Affinage

SHKBP1

SH3KBP1-binding protein 1 · UniProt Q8TBC3

Length
707 aa
Mass
76.3 kDa
Annotated
2026-06-10
35 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SHKBP1 (SB1) is a Cullin-3 E3 ubiquitin ligase adaptor that controls the SQSTM1/p62–Keap1–Nrf2 antioxidant axis and contributes to tumor progression and anti-tumor immunity (PMID:41649860, PMID:34112919). It was first identified as a binding partner of SETA/SH3KBP1/CIN85, engaging the N-terminal SH3 domain of CIN85 (PMID:11152963). Mechanistically, SHKBP1 binds p62 directly at a site outside p62 bodies and inhibits p62 oligomerization and its incorporation into phase-separated p62 bodies; by limiting p62 assembly it prevents sequestration and degradation of Keap1, thereby restraining Nrf2 nuclear translocation and the cellular antioxidant response, a function that operates independently of SHKBP1's ubiquitination activity (PMID:41649860). In cancer, SHKBP1 acts downstream of TGFβ-induced EMT as a direct target of miR-499a, co-opting AKT activation to drive an EGFR-independent kinase switch that confers erlotinib resistance (PMID:31138318), and its genetic loss reduces tumor formation, migration, and invasion (PMID:34112919). SHKBP1 also regulates CD8+ T cell differentiation and anti-tumor immunity, as its knockout increases CD8+ T cell numbers and tumor infiltration while suppressing tumor growth (PMID:37343421).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2000 Medium

    Established the first molecular context for SHKBP1 by identifying it as a physical partner of the CIN85/SETA adaptor, implicating it in adaptor-mediated signaling.

    Evidence Yeast two-hybrid, in vitro confrontation assay, and co-immunoprecipitation mapping the interaction to CIN85's N-terminal SH3 domain

    PMID:11152963

    Open questions at the time
    • Functional consequence of the SHKBP1–CIN85 interaction not defined
    • No cellular pathway or downstream effect demonstrated
    • Single-lab interaction without orthogonal structural validation
  2. 2019 Medium

    Connected SHKBP1 to therapy resistance by showing it is a direct miR-499a target acting downstream of TGFβ-induced EMT to drive AKT-dependent, EGFR-independent kinase switching.

    Evidence Luciferase reporter assays, western blot, and in vitro/in vivo erlotinib resistance assays in osteosarcoma stem cell-like cells

    PMID:31138318

    Open questions at the time
    • Molecular mechanism by which SHKBP1 promotes AKT activation not resolved
    • Direct link to EGFR regulation at biochemical level unclear
    • Restricted to a single tumor model
  3. 2021 Medium

    Provided genetic causal evidence that SHKBP1 promotes tumor initiation and metastatic phenotypes via EMT, moving it from a candidate to a functional driver.

    Evidence Shkbp1 knockout mouse with chemical tumor induction plus migration/invasion and transplant/metastasis cell models

    PMID:34112919

    Open questions at the time
    • Molecular effector linking SHKBP1 to EMT markers not identified
    • Cell-autonomous versus immune-microenvironment contributions not separated
  4. 2023 Medium

    Defined a previously unknown immunoregulatory role, showing SHKBP1 restrains CD8+ T cell differentiation and anti-tumor immunity.

    Evidence Germline and adenoviral Shkbp1 knockout with subcutaneous melanoma model, flow cytometry, and spleen histology

    PMID:37343421

    Open questions at the time
    • Molecular pathway in T cells controlled by SHKBP1 not identified
    • Whether the immune phenotype reflects T cell-intrinsic function not resolved
  5. 2025 High

    Resolved a direct molecular mechanism: SHKBP1 binds p62 to block its oligomerization and phase separation, thereby preventing Keap1 sequestration and tuning Nrf2-dependent antioxidant responses independent of ubiquitination.

    Evidence Protein-protein interaction and domain mapping, live-cell imaging of p62 bodies, and Keap1/Nrf2 reporter assays (peer-reviewed, extended from a 2025 bioRxiv preprint)

    PMID:39896619 PMID:41649860

    Open questions at the time
    • Whether the antioxidant function explains the tumor and immune phenotypes not established
    • Role of SHKBP1's Cullin-3 adaptor/ubiquitination activity in vivo not defined
    • Structural basis of the SHKBP1–p62 interaction not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SHKBP1's distinct activities — CIN85 binding, p62/Keap1/Nrf2 regulation, AKT-driven kinase switching, and CD8+ T cell control — are mechanistically unified remains unresolved.
  • No single mechanism links the antioxidant, EMT, and immune phenotypes
  • Substrates of the SHKBP1–Cullin-3 complex unidentified
  • Tissue- and cell-type-specific functions not delineated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 1 R-HSA-8953897 Cellular responses to stimuli 1
Partners
CUL3KEAP1SH3KBP1SQSTM1

