Affinage

STEAP2

Metalloreductase STEAP2 · UniProt Q8NFT2

Length
490 aa
Mass
56.1 kDa
Annotated
2026-06-10
22 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STEAP2 is a six-transmembrane metalloreductase that transfers electrons from cytosolic NADPH through FAD and heme cofactors to reduce extracellular metal ions, a mechanism resolved by crystal structures of its NADPH-bound N-terminal oxidoreductase domain with spectroscopic validation of the cofactor redox state (PMID:41101505). The protein traffics dynamically among the trans-Golgi network, plasma membrane, and endosomes, undergoing rapid surface internalization, and its second extracellular loop adopts a cholesterol-modulated conformation; notably, its metalloreductase activity is not detectable at the plasma membrane (PMID:12095985, PMID:29940176). Functionally, STEAP2 acts as a metal-handling driver of cancer cell behavior, but with context-dependent and opposing outcomes across tissues: in prostate cancer it promotes proliferation, survival, migration, and invasion through ERK activation and regulation of invasion-associated gene programs (PMID:20587517, PMID:29674723), whereas in hepatocellular carcinoma it elevates intracellular copper to activate the stress kinases p38 and JNK and thereby drive migration and invasion (PMID:38830975). In breast cancer, thyroid cancer, and glioma, by contrast, STEAP2 suppresses malignant phenotypes—inhibiting EMT and PI3K/AKT/mTOR signaling (PMID:31696760) and acting as a tumor suppressor (PMID:41856673). STEAP2 expression is post-transcriptionally controlled by METTL3-deposited m6A marks read by YTHDF1, which stabilize and promote translation of STEAP2 mRNA (PMID:35436987), and transcriptionally repressed through an ETV1-driven miR-3175 axis (PMID:41856673).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2002 Medium

    Established the subcellular distribution of STEAP2, framing it as a protein of the secretory and endocytic system rather than a static surface marker.

    Evidence GFP-fusion live imaging and immunofluorescence with EEA1 colocalization in cultured cells

    PMID:12095985 PMID:12429817

    Open questions at the time
    • Localization studies alone did not assign a molecular activity
    • Relative steady-state distribution between Golgi and plasma membrane unresolved across the two reports
  2. 2010 High

    Provided the first functional link between STEAP2 and cancer, showing it drives prostate cancer proliferation and survival via ERK.

    Evidence Ectopic overexpression and siRNA knockdown with cell cycle/apoptosis assays, ERK Western blot, and nude mouse xenograft

    PMID:20587517

    Open questions at the time
    • Did not connect the proliferative phenotype to STEAP2's enzymatic metalloreductase activity
    • Mechanism of ERK activation downstream of STEAP2 not defined
  3. 2014 Medium

    Demonstrated that STEAP2 is sufficient to confer invasive/migratory capacity, extending its role beyond proliferation to metastatic behavior.

    Evidence Gain-of-function overexpression in normal PNT2 prostate epithelial cells with transwell migration/invasion assays

    PMID:25248617

    Open questions at the time
    • No molecular effectors of the invasive phenotype identified
    • Gain-of-function in a single normal cell line
  4. 2018 Medium

    Mapped invasion-related transcriptional targets of STEAP2 and clarified its trafficking and the spatial restriction of its enzymatic activity.

    Evidence siRNA knockdown with invasion assays and gene-expression analysis (MMPs, CD82 etc.); conformation-sensitive antibody internalization, cholesterol manipulation, and cell-based metalloreductase assay

    PMID:29674723 PMID:29940176

    Open questions at the time
    • Whether the identified invasion genes are direct or indirect targets unresolved
    • Why metalloreductase activity is undetectable at the plasma membrane mechanistically unexplained
    • Functional role of cholesterol-dependent conformational change not established
  5. 2019 Medium

    Revealed that STEAP2 can act as a suppressor of EMT and PI3K/AKT/mTOR signaling, introducing tissue-dependent directionality to its function.

