Affinage

STAMBPL1

AMSH-like protease · UniProt Q96FJ0

Length
436 aa
Mass
49.8 kDa
Annotated
2026-06-10
24 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STAMBPL1 (AMSH-LP) is a JAMM-family zinc metalloprotease deubiquitinase whose catalytic domain coordinates zinc through a JAMM motif and is structurally configured to recognize and cleave Lys63-linked polyubiquitin chains (PMID:12810066, PMID:21888914). Through this isopeptidase activity it stabilizes a broad panel of substrates by reversing their ubiquitin-dependent degradation, functioning predominantly as a pro-survival, pro-tumorigenic regulator. It deubiquitinates and stabilizes anti-apoptotic proteins including survivin, c-FLIP, and XIAP, so that its depletion drives caspase-dependent apoptosis, ROS accumulation, and sensitization to TRAIL (PMID:31817770, PMID:31004702, PMID:37511599). STAMBPL1 also controls nutrient signaling by removing polyubiquitin from Sestrin2 to antagonize the E3 ligase RNF167, relieving Sestrin2-mediated inhibition of mTORC1 in response to leucine (PMID:35114100). Across cancer contexts it stabilizes additional K63-ubiquitinated substrates—SNAI1 to promote EMT and migration (PMID:32636467), MKP-1/DUSP1 to suppress JNK signaling and confer cisplatin resistance (PMID:35236965), TRAF2 to activate WNT/PI3K/NF-κB signaling (PMID:38419066), EGFR (preventing its lysosomal degradation, with additional enhancement of EGFR mRNA splicing via TOE1 deubiquitination) (PMID:39388352), NRF2 to activate GPX4 and impede ferroptosis through a positive feedback loop (PMID:39706065), AXL to drive mesenchymal gene expression and immune evasion (PMID:39527690), and IQGAP1 at K1368 to activate JAK2/STAT3 signaling (PMID:41307657). STAMBPL1 abundance is itself regulated: it is stabilized through interaction with the COP9 signalosome subunits CSN5/CSN6 and degraded by ROS-induced CRL1/proteasome activity, while its transcription is driven by NRF2, SREBP1, and an EGFR-MYC axis (PMID:35066747, PMID:39706065, PMID:39150093, PMID:39388352). Beyond its catalytic functions, STAMBPL1 can act non-enzymatically by binding FOXO1 to drive a GRHL3–HIF1A–VEGFA axis promoting angiogenesis (PMID:40208233), and it positively regulates HTLV-1 Tax-mediated NF-κB activation by controlling Tax nuclear export (PMID:22258247).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2003 Medium

    Established STAMBPL1 as a distinct JAMM/MPN-domain protein, defining its domain architecture and distinguishing it from the related AMSH by its inability to bind STAM1/Grb2 SH3 domains and its NLS-dependent nuclear access.

    Evidence cDNA cloning, domain analysis, subcellular localization and binding assays

    PMID:12810066

    Open questions at the time
    • No catalytic activity or substrate demonstrated
    • Functional consequence of nuclear localization unresolved
  2. 2011 High

    Provided the structural basis for STAMBPL1 enzymatic specificity, showing its catalytic JAMM domain coordinates zinc and is configured for Lys63-linked polyubiquitin recognition, with greater thermodynamic stability than AMSH.

    Evidence X-ray crystallography, unfolding studies, active-site mutagenesis

    PMID:21888914

    Open questions at the time
    • Structure does not identify physiological substrates
    • Cellular pathways using this activity not addressed
  3. 2012 Medium

    Linked STAMBPL1 catalytic activity to NF-κB regulation by showing it controls HTLV-1 Tax nuclear export, the first signaling role tied to its enzymatic function.

    Evidence siRNA screen/knockdown, catalytic-mutant comparison, NF-κB reporter, nuclear/cytoplasmic fractionation

    PMID:22258247

    Open questions at the time
    • Direct deubiquitination substrate in this pathway not identified
    • Mechanism of Tax transport control indirect
  4. 2018 Low

    Implicated STAMBPL1 in stabilizing the anti-apoptotic protein survivin post-translationally, an early indication of its pro-survival substrate repertoire.

