PSCA encodes prostate stem cell antigen, a small glycosylphosphatidylinositol (GPI)-anchored glycoprotein of the Ly-6/uPAR (LU domain, three-finger) superfamily that is displayed on the outer face of the plasma membrane. It is expressed in prostate basal and secretory epithelium, bladder urothelium, stomach and colon neuroendocrine cells, placenta and kidney, is strongly overexpressed in prostate and bladder carcinoma, and is also present in human cerebral cortex. Like other Ly-6 (lynx-type) proteins, PSCA binds nicotinic acetylcholine receptor subunits - it forms stable complexes with the alpha-4 subunit CHRNA4 - and dampens nicotinic signalling, reducing nicotine-induced ERK phosphorylation. Being GPI-anchored, PSCA can be released from the surface by phospholipase cleavage and is recovered in prostatic exosomes. Common PSCA promoter and N-terminal-extension polymorphisms modify susceptibility to gastric and bladder cancer, and PSCA protein is elevated in Alzheimer disease frontal cortex.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8940388 | KEEP AS NON CORE | Summary: GPI-anchored PSCA can be released into the extracellular space. Reason: Reactome annotates PSCA as a GPLD1 substrate, so a soluble shed form exists outside the cell. The functional pool is the surface-anchored protein, so this is a secondary location. Supporting Evidence: Reactome:R-HSA-8940388 Phosphatidylinositol-glycan-specific phospholipase D (GPLD1) (Schofield et al. 2000) is a secreted protein that specifically cleaves GPI-anchored proteins |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference places Ly-6/lynx family activity at the plasma membrane. Reason: All characterized members of this GPI-anchored family act at the cell surface, and human PSCA surface anchoring is shown directly. Supporting Evidence: PMID:9465086 PSCA is expressed predominantly on the cell surface and is anchored by a GPI linkage |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: PSCA is GPI-anchored at the plasma membrane. Reason: Flow cytometry of intact cells and phospholipase sensitivity establish a cell-surface, GPI-linked protein, and UniProt records Cell membrane, GPI-anchor from the same study. Supporting Evidence: PMID:9465086 Flow cytometric analysis demonstrates that PSCA is expressed predominantly on the cell surface and is anchored by a GPI linkage. file:human/PSCA/PSCA-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:9465086}; |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: PSCA is GPI-anchored at the plasma membrane. Reason: Flow cytometry of intact cells and phospholipase sensitivity establish a cell-surface, GPI-linked protein, and UniProt records Cell membrane, GPI-anchor from the same study. Supporting Evidence: PMID:9465086 Flow cytometric analysis demonstrates that PSCA is expressed predominantly on the cell surface and is anchored by a GPI linkage. file:human/PSCA/PSCA-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:9465086}; |
| GO:0005886 plasma membrane | TAS PMID:9465086 Prostate stem cell antigen: a cell surface marker overexpres... | ACCEPT | Summary: PSCA is GPI-anchored at the plasma membrane. Reason: Flow cytometry of intact cells and phospholipase sensitivity establish a cell-surface, GPI-linked protein, and UniProt records Cell membrane, GPI-anchor from the same study. Supporting Evidence: PMID:9465086 Flow cytometric analysis demonstrates that PSCA is expressed predominantly on the cell surface and is anchored by a GPI linkage. file:human/PSCA/PSCA-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:9465086}; |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8940388 | ACCEPT | Summary: PSCA is GPI-anchored at the plasma membrane. Reason: Flow cytometry of intact cells and phospholipase sensitivity establish a cell-surface, GPI-linked protein, and UniProt records Cell membrane, GPI-anchor from the same study. Supporting Evidence: PMID:9465086 Flow cytometric analysis demonstrates that PSCA is expressed predominantly on the cell surface and is anchored by a GPI linkage. file:human/PSCA/PSCA-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:9465086}; |
| GO:0030548 acetylcholine receptor regulator activity | IBA GO_REF:0000033 | ACCEPT | Summary: PSCA is a lynx-type modulator of nicotinic acetylcholine receptors. Reason: PSCA belongs to the Ly-6/lynx family whose members bind and modulate nAChRs, and human PSCA forms stable complexes with the alpha-4 subunit and reduces nicotine-evoked signalling. The PAINT node placement matches direct human evidence. Supporting Evidence: PMID:25680266 We further showed that PSCA forms stable complexes with the Ξ±4 nAChR subunit and decreases nicotine-induced extracellular-signal regulated kinase phosphorylation in PC12 cells. file:human/PSCA/PSCA-uniprot.txt May act as a modulator of nicotinic acetylcholine receptors (nAChRs) activity. |
