STEAP2 (six-transmembrane epithelial antigen of the prostate 2, also STAMP1) is a multi-pass membrane metalloreductase of the STEAP family. It combines a cytoplasmic N-terminal NADPH-binding oxidoreductase domain with a six-helix transmembrane domain that binds FAD and heme b, transferring electrons from cytosolic NADPH across the membrane to reduce extracellular or luminal Fe(3+) and Cu(2+) chelates, thereby supporting cellular uptake of iron and copper. STEAP2 is expressed predominantly in prostate epithelium, where it localizes to the plasma membrane, the trans-Golgi network and endosomal vesicles, and it is highly expressed on the surface of prostate cancer cells.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | IDA PMID:12095985 Molecular cloning and characterization of STAMP1, a highly p... | KEEP AS NON CORE | Summary: GFP-STAMP1 localizes to Golgi, predominantly the trans-Golgi network. Reason: Direct imaging evidence of a biosynthetic/secretory pool; the functional sites are the plasma membrane and endosomes. Supporting Evidence: PMID:12095985 STAMP1 is localized to the Golgi complex, predominantly to the trans-Golgi network, and to the plasma membrane |
| GO:0005768 endosome | IBA GO_REF:0000033 | MODIFY | Summary: Endosome localization inherited across the STEAP family. Reason: Correct but general; human STEAP2 colocalizes with EEA1 (early endosome), a descendant term already carried. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1923560 SUPPORTS TRANSFER Mouse Steap2 colocalizes with Tf/TfR1 endosomes; the transfer is sound, but the human-specific early-endosome term is more precise. Proposed replacements: early endosome Supporting Evidence: PMID:12095985 colocalizes with the early endosome antigen 1 (EEA1) |
| GO:0005768 endosome | IEA GO_REF:0000107 | MODIFY | Summary: Endosome via Ensembl Compara from mouse Steap2. Reason: Correct but general; early endosome is supported by direct human evidence. Proposed replacements: early endosome Supporting Evidence: PMID:16609065 However, Steap2 colocalizes nearly completely with Tf and TfR1 |
| GO:0005769 early endosome | IDA PMID:12095985 Molecular cloning and characterization of STAMP1, a highly p... | KEEP AS NON CORE | Summary: STAMP1 vesicles colocalize with EEA1. Reason: Direct evidence for an endosomal pool where reduction of transferrin-released iron could occur. Supporting Evidence: PMID:12095985 STAMP1 also localizes to vesicular tubular structures in the cytosol and colocalizes with the early endosome antigen 1 (EEA1) |
| GO:0005829 cytosol | IDA PMID:12095985 Molecular cloning and characterization of STAMP1, a highly p... | MARK AS OVER ANNOTATED | Summary: The paper describes vesicular tubular structures "in the cytosol". Reason: These are membrane-bound vesicles within the cytoplasm; a six-TM protein is not a cytosolic protein. The text supports vesicle/endosome localization, already captured. Supporting Evidence: PMID:12095985 STAMP1 also localizes to vesicular tubular structures in the cytosol |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane localization inherited across the STEAP family. Reason: Consistent with direct human data. Supporting Evidence: PMID:37966111 more than 75% of all tumor cells as positive for cell surface STEAP2 |
| GO:0005886 plasma membrane | IDA PMID:12095985 Molecular cloning and characterization of STAMP1, a highly p... | ACCEPT | Summary: GFP-STAMP1 at the plasma membrane. Reason: Direct imaging evidence, corroborated by IHC of cell-surface STEAP2 in prostate cancer. Supporting Evidence: PMID:12095985 STAMP1 is localized to the Golgi complex, predominantly to the trans-Golgi network, and to the plasma membrane |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Automated plasma membrane annotation. Reason: Consistent with experimental evidence. Supporting Evidence: PMID:37966111 more than 75% of all tumor cells as positive for cell surface STEAP2 |
| GO:0006893 Golgi to plasma membrane transport | IDA PMID:12095985 Molecular cloning and characterization of STAMP1, a highly p... | MARK AS OVER ANNOTATED | Summary: Inferred from GFP-STAMP1 trafficking between Golgi and plasma membrane. Reason: STEAP2 is cargo of the secretory pathway rather than a component that performs Golgi-to-plasma membrane transport; the paper only speculates on pathway involvement. Supporting Evidence: PMID:12095985 suggesting that it may be involved in the secretory/endocytic pathways |
| GO:0006897 endocytosis | IDA PMID:12095985 Molecular cloning and characterization of STAMP1, a highly p... | MARK AS OVER ANNOTATED | Summary: Inferred from endosomal colocalization. Reason: Being internalized does not make STEAP2 a component that executes endocytosis; no mechanistic role is shown. Supporting Evidence: PMID:12095985 suggesting that it may be involved in the secretory/endocytic pathways |
| GO:0008823 cupric reductase (NADH) activity | IBA GO_REF:0000033 | ACCEPT | Summary: Cupric reductase (NADH) activity inherited across the STEAP2/3/4 clade. Reason: Core enzymatic activity; mouse Steap2 reduces Cu(2+) in vitro. Supporting Evidence: PMID:16609065 Steap2, Steap3, and Steap4 not only reduce iron but also copper |
