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SPSB1

SPRY domain-containing SOCS box protein 1 · UniProt Q96BD6

Length
273 aa
Mass
30.9 kDa
Annotated
2026-06-10
26 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SPSB1 is a substrate-recognition adaptor of Cullin-RING E3 ubiquitin ligase complexes that couples a SPRY substrate-binding domain to a SOCS box recruiting Elongin B/C-Cullin modules, directing diverse substrates to ubiquitin-mediated proteasomal degradation (PMID:28084329, PMID:20561531). Its SPRY domain recognizes substrates through a conserved Asn-rich consensus motif, with all three core asparagines required for binding (PMID:20561531). Through this activity SPSB1 negatively regulates signaling across multiple processes: it destabilizes the TGF-β type II receptor TβRII (but not TβRI), dampening TGF-β/Smad-driven migration and invasion and, in myocytes, TβRII-Akt-Myogenin-dependent protein synthesis during inflammatory muscle atrophy (PMID:26032413, PMID:37209006); it limits inducible nitric oxide synthase levels and NO output downstream of TLR3/TLR4 as a negative-feedback brake (PMID:21876038); and it suppresses NF-κB activity through association with the p65 subunit at or downstream of the heterodimer (PMID:32038638). SPSB1 further ubiquitinates the splicing regulator hnRNP A1 via K29-linked chains upon EGF stimulation, shifting Rac1 alternative splicing toward Rac1b and promoting migration (PMID:28084329), destabilizes p21 to enhance cancer cell survival (PMID:30712944), degrades the circadian repressor RevErbα to set period length (PMID:31607207), and destabilizes the transcription factor KLF6 to restrain PD-L1 expression and prevent T cell exhaustion (PMID:42055144). Independent of its degradative role, SPSB1 binds the MET receptor tyrosine kinase through its SPRY domain, is tyrosine-phosphorylated upon HGF stimulation, and potentiates HGF-induced Erk-Elk-1-SRE signaling to protect tumor cells from apoptosis (PMID:15713673, PMID:24786206). SPSB1 abundance is itself controlled, being degraded upon Ras-driven ubiquitination and stabilized by PTBP3 binding to its 3'UTR (PMID:29534718, PMID:42055144).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2005 Medium

    Established the first SPSB1 binding partner and an unexpected non-degradative signaling role, linking SPSB1 to receptor tyrosine kinase output.

    Evidence Co-IP, SRE luciferase reporters, RNAi, and tyrosine phosphorylation analysis in HGF-stimulated cells

    PMID:15713673

    Open questions at the time
    • Mechanism by which SPSB1 enhances Erk-Elk-1 signaling without degrading MET or p120RasGAP unresolved
    • Functional consequence of Y31 phosphorylation not defined
  2. 2010 High

    Defined the structural and sequence basis for SPSB substrate recognition, showing the SPRY domain reads a conserved Asn-rich motif.

    Evidence X-ray crystallography of SPSB1/2/4, NMR, and mutagenesis of Par-4 binding motif

    PMID:20561531

    Open questions at the time
    • Did not establish which endogenous substrates use this motif in cells
    • No ubiquitination or degradation readout
  3. 2011 High

    Demonstrated SPSB1 functions as a degradative adaptor in innate immunity, targeting iNOS to limit NO as a negative-feedback control.

    Evidence Transgenic mouse macrophages, shRNA, reciprocal Co-IP, NO assays, and proteasome inhibition

    PMID:21876038

    Open questions at the time
    • Direct ubiquitination of iNOS by an SPSB1-containing ligase not biochemically reconstituted
    • Lysine linkage type not defined
  4. 2014 Medium

    Placed SPSB1 in a disease context, showing it potentiates c-MET signaling to drive breast cancer recurrence and survival.

    Evidence Genetically engineered mouse models with gain/loss-of-function and apoptosis assays

    PMID:24786206

    Open questions at the time
    • Molecular link between SPSB1 and c-MET potentiation mechanistically distinct from its E3 adaptor role unclear
    • Single lab
  5. 2015 High

    Identified TβRII as a degradation substrate, defining SPSB1 as a negative regulator of TGF-β/Smad signaling and invasion.

    Evidence Co-IP, co-localization imaging, ubiquitination assay, siRNA, and reporter/migration assays

    PMID:26032413

    Open questions at the time
    • Receptor selectivity (TβRII not TβRI) structural basis not resolved
    • In vivo relevance not tested in this study
  6. 2017 High

    Showed SPSB1 links EGF signaling to splicing control, ubiquitinating hnRNP A1 with atypical K29 chains to reprogram Rac1 splicing and migration.