| GO:0033130 acetylcholine receptor binding | IBA GO_REF:0000033 | ACCEPT | Summary: PSCA binds nicotinic acetylcholine receptor subunits. Reason: Co-immunoprecipitation from human cortex and heterologous cells shows stable complexes between PSCA and the alpha-4 nAChR subunit (CHRNA4). Supporting Evidence: PMID:25680266 PSCA forms stable complexes with the Ξ±4 nAChR subunit file:human/PSCA/PSCA-uniprot.txt SUBUNIT: Interacts with CHRNA4. |
| GO:0033130 acetylcholine receptor binding | IDA PMID:25680266 Prostate stem cell antigen interacts with nicotinic acetylch... | ACCEPT | Summary: PSCA binds nicotinic acetylcholine receptor subunits. Reason: Co-immunoprecipitation from human cortex and heterologous cells shows stable complexes between PSCA and the alpha-4 nAChR subunit (CHRNA4). Supporting Evidence: PMID:25680266 PSCA forms stable complexes with the Ξ±4 nAChR subunit file:human/PSCA/PSCA-uniprot.txt SUBUNIT: Interacts with CHRNA4. |
| GO:0045202 synapse | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Synapse location inferred logically from the acetylcholine receptor signalling pathway. Reason: PSCA is present in human cortex and binds nAChR subunits, so a synaptic pool is plausible, but no direct synaptic localization experiment is available for the human protein; retained as a non-core, inferred compartment. Supporting Evidence: PMID:25680266 we detected bands corresponding to the Lynx proteins prostate stem cell antigen (PSCA) and Lypd6 in human cortex indicating that both proteins are present in the human brain |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: PSCA is detected in prostatic exosomes. Reason: Large-scale proteomics of exosomes from expressed prostatic secretions detects PSCA, consistent with release of a GPI-anchored surface protein in vesicles. Secondary to its plasma-membrane residence. |
| GO:0070373 negative regulation of ERK1 and ERK2 cascade | IDA PMID:25680266 Prostate stem cell antigen interacts with nicotinic acetylch... | ACCEPT | Summary: PSCA reduces nicotine-induced ERK1/2 phosphorylation. Reason: Direct cellular experiment - PSCA expression decreases nicotine-evoked ERK phosphorylation, the measured output of its negative modulation of nicotinic receptor signalling. Supporting Evidence: PMID:25680266 decreases nicotine-induced extracellular-signal regulated kinase phosphorylation in PC12 cells |
| GO:0095500 acetylcholine receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: PSCA acts in acetylcholine receptor signalling as a negative modulator. Reason: Phylogenetic inference from the lynx/Ly-6 family is supported for human PSCA by direct nAChR binding and suppression of nicotine-evoked signalling. Supporting Evidence: file:human/PSCA/PSCA-uniprot.txt In vitro inhibits nicotine-induced signaling |
| GO:0099601 regulation of neurotransmitter receptor activity | IDA PMID:25680266 Prostate stem cell antigen interacts with nicotinic acetylch... | ACCEPT | Summary: PSCA regulates nicotinic acetylcholine receptor activity. Reason: Binding to the alpha-4 subunit combined with reduced nicotine-induced downstream signalling demonstrates regulation of a neurotransmitter receptor. Supporting Evidence: PMID:25680266 These findings identify PSCA as a nAChR-binding protein in the human brain that is affected in AD |
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Download this section (compressed HTML)Q: Which nicotinic receptor subtypes does PSCA modulate in prostate and bladder epithelium, where it is most abundant but where cholinergic signalling is less studied than in brain?
Q: Does the reported in vitro cell-proliferation inhibition by PSCA depend on its nicotinic receptor modulation, or on a separate activity of the LU domain?
Q: Is the soluble, phospholipase-released form of PSCA biologically active, for example as a diffusible nicotinic receptor modulator?
Experiment: Electrophysiological recording of defined nAChR subtype combinations (alpha4beta2, alpha7, alpha3beta2) co-expressed with GPI-anchored or soluble PSCA, to quantify the direction and subtype selectivity of PSCA modulation.
Experiment: Surface-restricted proximity labelling from PSCA in human prostate epithelial and urothelial cells, to identify its physiological surface partners outside the nervous system.
Experiment: PSCA knockout and re-expression in human cortical neuron cultures, measuring nicotinic currents and ERK signalling, to test whether the elevated PSCA seen in Alzheimer cortex is sufficient to blunt cholinergic responses.
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