    Evidence Bidirectional lentiviral overexpression/shRNA in breast cancer cells with PI3K/AKT/mTOR Western blots, EMT profiling, invasion assays, and xenograft

    PMID:31696760

    Open questions at the time
    • Does not explain why STEAP2 is oncogenic in prostate but suppressive in breast
    • Link between metalloreductase activity and PI3K/AKT/mTOR not made
  6. 2022 Medium

    Defined upstream regulatory inputs to STEAP2 and placed it within signaling epistasis, identifying m6A control and an EFEMP2 axis.

    Evidence m6A assays with METTL3/YTHDF1 manipulation and rescue in thyroid cancer; STEAP2/EFEMP2 double-knockdown epistasis with PI3K/AKT/mTOR readouts in osteosarcoma

    PMID:35436987 PMID:36316642

    Open questions at the time
    • Direct binding of YTHDF1 to STEAP2 transcript versus indirect effect not fully separated
    • How EFEMP2 connects mechanistically to STEAP2 unresolved
  7. 2024 High

    Linked STEAP2's enzymatic identity to a downstream signaling output by showing it raises intracellular copper to activate p38/JNK.

    Evidence Bidirectional knockdown/overexpression in HCC cells with copper measurement, p38/JNK Western blots, copper rescue, pharmacological kinase inhibition, and in vivo growth

    PMID:38830975

    Open questions at the time
    • Whether copper elevation reflects direct cupric reductase activity of STEAP2 not structurally confirmed in this context
    • Mechanism connecting copper to p38/JNK activation undefined
  8. 2025 High

    Resolved the structural basis of the electron-transfer mechanism, validating NADPH→FAD→heme→metal flux through the oxidoreductase domain.

    Evidence High-resolution X-ray crystallography of the NADPH-bound OxRD with single-crystal UV-visible spectroscopy and cryo-EM comparison

    PMID:41101505

    Open questions at the time
    • Dynamics of OxRD-transmembrane domain reorientation not directly observed in real time
    • Structure does not address physiological metal-substrate selectivity in cells
  9. 2026 Medium

    Established a transcriptional repression circuit and reinforced STEAP2's tumor-suppressive role in glioma.

    Evidence ChIP, luciferase reporters, biotin-streptavidin pulldown, RNA immunoprecipitation, gain/loss-of-function, and rescue with xenograft

    PMID:41856673

    Open questions at the time
    • Does not reconcile tumor-suppressive role with oncogenic roles in other tissues
    • Whether suppression depends on STEAP2 metalloreductase activity untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how STEAP2's metalloreductase electron-transfer activity is mechanistically coupled to its opposing oncogenic versus tumor-suppressive signaling outcomes across tissues.
  • No unifying model linking metal reduction to context-dependent ERK/AKT/p38/JNK outcomes
  • Catalytically inactive mutants not used to test whether signaling roles require enzymatic activity
  • Physiological (non-cancer) function not characterized in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 2 GO:0016740 transferase activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 2 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1430728 Metabolism 1