    Evidence Co-IP, ubiquitylation assays, splicing analysis, RNAi, and migration assays

    PMID:28084329

    Open questions at the time
    • Functional consequence of K29-linked (vs degradative) chains on hnRNP A1 fate not fully dissected
    • Whether SPSB1 directly determines linkage specificity unknown
  7. 2018 Medium

    Revealed SPSB1 itself is a regulated target, with Ras driving its ubiquitination and turnover to relieve TGF-β suppression.

    Evidence Co-IP, co-localization, ubiquitination, reporter, and transwell assays in Ras-transformed cells

    PMID:29534718

    Open questions at the time
    • E3 ligase responsible for Ras-induced SPSB1 ubiquitination not identified
    • Mono/di-ubiquitination role in turnover mechanism incomplete
  8. 2019 Medium

    Extended SPSB1 substrate range to p21 and the circadian repressor RevErbα, connecting it to cancer cell survival and clock period control.

    Evidence Co-IP, ubiquitination and stability assays, ligase screen, and circadian period measurement

    PMID:30712944 PMID:31607207

    Open questions at the time
    • Substrate motif on p21 and RevErbα not mapped
    • Paralog redundancy (SPSB4) for RevErbα not fully separated functionally
  9. 2020 Medium

    Showed SPSB1 restrains NF-κB at or downstream of the p65 heterodimer via its SOCS box, broadening its innate-immune brake function.

    Evidence Systematic SOCS-box siRNA screen, NF-κB reporters, endogenous Co-IP, and translocation imaging

    PMID:32038638

    Open questions at the time
    • Whether p65 is a degradation substrate or sequestered partner unresolved
    • Step downstream of nuclear translocation not pinpointed
  10. 2023 High

    Established an in vivo pathological role: inflammatory cytokines induce SPSB1 to degrade TβRII and drive sepsis muscle atrophy, reversible by knockdown.

    Evidence Co-IP, ubiquitination, half-life and protein synthesis assays, plus AAV9-shRNA in vivo rescue in septic mice

    PMID:37209006

    Open questions at the time
    • Relative contribution of TβRII degradation vs other substrates to atrophy not quantified
  11. 2026 Medium

    Connected SPSB1 to tumor immune evasion, showing it degrades KLF6 to limit PD-L1 and is post-transcriptionally controlled by PTBP3.

    Evidence Knockdown, ubiquitination assay, T cell exhaustion co-culture, in vivo tumor models, and mRNA stability assay

    PMID:42055144

    Open questions at the time
    • Direct vs indirect ubiquitination of KLF6 not biochemically isolated
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SPSB1 selects among its many substrates in a given cell context, and what governs whether it builds degradative versus non-degradative ubiquitin chains, remains unresolved.
  • No unified model for context-dependent substrate prioritization
  • Chain-linkage determinants for K29 vs canonical degradative chains undefined
  • No structural model of the assembled SPSB1-Cullin-5-substrate ligase

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016874 ligase activity 2 GO:0098772 molecular function regulator activity 2 GO:0060089 molecular transducer activity 1
Localization
GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3 R-HSA-9909396 Circadian clock 1
Partners
CDKN1AHNRNPA1KLF6METNOS2NR1D1RELATGFBR2
Complex memberships
Elongin B/C-Cullin-5-Rbx2 E3 ligase