    Evidence Overexpression/knockdown rescue, western blotting

    PMID:30360403

    Open questions at the time
    • No direct ubiquitination assay reported
    • Single method, single lab
  5. 2019 Medium

    Demonstrated STAMBPL1 directly deubiquitinates and stabilizes the anti-apoptotic proteins survivin and c-FLIP, and that loss diverts XIAP to lysosomal degradation, establishing apoptosis suppression as a core function.

    Evidence Co-IP, ubiquitination assays, RNAi, caspase/ROS assays, XIAP rescue

    PMID:31004702 PMID:31817770

    Open questions at the time
    • Ubiquitin linkage specificity on these substrates not resolved
    • Direct vs indirect XIAP effect unclear
  6. 2020 Medium

    Showed STAMBPL1 catalytic activity is required to stabilize the EMT transcription factor SNAI1, connecting its deubiquitinase function to migration and metastasis, with upstream control by mutant p53.

    Evidence CRISPR KO, siRNA, Co-IP/ubiquitination, IHC, migration assays

    PMID:32636467

    Open questions at the time
    • Ubiquitin linkage type on SNAI1 not defined
    • Mechanism of mutant-p53 regulation not detailed
  7. 2022 High

    Defined STAMBPL1 as a nutrient-signaling node that deubiquitinates Sestrin2 to antagonize RNF167 and relieve mTORC1 inhibition, and identified CSN5/CSN6 binding plus ROS-triggered CRL1 degradation as controls of its own stability.

    Evidence Reciprocal Co-IP, ubiquitination assays, KO rescue, xenograft, cell-permeable peptide, mTORC1 assays; proteasome/ROS dissection

    PMID:35066747 PMID:35114100

    Open questions at the time
    • In vivo relevance of mTORC1 axis to specific tumor types still developing
    • Determinants of substrate selection by the COP9-stabilized enzyme unclear
  8. 2022 High

    Identified MKP-1/DUSP1 as a STAMBPL1 substrate whose stabilization restrains JNK activation and confers cisplatin resistance, establishing a therapeutically actionable resistance mechanism.

    Evidence Genome-wide siRNA DUB screen, Co-IP, ubiquitination assay, rescue, xenograft, JNK phosphorylation

    PMID:35236965

    Open questions at the time
    • Ubiquitin linkage on MKP-1 not specified
    • Rescue only partial, implying additional effectors
  9. 2023 Medium

    Confirmed direct binding-dependent deubiquitination and stabilization of c-FLIP, mechanistically tying STAMBPL1 to TRAIL-resistance.

    Evidence Co-IP, ubiquitination assay, knockdown, xenograft

    PMID:37511599

    Open questions at the time
    • Linkage specificity not resolved
    • Single lab
  10. 2024 High

    Expanded the substrate map to K63-specific deubiquitination of TRAF2, EGFR, NRF2, and AXL, linking STAMBPL1 to NF-κB/WNT/PI3K, EGFR stability and splicing, ferroptosis resistance via a NRF2 feedback loop, and immune evasion, and identified SREBP1 as a transcriptional driver.

    Evidence Co-IP, GST pulldown, IP/MS, ubiquitination assays, DNA pulldown/luciferase/ChIP, domain mapping, splicing analysis, in vivo models

    PMID:38419066 PMID:39150093 PMID:39388352 PMID:39527690 PMID:39706065

    Open questions at the time
    • Substrate specificity determinants across this diverse panel unexplained
    • Relative contribution of each substrate in vivo not ranked
  11. 2025 High

    Demonstrated both catalytic site-specific (IQGAP1 K1368, dual K48/K63 removal driving JAK2/STAT3) and non-enzymatic (FOXO1–GRHL3–HIF1A–VEGFA angiogenesis) modes of STAMBPL1 action, broadening its mechanism beyond canonical K63 deubiquitination.