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 STEAP2 (STAMP1) protein localizes to the Golgi complex (predominantly trans-Golgi network), plasma membrane, and vesicular tubular structures in the cytosol; it colocalizes with early endosome antigen 1 (EEA1), suggesting involvement in secretory/endocytic pathways. GFP-fusion construct imaged by quantitative time-lapse and immunofluorescence confocal microscopy; colocalization with EEA1 marker The Journal of biological chemistry Medium 12095985
2002 STEAP2 protein localizes mainly to the plasma membrane, as demonstrated by GFP fusion construct. GFP fusion construct and fluorescence microscopy Laboratory investigation; a journal of technical methods and pathology Low 12429817
2010 STEAP2 (STAMP1) promotes prostate cancer cell proliferation and survival: ectopic expression increased proliferation and activated ERK signaling, while siRNA knockdown inhibited growth, induced cell cycle arrest, and increased apoptosis (including TRAIL-induced apoptosis). Knockdown cells showed dramatically reduced xenograft growth in nude mice. Ectopic overexpression in DU145/COS-7 cells; siRNA knockdown in LNCaP cells; cell cycle analysis; apoptosis assays; ERK activation by Western blot; nude mouse xenograft Cancer research High 20587517
2014 STEAP2 overexpression in normal prostate epithelial PNT2 cells conferred the ability to migrate and invade, establishing a direct functional role for STEAP2 in driving invasive behavior. STEAP2 overexpression in PNT2 cells; migration and invasion assays (transwell) Clinical & experimental metastasis Medium 25248617
2018 STEAP2 knockdown in PC3 and LNCaP prostate cancer cells significantly decreased invasion; downstream targets identified include MMP3, MMP10, MMP13, FGFR4, IL1β, KiSS1, SERPINE1 (PC3), MMP7 (LNCaP), and CD82 (both lines), indicating STEAP2 regulates invasion-related gene expression programs. siRNA knockdown; proliferation, migration, and invasion assays; gene expression analysis Scientific reports Medium 29674723
2018 STEAP2 undergoes rapid internalization from the cell surface and traffics to the Golgi region and endosome-like puncta; acute inhibition of endocytosis increases detectable STEAP2 at the plasma membrane. Membrane cholesterol content modulates a conformation-sensitive epitope in the second extracellular loop of STEAP2, suggesting cholesterol-dependent conformational regulation during trafficking. STEAP2's metalloreductase activity was not detectable at the plasma membrane (negative finding). Monoclonal antibody recognizing conformation-sensitive epitope; antibody internalization assay; cholesterol manipulation; endocytosis inhibition; cell-based metalloreductase activity assay using STEAP4 as positive control Experimental cell research Medium 29940176
2019 STEAP2 upregulation in breast cancer cells inhibited EMT and suppressed PI3K/AKT/mTOR signaling pathway activity, reducing proliferation and invasion; conversely, STEAP2 downregulation promoted EMT and activated PI3K/AKT/mTOR signaling. Lentiviral overexpression and shRNA knockdown; Western blot for PI3K/AKT/mTOR phosphorylation; EMT marker profiling; in vitro invasion assays; in vivo xenograft Cancer biology & therapy Medium 31696760
2022 METTL3-mediated m6A modification of STEAP2 mRNA stabilizes STEAP2 mRNA and promotes its translation in an m6A-dependent manner via the reader protein YTHDF1; this METTL3-STEAP2 axis suppresses EMT and Hedgehog signaling in papillary thyroid cancer cells. m6A modification assays; METTL3 overexpression/silencing; YTHDF1 reader identification; rescue experiments; cell proliferation, migration and invasion assays; in vivo xenograft Cell death & disease Medium 35436987
2022 STEAP2 promotes osteosarcoma cell EMT, invasion, and migration via the PI3K/AKT/mTOR signaling axis; EFEMP2 overexpression reduces invasiveness and EMT partly by targeting STEAP2, and EFEMP2-induced PI3K/AKT/mTOR activation and EMT are abrogated when STEAP2 or Akt is knocked down, placing STEAP2 downstream of EFEMP2 in this pathway. STEAP2 and EFEMP2 overexpression/knockdown; Western blot for PI3K/AKT/mTOR; EMT markers; invasion/migration assays; epistasis via double KD; in vivo assays Cancer biology & therapy Medium 36316642
2024 STEAP2 functions as a metalloreductase that drives HCC cell migration and invasion by increasing intracellular copper levels and activating stress-activated MAP kinases p38 and JNK; copper supplementation rescued migration defects caused by STEAP2 knockdown, and p38 or JNK inhibitors blocked copper-mediated migration rescue. Stable STEAP2 KD and overexpression in HCC cell lines; intracellular copper measurement; Western blot for p38 and JNK activation; copper rescue experiment; p38/JNK pharmacological inhibition; in vitro migration/invasion; in vivo tumor growth Scientific reports High 38830975
2025 High-resolution crystal structures of the STEAP2 N-terminal cytosolic oxidoreductase domain (OxRD) bound to NADPH were solved; single-crystal spectroscopy directly validated the redox state of bound NADPH. Comparison with cryo-EM structure revealed conformational differences in the FAD-binding region, suggesting domain reorientation between OxRD and the transmembrane domain facilitates FADH2 loading and FAD release as part of the electron transfer pathway (NADPH→FAD→heme→extracellular metal ions). High-resolution X-ray crystallography; single-crystal UV-visible spectroscopy for redox-state validation; comparison with cryo-EM structure The Journal of biological chemistry High 41101505
2026 ETV1 transcriptionally activates miR-3175 through direct promoter binding; miR-3175 directly suppresses STEAP2 expression via conserved 3'UTR binding sites; STEAP2 functions as a tumor suppressor in glioma such that its overexpression inhibits malignant phenotypes. This ETV1/miR-3175/STEAP2 axis was confirmed by rescue experiments. Chromatin immunoprecipitation (ChIP); luciferase reporter assays; biotin-streptavidin pulldown; RNA immunoprecipitation; gain/loss-of-function studies; rescue experiments; in vivo xenograft BioFactors (Oxford, England) Medium 41856673