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 SPSB1 acts as an E3 ubiquitin ligase adaptor that, upon EGF stimulation, recruits Elongin B/C-Cullin complexes to conjugate lysine 29-linked polyubiquitin chains onto hnRNP A1, a splicing regulator, leading to altered alternative splicing of Rac1 (producing Rac1b isoform) and promoting cell migration. Co-immunoprecipitation, ubiquitylation assays, RNA splicing analysis, RNAi knockdown, cell migration assays Cell research High 28084329
2010 SPSB1 binds substrate peptides via its SPRY domain using a consensus motif (ELNNNL in Par-4; DINNNN in Drosophila VASA). Crystal structures of SPSB1, SPSB2, and SPSB4 revealed the structural basis for substrate recognition; mutation of each of the three Asn residues in Par-4 abrogated binding to all three SPSB proteins. X-ray crystallography, NMR chemical shift perturbation, site-directed mutagenesis, binding affinity measurements Journal of molecular biology High 20561531
2011 SPSB1 interacts with inducible nitric oxide synthase (iNOS) and negatively regulates iNOS protein levels and NO production downstream of TLR3 and TLR4 signaling via a proteasome-dependent mechanism, acting as part of a negative-feedback loop. SPSB1 transgenic mouse macrophages, shRNA knockdown, co-immunoprecipitation, NO production assays, proteasome inhibitor experiments Journal of immunology High 21876038
2015 SPSB1 negatively regulates the TGF-β signaling pathway by interacting with TGF-β type II receptor (TβRII) — but not TβRI — via its SPRY domain, co-localizing with TβRII on the cell membrane, and promoting TβRII ubiquitination and proteasomal degradation via its SOCS box. siRNA-mediated silencing of SPSB1 enhanced TGF-β signaling, cell migration, and invasion. Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assay, siRNA knockdown, TGF-β reporter assay, migration/invasion assays The Journal of biological chemistry High 26032413
2005 SPSB1 (SSB-1) binds to the MET receptor tyrosine kinase through its SPRY domain in both basal and HGF-stimulated conditions. HGF stimulation recruits more SPSB1 to MET and induces SPSB1 phosphorylation at tyrosine 31. Overexpression of SPSB1 enhances HGF-induced Erk phosphorylation and Elk-1/SRE activation; RNAi knockdown reduces these responses. Phosphorylated SPSB1 binds p120RasGAP but does not promote its degradation. Co-immunoprecipitation, luciferase reporter assays (SRE), RNAi knockdown, Western blot (Erk phosphorylation), tyrosine phosphorylation analysis The Journal of biological chemistry Medium 15713673
2014 SPSB1 potentiates c-MET signaling to protect tumor cells from apoptosis induced by HER2/neu pathway inhibition or chemotherapy, promoting breast cancer recurrence in genetically engineered mouse models. SPSB1 overexpression is sufficient to promote tumor recurrence and necessary for it. Genetically engineered mouse models, gain- and loss-of-function experiments, apoptosis assays, c-MET signaling pathway analysis Cancer discovery Medium 24786206
2019 SPSB1 directly interacts with p21 and promotes its ubiquitin-mediated proteasomal degradation, thereby destabilizing p21 and enhancing ovarian cancer cell survival and migration. Co-immunoprecipitation, ubiquitination assay, protein stability assay, siRNA knockdown, cell viability and migration assays Biochemical and biophysical research communications Medium 30712944
2019 SPSB1 and its paralog SPSB4, but not SPSB2 or SPSB3, interact with the circadian clock protein RevErbα and facilitate its ubiquitination and proteasomal degradation, thereby regulating circadian period length. Cell-based functional ubiquitin ligase screen, co-immunoprecipitation, ubiquitination assay, circadian period measurement Journal of biological rhythms Medium 31607207
2018 Ras interacts with the SPRY domain of SPSB1 and co-localizes with SPSB1 on the cell membrane, promoting SPSB1 protein degradation via enhanced mono- and di-ubiquitination. Reduced SPSB1 stabilizes TβRII, enhancing Smad2/3 phosphorylation and TGF-β signaling. Forced SPSB1 expression in Ras-transformed cells suppresses TGF-β signaling and migration/invasion. Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assay, luciferase reporter assay, transwell migration/invasion assay Cell communication and signaling Medium 29534718
2020 SPSB1 acts as a negative regulator of NF-κB activation downstream of multiple signaling pathways (TLRs, RNA and DNA sensing adaptors) via its SOCS-box domain. SPSB1 co-precipitates with the NF-κB subunit p65 at both overexpressed and endogenous levels but does not affect IκBα phosphorylation/degradation or p65 nuclear translocation, suggesting inhibition at or downstream of the NF-κB heterodimer level. Systematic siRNA depletion of SOCS-box proteins, NF-κB luciferase reporter assay, overexpression, co-immunoprecipitation (endogenous and overexpressed), p65 nuclear translocation imaging, cytokine measurement Frontiers in immunology Medium 32038638
2023 SPSB1 interacts with TβRII via its SPRY domain and promotes TβRII ubiquitination and destabilization via its SOCS box, impairing TβRII-Akt-Myogenin signaling and protein synthesis in myocytes. Inflammatory cytokines (TNF, IL-1β, IL-6) upregulate SPSB1 via NF-κB and gp130/JAK2/STAT3 pathways. AAV9-shRNA-mediated Spsb1 knockdown in vivo attenuated muscle atrophy in septic mice. Co-immunoprecipitation, ubiquitination assay, protein half-life assay, protein synthesis assay, immunocytochemistry, retroviral overexpression, AAV9-shRNA in vivo knockdown, qRT-PCR, Western blot Journal of cachexia, sarcopenia and muscle High 37209006
2026 SPSB1 ubiquitinates and destabilizes the transcription factor KLF6, thereby relieving KLF6-mediated transcriptional promotion of PD-L1. SPSB1 loss leads to KLF6 stabilization, increased PD-L1 expression, and T cell exhaustion. Upstream, PTBP3 binds the SPSB1 3'UTR to stabilize its mRNA. siRNA/shRNA knockdown, ubiquitination assay, co-culture T cell exhaustion assay, in vivo mouse tumor models, rescue experiments, mRNA stability assay Biochemical pharmacology Medium 42055144