    Evidence MS, Co-IP, ubiquitination/site-directed mutagenesis, pharmacologic JAK2/epistasis, organoids; RNA-seq, catalytic-mutant comparison, angiogenesis assays

    PMID:40208233 PMID:41307657

    Open questions at the time
    • How a JAMM K63-specific enzyme also cleaves K48 chains on IQGAP1 unexplained
    • Structural basis of non-enzymatic FOXO1 function unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single Lys63-specific JAMM deubiquitinase achieves selectivity across such a broad and context-dependent substrate panel, and what governs the switch between its catalytic and non-enzymatic activities.
  • No unifying recruitment/specificity model
  • No structural basis for non-catalytic functions
  • Substrate hierarchy in physiological vs tumor contexts undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016787 hydrolase activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 2
Partners
CSN5EGFRIQGAP1NRF2RNF167SESN2SNAI1TRAF2

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 STAMBPL1 (AMSH-LP) contains a JAMM (JAB1/MPN domain metalloenzyme) motif and an MPN domain, is expressed ubiquitously, contains a putative nuclear localization signal (NLS), and is excluded from the nucleus when lacking either the NLS or MPN domain. Unlike AMSH, STAMBPL1 fails to bind to the SH3 domains of STAM1 and Grb2. cDNA cloning, domain analysis, subcellular localization experiments, binding assays Biochemical and biophysical research communications Medium 12810066
2011 The catalytic domain of STAMBPL1 (AMSH-LP) is nearly identical in structure to that of AMSH, both containing zinc coordination in the JAMM motif, but STAMBPL1 is thermodynamically more stable than AMSH. The crystal structure of STAMBPL1 reveals the structural basis for Lys63-linked polyubiquitin chain specificity. X-ray crystallography, guanidine-hydrochloride-induced unfolding studies, active-site mutagenesis (E280A in AMSH) Journal of molecular biology High 21888914
2012 STAMBPL1 is a positive regulator of HTLV-1 Tax-mediated NF-κB activation; its catalytic activity is required, as a catalytically inactive mutant does not enhance NF-κB activation. STAMBPL1 regulates Tax nuclear/cytoplasmic transport and is required for DNA damage-induced Tax nuclear export, indirectly controlling NF-κB signaling. siRNA library screen, siRNA knockdown, overexpression of wild-type vs. catalytically inactive STAMBPL1, NF-κB reporter assays, nuclear/cytoplasmic fractionation Journal of virology Medium 22258247
2019 STAMBPL1 interacts with survivin and c-FLIP, deubiquitinates them (reducing their ubiquitination levels), and thereby stabilizes these anti-apoptotic proteins. STAMBPL1 knockdown reduces survivin and c-FLIP protein levels, while overexpression of STAMBPL1 inhibits honokiol-induced survivin and c-FLIP degradation. Co-immunoprecipitation, ubiquitination assay, overexpression and knockdown (RNAi), western blotting Biomolecules Medium 31817770
2018 STAMBPL1 deubiquitinates survivin at the post-translational level to stabilize it; CEP-induced downregulation of STAMBPL1 leads to survivin degradation. Overexpression of STAMBPL1 markedly recovers CEP-mediated survivin downregulation. Overexpression, knockdown, western blotting, post-translational regulation assays International journal of molecular sciences Low 30360403
2019 STAMBPL1 knockdown in prostate cancer cells induces caspase-3/-7-dependent apoptosis accompanied by accumulation of cellular ROS and decreased XIAP protein content. STAMBPL1 depletion diverts XIAP protein to lysosomal degradation pathway, and ectopic XIAP expression almost completely abrogates STAMBPL1-KD-induced apoptosis. RNAi knockdown, caspase activity assays, ROS measurement, lysosomal inhibitor experiments, XIAP overexpression rescue Cancer letters Medium 31004702
