor agonist, DOP receptor antagonist and KOP receptor agonist, evokes constipation but not respiratory depression relative to morphine in rats. Pharmacological reports : PR 2 36637684
2025 DNMT1-mediated SPINT2 expression drives early senescence by suppressing c-Met signaling in human fibroblasts. Aging 1 40838961
2025 SPINT2 inhibits NEDD4L-mediated ACSL4 ubiquitination to promote ferroptosis and suppress gallbladder cancer progression. International journal of biological macromolecules 1 41067336
2023 Early-onset tufting enteropathy in HAI-2-deficient mice is independent of matriptase-mediated cleavage of EpCAM. Development (Cambridge, England) 1 37539662
2021 The comparison of the phytochemical composition, antioxidant and enzyme inhibition activity of two moss species: Plagiomnium ellipticum (Brid.) T. Kop. and Antitrichia californica Sull., from southwest ecological region in Turkey. Natural product research 1 33949257
2018 Isolated choanal and gut atresias: pathogenetic role of serine protease inhibitor type 2 (SPINT2) gene mutations unlikely. European journal of medical research 1 29499739
2018 [Expression and Clinical Significances of HGFA, Matriptase, HAI-1 and HAI-2 in Acute Myeloid Leukemia]. Zhongguo shi yan xue ye xue za zhi 1 30111395
2025 Efficient production of fully active, SARS-CoV-2-priming, wildtype TMPRSS2 ectodomain via co-expression of HAI-2 allows for both auto- and cross-activation mechanisms. The Biochemical journal 0 41408854

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