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 SHKBP1 (SB1) was identified as a novel binding partner of SETA (SH3KBP1/CIN85), interacting via SETA's N-terminal SH3 domain. The interaction was confirmed by in vitro confrontation assays and co-immunoprecipitation. SHKBP1 shares 55% amino acid identity with the renal tumor antigen NY-REN-45. Yeast two-hybrid screening, in vitro confrontation assay, co-immunoprecipitation Cellular signalling Medium 11152963
2019 SHKBP1 is a direct target of miR-499a and functions downstream of TGFβ-induced EMT to regulate EGFR activity. Increased SHKBP1 expression co-opts TGFβ-induced AKT activation and contributes to an EGFR-independent, AKT-activated kinase switch that confers resistance to erlotinib in osteosarcoma stem cell-like cells. Luciferase reporter assays confirmed miR-499a directly targets SHKBP1. Luciferase reporter assay, western blot, in vitro and in vivo erlotinib resistance assays, miRNA overexpression/knockdown Journal of experimental & clinical cancer research : CR Medium 31138318
2021 Shkbp1 knockout mice showed significantly reduced lung tumor formation after chemical induction, and Shkbp1 loss in cancer cell lines inhibited migration and invasion while overexpression promoted these phenotypes. SHKBP1 was associated with epithelial-mesenchymal transition (EMT) markers, placing it upstream of EMT-driven tumor progression. SHKBP1 was also found to be expressed in immune cells, and its knockout reduced tumor growth in subcutaneous transplant and metastasis models. Shkbp1 knockout mouse model, chemical tumor induction, cell migration/invasion assays, overexpression/knockdown cell lines, subcutaneous and tail-vein transplant tumor models Cancer gene therapy Medium 34112919
2023 Shkbp1 knockout mice exhibited abnormal spleen architecture (disrupted red and white pulp) and increased CD8+ T cell numbers and function in the spleen. Knockout of Shkbp1 enhanced CD8+ T cell infiltration into tumor tissue and inhibited subcutaneous melanoma tumor growth. Adenoviral-mediated Shkbp1 knockout similarly increased CD8+ T cell numbers and suppressed tumor growth, establishing a role for SHKBP1 in regulating CD8+ T cell differentiation and anti-tumor immunity. Shkbp1 knockout mouse model, subcutaneous melanoma model, adenoviral Shkbp1 targeting, flow cytometry of immune cells, histology Molecular immunology Medium 37343421
2025 SHKBP1 functions as a Cullin-3 E3 ubiquitin ligase adaptor that inhibits SQSTM1/p62 oligomerization through a direct protein-protein interaction mapped outside of p62 bodies. This interaction limits p62 assembly into phase-separated p62 bodies and prevents sequestration and degradation of Keap1, thereby affecting nuclear translocation of Nrf2 and the cellular antioxidant response. This mechanism is independent of SHKBP1's potential role in ubiquitination. Protein-protein interaction mapping, co-immunoprecipitation, live-cell imaging of p62 bodies, Keap1/Nrf2 reporter assays, domain mapping The Journal of cell biology High 41649860
2025 SHKBP1 interacts with SQSTM1/p62 outside p62 bodies to inhibit p62 oligomerization and incorporation into p62 bodies, preventing Keap1 sequestration. This is a non-ubiquitination-based function of the Cullin-3 adaptor SHKBP1 in regulating p62 phase separation and oxidative stress responses (preprint version of the above peer-reviewed paper). Protein-protein interaction mapping, p62 body phase-separation assays, Keap1 sequestration assays bioRxivpreprint Medium 39896619