2020 STAMBPL1 catalytic activity is required to affect the transcription factor SNAI1 stability; CRISPR knockout or genetic depletion of STAMBPL1 leads to SNAI1 destabilization, recovery of epithelial markers, and impaired migratory capacity. STAMBPL1 expression can be regulated by mutant p53. CRISPR knockout, siRNA knockdown, biochemistry (co-IP/ubiquitination), immunohistochemistry, cell migration assays British journal of cancer Medium 32636467
2021 Ubiquitin variant (UbV) inhibitors UbVSP.1 and UbVSP.3 bind to STAMBP with high affinity and inhibit its isopeptidase activity; UbVSP.1 also binds STAMBPL1. The crystal structure of the STAMBPL1-UbVSP.1 complex reveals hotspots of the JAMM-UbV interaction interface. Phage display, X-ray crystallography of STAMBPL1-UbV complex, in vitro isopeptidase activity assay The Journal of biological chemistry High 34425109
2022 STAMBPL1 is a deubiquitinase that removes polyubiquitin chains from Sestrin2, opposing the E3 ligase RNF167. Ubiquitination of Sestrin2 by RNF167 promotes its interaction with GATOR2 and inhibits mTORC1 signaling; STAMBPL1 deubiquitinates Sestrin2 to reverse this inhibition in response to leucine availability. A cell-permeable peptide blocking the STAMBPL1-Sestrin2 interaction inhibits mTORC1. Co-immunoprecipitation, ubiquitination assays, knockout/knockdown, xenograft tumor model, cell-permeable peptide inhibition, mTORC1 activity assays Molecular cell High 35114100
2022 STAMBPL1 directly interacts with COP9 signalosome subunits CSN5 and CSN6; this interaction with the CSN is required for STAMBPL1 protein stabilization and function. ROS induced by chemotherapeutic agents or H. pylori triggers CRL1 (cullin 1-RING ubiquitin ligase) and 26S proteasome-dependent degradation of STAMBPL1. STAMBPL1 deubiquitinates the anti-apoptotic protein Survivin to stabilize it and promote cell survival. Co-immunoprecipitation, proteasome inhibitor experiments, ROS induction, western blotting, ubiquitination assay Cellular and molecular life sciences Medium 35066747
2022 STAMBPL1 interacts with MKP-1 (DUSP1) and stabilizes it via deubiquitination. STAMBPL1 depletion sensitizes breast cancer cells to cisplatin in vitro and in vivo. Ectopic overexpression of MKP-1 partially rescues STAMBPL1 depletion-induced cisplatin sensitivity, and both STAMBPL1 and MKP-1 depletion increase JNK phosphorylation/activation. Genome-wide siRNA DUB screen, Co-immunoprecipitation, ubiquitination assay, overexpression rescue, in vivo xenograft, JNK phosphorylation assay Oncogene High 35236965
2023 STAMBPL1 directly binds and deubiquitinates c-FLIP when bound together, stabilizing c-FLIP protein levels. STAMBPL1 knockdown destabilizes c-FLIP and enhances TRAIL-mediated apoptosis. Co-immunoprecipitation, ubiquitination assay, knockdown, in vivo xenograft International journal of molecular sciences Medium 37511599
2024 STAMBPL1 interacts with TRAF2 via its 251-436 residues binding TRAF2's 294-496 residues, and deubiquitinates TRAF2 at K63 linkage, stabilizing TRAF2 protein levels. Stabilized TRAF2 promotes nuclear translocation of P65 and activates WNT/PI3K/NF-κB signaling. Co-immunoprecipitation, ubiquitination assay, domain mapping, western blotting, nuclear fractionation Biology direct Medium 38419066