| GO:0008823 cupric reductase (NADH) activity | IEA GO_REF:0000107 | ACCEPT | Summary: Cupric reductase activity by Compara transfer from mouse Steap2. Reason: Consistent with direct functional data. Supporting Evidence: PMID:16609065 Steap2, Steap3, and Steap4 not only reduce iron but also copper |
| GO:0009725 response to hormone | IDA PMID:12095985 Molecular cloning and characterization of STAMP1, a highly p... | MARK AS OVER ANNOTATED | Summary: Response to hormone, inferred from androgen regulation of STAMP1 expression. Reason: The annotation rests on androgen regulation of STAMP1 expression reported in the cloning paper, so it records a real expression response; only the abstract is available. A gene whose expression depends on a hormone is regulated by that hormone, which does not make its protein a participant in the response. The term over-states the evidence, as the earlier assessment itself concluded, and is marked as an over-annotation rather than removed. Supporting Evidence: PMID:12095985 STAMP1 is highly expressed in the androgen-sensitive, androgen receptor-positive prostate cancer cell line LNCaP |
| GO:0010008 endosome membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt endosome membrane location. Reason: Supported by EEA1 colocalization; the endosomal membrane is a genuine functional site but secondary to the plasma membrane. Supporting Evidence: PMID:12095985 colocalizes with the early endosome antigen 1 (EEA1) |
| GO:0010008 endosome membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Endosome membrane by similarity to mouse Q8BWB6. Reason: Same functional site; consistent with the IEA and direct colocalization evidence. Supporting Evidence: PMID:16609065 However, Steap2 colocalizes nearly completely with Tf and TfR1 |
| GO:0015677 copper ion import | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Copper ion import, inherited across the STEAP2/3/4 clade. Reason: STEAP2 cupric reductase activity promotes cellular copper uptake; a downstream physiological process the reductase contributes to. Supporting Evidence: PMID:16609065 cupric reductases that stimulate cellular uptake of both iron and copper in vitro |
| GO:0030140 trans-Golgi network transport vesicle | IDA PMID:12095985 Molecular cloning and characterization of STAMP1, a highly p... | KEEP AS NON CORE | Summary: STAMP1 in trans-Golgi network transport vesicles. Reason: Consistent with the TGN pool seen by live imaging; a secretory-pathway location. Supporting Evidence: PMID:12095985 STAMP1 is localized to the Golgi complex, predominantly to the trans-Golgi network |
| GO:0045055 regulated exocytosis | IDA PMID:12095985 Molecular cloning and characterization of STAMP1, a highly p... | MARK AS OVER ANNOTATED | Summary: Regulated exocytosis, inferred from vesicular trafficking of STAMP1. Reason: The imaging shows STAMP1 as cargo trafficking through vesicles; it does not establish that STEAP2 executes regulated exocytosis. Supporting Evidence: PMID:12095985 suggesting that it may be involved in the secretory/endocytic pathways |
| GO:0052851 ferric-chelate reductase (NADPH) activity | IBA GO_REF:0000033 | ACCEPT | Summary: Ferric-chelate reductase (NADPH) activity inherited across the STEAP2/3/4 clade. Reason: Core enzymatic activity; mouse Steap2 reduces Fe(III) in vitro. Supporting Evidence: PMID:16609065 Figure 5A demonstrates that Steap2, Steap3, and Steap4 all promote the reduction of iron in vitro |
| GO:0052851 ferric-chelate reductase (NADPH) activity | IEA GO_REF:0000107 | ACCEPT | Summary: Ferric-chelate reductase activity by Compara transfer from mouse Steap2. Reason: Consistent with direct functional data. Supporting Evidence: PMID:16609065 Figure 5A demonstrates that Steap2, Steap3, and Steap4 all promote the reduction of iron in vitro |
| GO:7770068 ferric iron reductase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Ferric iron reductase activity from Rhea reaction mapping (RHEA:71767). Reason: Correct electron-transfer chemistry for STEAP2; consistent with the curated catalytic activity and the ferric-chelate reductase annotations. Supporting Evidence: file:human/STEAP2/STEAP2-uniprot.txt Mediates sequential transmembrane electron transfer from NADPH to FAD and onto heme, and finally to the Fe(3+) chelate |
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Download this section (compressed HTML)Q: Does human STEAP2 reduce Fe(3+) and Cu(2+) directly in intact cells, or does it require partner STEAP subunits as proposed for STEAP1?
Q: Which cellular pool (plasma membrane vs transferrin-cycle endosome) predominates for STEAP2 metalloreductase activity in prostate epithelium?
Experiment: Reconstitute purified human STEAP2 in nanodiscs and measure NADPH-dependent Fe(3+)/Cu(2+) reductase kinetics, and knock down STEAP2 in LNCaP cells to quantify surface ferrireductase activity and iron/copper uptake.
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