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1984 Characterization of the structural and functional defect in the Escherichia coli single-stranded DNA binding protein encoded by the ssb-1 mutant gene. Expression of the ssb-1 gene under lambda pL regulation. The Journal of biological chemistry 95 6384214
1990 SSB-1 of the yeast Saccharomyces cerevisiae is a nucleolar-specific, silver-binding protein that is associated with the snR10 and snR11 small nuclear RNAs. The Journal of cell biology 82 2121740
1991 Monomer-tetramer equilibrium of the Escherichia coli ssb-1 mutant single strand binding protein. The Journal of biological chemistry 70 1988441
2017 SPSB1-mediated HnRNP A1 ubiquitylation regulates alternative splicing and cell migration in EGF signaling. Cell research 65 28084329
2010 Structural basis for Par-4 recognition by the SPRY domain- and SOCS box-containing proteins SPSB1, SPSB2, and SPSB4. Journal of molecular biology 54 20561531
2011 TLR regulation of SPSB1 controls inducible nitric oxide synthase induction. Journal of immunology (Baltimore, Md. : 1950) 53 21876038
1982 Effects of the ssb-1 and ssb-113 mutations on survival and DNA repair in UV-irradiated delta uvrB strains of Escherichia coli K-12. Journal of bacteriology 47 7045074
2005 The SPRY domain-containing SOCS box protein 1 (SSB-1) interacts with MET and enhances the hepatocyte growth factor-induced Erk-Elk-1-serum response element pathway. The Journal of biological chemistry 46 15713673
1983 Amplification of ssb-1 mutant single-stranded DNA-binding protein in Escherichia coli. Journal of molecular biology 46 6341603
1991 Monomers of the Escherichia coli SSB-1 mutant protein bind single-stranded DNA. Journal of molecular biology 41 1988680
2014 SPSB1 promotes breast cancer recurrence by potentiating c-MET signaling. Cancer discovery 38 24786206
2015 SPSB1, a Novel Negative Regulator of the Transforming Growth Factor-β Signaling Pathway Targeting the Type II Receptor. The Journal of biological chemistry 37 26032413
1981 Variable expression of the ssb--1 allele in different strains of Escherichia coli K12 and B: differential suppression of its effects on DNA replication, DNA repair and ultraviolet mutagenesis. Molecular & general genetics : MGG 37 6276686
1982 Suppression of the ssb-1 and ssb-113 mutations of Escherichia coli by a wild-type rep gene, NaCl, and glucose. Journal of bacteriology 29 6752116
1988 Suppression of the Escherichia coli ssb-1 mutation by an allele of groEL. Proceedings of the National Academy of Sciences of the United States of America 17 2897690
2023 SPSB1-mediated inhibition of TGF-β receptor-II impairs myogenesis in inflammation. Journal of cachexia, sarcopenia and muscle 16 37209006
2018 Ras enhances TGF-β signaling by decreasing cellular protein levels of its type II receptor negative regulator SPSB1. Cell communication and signaling : CCS 15 29534718
2019 SPSB1 enhances ovarian cancer cell survival by destabilizing p21. Biochemical and biophysical research communications 12 30712944
2020 Cullin-5 Adaptor SPSB1 Controls NF-κB Activation Downstream of Multiple Signaling Pathways. Frontiers in immunology 10 32038638
2009 Cloning and characterization of the SSB-1 and SSB-4 genes expressed in zebrafish gonads. Biochemical genetics 10 19184407
1987 Differential suppressor effects of the ssb-1 and ssb-113 alleles on uvrD mutator of Escherichia coli in DNA repair and mutagenesis. Journal of basic microbiology 10 2964522
2019 The E3 Ligases Spsb1 and Spsb4 Regulate RevErbα Degradation and Circadian Period. Journal of biological rhythms 8 31607207
2025 Testis-enriched Spsb1 is not required for spermatogenesis and fertility in mice. American journal of translational research 1 40226024
2026 Expanding the Fish-Brain Invitrome With the Senegalese Sole SsB-1 Cell Line-A Versatile Model for Neurotropic Virus Research. Journal of fish diseases 0 42046907
2026 SPSB1 inhibition induces cancer immune evasion by modulating the KLF6/PD-L1 axis in non-small cell lung cancer cells. Biochemical pharmacology 0 42055144
2025 Novel variants in ARID1B, SPSB1, and RAET1-AS shape genetic susceptibility and protection in systemic lupus erythematosus and lupus nephritis. Journal of translational autoimmunity 0 41146881

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