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 METTL3-mediated m6A modification of STEAP2 mRNA inhibits papillary thyroid cancer progress by blocking the Hedgehog signaling pathway and epithelial-to-mesenchymal transition. Cell death & disease 78 35436987
2002 Molecular cloning and characterization of STAMP1, a highly prostate-specific six transmembrane protein that is overexpressed in prostate cancer. The Journal of biological chemistry 71 12095985
2002 Cloning and characterization of a novel six-transmembrane protein STEAP2, expressed in normal and malignant prostate. Laboratory investigation; a journal of technical methods and pathology 50 12429817
2023 Antitumor activity of AZD0754, a dnTGFβRII-armored, STEAP2-targeted CAR-T cell therapy, in prostate cancer. The Journal of clinical investigation 44 37966111
2010 STAMP1 is both a proliferative and an antiapoptotic factor in prostate cancer. Cancer research 43 20587517
2014 A role for STEAP2 in prostate cancer progression. Clinical & experimental metastasis 41 25248617
2018 Phosphoesterification of soybean and peanut proteins with sodium trimetaphosphate (STMP): Changes in structure to improve functionality for food applications. Food chemistry 38 29699673
2018 STEAP2 Knockdown Reduces the Invasive Potential of Prostate Cancer Cells. Scientific reports 35 29674723
2019 STEAP2 is down-regulated in breast cancer tissue and suppresses PI3K/AKT signaling and breast cancer cell invasion in vitro and in vivo. Cancer biology & therapy 25 31696760
2022 STEAP2 promotes osteosarcoma progression by inducing epithelial-mesenchymal transition via the PI3K/AKT/mTOR signaling pathway and is regulated by EFEMP2. Cancer biology & therapy 18 36316642
2001 Sequence-tagged microsatellite profiling (STMP): a rapid technique for developing SSR markers. Nucleic acids research 15 11292857
2009 Six-transmembrane epithelial antigen of the prostate (STEAP1 and STEAP2)-differentially expressed by murine and human mesenchymal stem cells. Tissue engineering. Part A 14 19196137
2024 STEAP2 promotes hepatocellular carcinoma progression via increased copper levels and stress-activated MAP kinase activity. Scientific reports 8 38830975
2002 Sequence tagged microsatellite profiling (STMP): improved isolation of DNA sequence flanking target SSRs. Nucleic acids research 7 12466561
2024 Unveiling the role of copper metabolism and STEAP2 in idiopathic pulmonary fibrosis molecular landscape. Journal of cellular and molecular medicine 6 38872435
2018 Membrane cholesterol modulates STEAP2 conformation during dynamic intracellular trafficking processes leading to broad subcellular distribution. Experimental cell research 6 29940176
2022 A Molecular Docking Study of Human STEAP2 for the Discovery of New Potential Anti-Prostate Cancer Chemotherapeutic Candidates. Frontiers in bioinformatics 4 36304279
2023 Investigating STEAP2 as a potential therapeutic target for the treatment of aggressive prostate cancer. Cellular and molecular biology (Noisy-le-Grand, France) 2 37329528
2026 ETV1 Promotes Glioma Progression via miR-3175/STEAP2 Axis. BioFactors (Oxford, England) 0 41856673
2026 Strong STMP-crosslinked lignin/chitosan hydrogel films with enhanced aqueous stability and bioactivity for active food packaging. International journal of biological macromolecules 0 41997331
2026 STEAP2-associated modulation of PI3K/AKT/mTOR signaling contributes to ginkgetin-induced apoptosis in bladder cancer cells. Hereditas 0 42067902
2025 Structural and spectroscopic resolution of the NADPH redox state in the STEAP2 cytosolic oxidoreductase domain. The Journal of biological chemistry 0 41101505

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