2024 STAMBPL1 removes K63-linked ubiquitin chains from EGFR to prevent lysosomal degradation upon EGF stimulation, thereby stabilizing EGFR protein. Additionally, STAMBPL1 removes K63-linked ubiquitin chains from TOE1, which augments RNA splicing efficiency of EGFR mRNA by preventing intron retention. The EGFR-MYC axis positively feeds back to transcriptionally activate STAMBPL1. Co-immunoprecipitation, ubiquitination assay, in vitro and in vivo tumor models, RNA splicing analysis, knockdown/knockout Cell reports Medium 39388352
2024 STAMBPL1 stabilizes NRF2 through K63 deubiquitination; the 251-436 residues of STAMBPL1 interact with residues 228-605 of NRF2, facilitating DUB activity and protecting NRF2 from proteasome-mediated degradation. NRF2 in turn acts as a transcription factor binding the STAMBPL1 promoter to activate its transcription, forming a positive feedback loop. NRF2 stabilization by STAMBPL1 triggers GPX4 activation and ROS elimination, impeding ferroptosis. Co-immunoprecipitation, GST pull-down, IP/mass spectrometry, DNA pull-down, dual-luciferase reporter assay, ubiquitination assay, molecular docking, SPR, in vivo tumor models Phytomedicine High 39706065
2024 STAMBPL1 diminishes TRIM21-mediated K63-linked ubiquitination of AXL and its subsequent lysosomal degradation, thereby elevating AXL protein abundance and surface accumulation. This promotes mesenchymal gene expression while suppressing CXCL9/10 and HLA/B/C. STAMBPL1 also enhances PD-L1 transcription by facilitating nuclear translocation of p65. Co-immunoprecipitation, ubiquitination assay, knockdown, cell surface protein analysis, nuclear fractionation, in vivo models Advanced science Medium 39527690
2024 STAMBPL1 transcription is regulated by the transcription factor SREBP1; luciferase reporter and chromatin immunoprecipitation (ChIP) assays demonstrated SREBP1 binding to the STAMBPL1 promoter. STAMBPL1 activates the Wnt/β-catenin pathway and increases expression of downstream cancer-promoting genes in HCC. Luciferase reporter assay, chromatin immunoprecipitation (ChIP), overexpression and knockdown, western blotting, in vivo xenograft Molecular carcinogenesis Medium 39150093
2025 STAMBPL1 directly binds IQGAP1 and catalyzes the removal of both K48- and K63-linked ubiquitin chains specifically at the K1368 lysine residue of IQGAP1, stabilizing IQGAP1 protein levels. Stabilized IQGAP1 activates the JAK2/STAT3 signaling axis to promote gastric cancer malignant progression; pharmacological blockade of JAK2 with AG490 abrogated these oncogenic effects. Mass spectrometry, Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K1368), pharmacologic JAK2 blockade, patient-derived organoids, in vivo mouse models Journal of gastroenterology High 41307657
2025 SMAD3 stabilizes Sestrin2 protein levels by influencing the ubiquitination processes mediated by STAMBPL1 and RNF167; immunoprecipitation assays demonstrated interaction between SMAD3 and both ubiquitination-related enzymes. SMAD3 positively correlates with STAMBPL1 expression and modulates Sestrin2 stability in gastric cancer cells. Co-immunoprecipitation, western blotting, RT-qPCR, immunofluorescence, overexpression/knockdown functional assays Cell division Low 40751214
2025 STAMBPL1 increases HIF1A transcription in a non-enzymatic (catalytic-activity-independent) manner by interacting with the transcription factor FOXO1, which regulates GRHL3 transcription. GRHL3 in turn mediates HIF1A transcription, activating the HIF1α/VEGFA signaling pathway to facilitate tumor angiogenesis in triple-negative breast cancer. RNA-seq, Co-immunoprecipitation, knockdown/overexpression, reporter assays, in vitro angiogenesis assays eLife Medium 40208233