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Bacteriophage Sb-1 enhances antibiotic activity against biofilm, degrades exopolysaccharide matrix and targets persisters of Staphylococcus aureus. International journal of antimicrobial agents 160 30236955
2006 PGRP-SB1: an N-acetylmuramoyl L-alanine amidase with antibacterial activity. Biochemical and biophysical research communications 120 17046713
2017 circ-SHKBP1 Regulates the Angiogenesis of U87 Glioma-Exposed Endothelial Cells through miR-544a/FOXP1 and miR-379/FOXP2 Pathways. Molecular therapy. Nucleic acids 95 29499945
2011 Drosophila immunity: analysis of PGRP-SB1 expression, enzymatic activity and function. PloS one 81 21364998
2000 SETA is a multifunctional adapter protein with three SH3 domains that binds Grb2, Cbl, and the novel SB1 proteins. Cellular signalling 56 11152963
2019 The TGFβ-miR-499a-SHKBP1 pathway induces resistance to EGFR inhibitors in osteosarcoma cancer stem cell-like cells. Journal of experimental & clinical cancer research : CR 45 31138318
2019 Correlation of Host Range Expansion of Therapeutic Bacteriophage Sb-1 with Allele State at a Hypervariable Repeat Locus. Applied and environmental microbiology 44 31492663
2021 Synergy between Phage Sb-1 and Oxacillin against Methicillin-Resistant Staphylococcus aureus. Antibiotics (Basel, Switzerland) 36 34356770
2019 Inducing perylenequinone production from a bambusicolous fungus Shiraia sp. S9 through co-culture with a fruiting body-associated bacterium Pseudomonas fulva SB1. Microbial cell factories 36 31277643
1978 Protection against Marek's disease-derived tumor transplants by the nononcogenic SB-1 strain of Marek's disease virus. Infection and immunity 33 215543
2011 Comparative genomic sequence analysis of the Marek's disease vaccine strain SB-1. Virus genes 26 21336949
1995 The human SB1.8 gene (DXS423E) encodes a putative chromosome segregation protein conserved in lower eukaryotes and prokaryotes. Human molecular genetics 24 7757074
2010 Comparative efficacy of BAC-derived recombinant SB-1 vaccine and the parent wild type strain in preventing replication, shedding and disease induced by virulent Marek's disease virus. Research in veterinary science 16 20144837
2018 Gallid herpesvirus 3 SB-1 strain as a recombinant viral vector for poultry vaccination. NPJ vaccines 13 29872549
2021 The signaling role of extracellular ATP in co-culture of Shiraia sp. S9 and Pseudomonas fulva SB1 for enhancing hypocrellin A production. Microbial cell factories 12 34301268
2014 Biosynthesis and hyper production of pullulan by a newly isolated strain of Aspergillus japonicus-VIT-SB1. World journal of microbiology & biotechnology 10 24609496
1987 Endogenous lectin from cultured soybean cells. Chemical characterization of the lectin of SB-1 cells. The Journal of biological chemistry 10 3584143
1986 Clonal analysis of HLA-DPw1 (SB1) associated allodeterminants: recognition of novel epitopes and evidence for quantitative variation in class II antigen expression. Human immunology 10 2419289
1995 The mouse Sb1.8 gene located at the distal end of the X chromosome is subject to X inactivation. Human molecular genetics 9 7757076
2021 Suppression of tumor growth and metastasis in Shkbp1 knockout mice. Cancer gene therapy 5 34112919
2019 Transcriptional Analyses of Innate and Acquired Immune Patterning Elicited by Marek's Disease Virus Vaccine Strains: Turkey Herpesvirus (HVT), Marek's Disease Virus 2 (strain SB1), and Bivalent Vaccines (HVT/SB1 and HVT-LT/SB1). Avian diseases 5 31865682
2023 CD8 + T-cell number and function are altered by Shkbp1 knockout mediated suppression of tumor growth in mice. Molecular immunology 4 37343421
2014 Bactericidal genes of Staphylococcal bacteriophage Sb-1. Current microbiology 4 24077954
2004 Pharmacokinetics of PEG-hemoglobin SB1, a hemoglobin-based oxygen carrier, after its intravenous administration in beagle dogs. Archives of pharmacal research 4 15022731
1981 [Characteristics of the primary and secondary DNA structure of staphylococcal phage SB-1]. Voprosy virusologii 4 6455010
1980 [Morphologic and physico-chemical characteristics of staphylococcal bacteriophage SB-1 virions]. Voprosy virusologii 4 6447948
2023 Optimisation of β-Glucosidase Production in a Crude Aspergillus japonicus VIT-SB1 Cellulase Cocktail Using One Variable at a Time and Statistical Methods and its Application in Cellulose Hydrolysis. International journal of molecular sciences 3 37373076
2025 Inhibition of SQSTM1/p62 oligomerization and Keap1 sequestration by the Cullin-3 adaptor SHKBP1. bioRxiv : the preprint server for biology 2 39896619
1983 [New type of DNA structural organization in the composition of bacteriophage Sb-1 particles]. Voprosy virusologii 2 6225249
1989 Endogenous lectin from cultured soybean cells: exposure of the SB-1 lectin on the cell wall. Experimental cell research 1 2680536
2026 Cullin-3 adaptor SHKBP1 inhibits SQSTM1/p62 oligomerization and Keap1 sequestration. The Journal of cell biology 0 41649860
2025 Tegument Protein pUL47 Is Important but Not Essential for Horizontal Transmission of Vaccinal Strain SB-1 of Gallid Alphaherpesvirus 3. Viruses 0 40143358
2025 SHKBP1 is a target for sepsis: evidence from WGCNA and multiple machine learning algorithms. Frontiers in immunology 0 41445732
2019 Synthesis and Structural Determination of the Disordered Bixbyite Cu3-x Sb1+x O5.5+3x/2 with Spin-Glass Behaviour. Chemistry, an Asian journal 0 30690904
1991 Mechanism of immunosuppression by a murine non-specific suppressor T cell line, SB-1. Chemical & pharmaceutical bulletin 0 1832591

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