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 E3 ligase RNF167 and deubiquitinase STAMBPL1 modulate mTOR and cancer progression. Molecular cell 73 35114100
2024 A multi-omic analysis reveals that Gamabufotalin exerts anti-hepatocellular carcinoma effects by regulating amino acid metabolism through targeting STAMBPL1. Phytomedicine : international journal of phytotherapy and phytopharmacology 65 39348778
2011 Structural and thermodynamic comparison of the catalytic domain of AMSH and AMSH-LP: nearly identical fold but different stability. Journal of molecular biology 45 21888914
2012 An RNA interference screen identifies the Deubiquitinase STAMBPL1 as a critical regulator of human T-cell leukemia virus type 1 tax nuclear export and NF-κB activation. Journal of virology 38 22258247
2003 Identification of AMSH-LP containing a Jab1/MPN domain metalloenzyme motif. Biochemical and biophysical research communications 28 12810066
2019 Honokiol Enhances TRAIL-Mediated Apoptosis through STAMBPL1-Induced Survivin and c-FLIP Degradation. Biomolecules 27 31817770
2018 Cepharanthine Enhances TRAIL-Mediated Apoptosis Through STAMBPL1-Mediated Downregulation of Survivin Expression in Renal Carcinoma Cells. International journal of molecular sciences 26 30360403
2022 Helicobacter pylori-induced reactive oxygen species direct turnover of CSN-associated STAMBPL1 and augment apoptotic cell death. Cellular and molecular life sciences : CMLS 20 35066747
2019 Targeting the deubiquitinase STAMBPL1 triggers apoptosis in prostate cancer cells by promoting XIAP degradation. Cancer letters 20 31004702
2024 STAMBPL1/TRIM21 Balances AXL Stability Impacting Mesenchymal Phenotype and Immune Response in KIRC. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 18 39527690
2022 STAMBPL1 promotes breast cancer cell resistance to cisplatin partially by stabilizing MKP-1 expression. Oncogene 18 35236965
2020 Systematic analysis reveals a functional role for STAMBPL1 in the epithelial-mesenchymal transition process across multiple carcinomas. British journal of cancer 18 32636467
2021 Structural and functional characterization of ubiquitin variant inhibitors for the JAMM-family deubiquitinases STAMBP and STAMBPL1. The Journal of biological chemistry 17 34425109
2024 Unlocking hepatocellular carcinoma aggression: STAMBPL1-mediated TRAF2 deubiquitination activates WNT/PI3K/NF-kb signaling pathway. Biology direct 13 38419066
2019 STAMBPL1 knockdown has antitumour effects on gastric cancer biological activities. Oncology letters 13 31611951
2024 Liquidambaric acid inhibits cholangiocarcinoma progression by disrupting the STAMBPL1/NRF2 positive feedback loop. Phytomedicine : international journal of phytotherapy and phytopharmacology 9 39706065
2024 A MYC-STAMBPL1-TOE1 positive feedback loop mediates EGFR stability in hepatocellular carcinoma. Cell reports 7 39388352
2020 The Long Non-Coding RNA NEAT1 Promotes Gastric Cancer Cell Proliferation and Invasion by Regulating miR-103a/ STAMBPL1 Axis. Technology in cancer research & treatment 7 33111649
2023 STAMBPL1 promotes the progression of lung adenocarcinoma by inhibiting DHRS2 expression. Translational oncology 4 37393834
2024 STAMBPL1, transcriptionally regulated by SREBP1, promotes malignant behaviors of hepatocellular carcinoma cells via Wnt/β-catenin signaling pathway. Molecular carcinogenesis 3 39150093
2023 Tubeimoside-1 Enhances TRAIL-Induced Apoptotic Cell Death through STAMBPL1-Mediated c-FLIP Downregulation. International journal of molecular sciences 3 37511599
2025 STAMBPL1 activates the GRHL3/HIF1A/VEGFA axis through interaction with FOXO1 to promote angiogenesis in triple-negative breast cancer. eLife 1 40208233
2025 SMAD3 orchestrates RNF167 and STAMBPL1-mediated Sestrin2 ubiquitination to drive gastric cancer progression. Cell division 0 40751214
2025 STAMBPL1 promotes the progression of gastric cancer via deubiquitinating IQGAP1 to activate the JAK2/STAT3 pathway. Journal of gastroenterology 0 41307657

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