LYPD3 (C4.4A) is a glycosylphosphatidylinositol (GPI)-anchored cell-surface glycoprotein of the Ly6/uPAR family, a structural homologue of the urokinase receptor (PLAUR) with two Ly6/uPAR domains followed by a heavily O-glycosylated Ser/Thr/Pro-rich stalk. The mature protein is displayed entirely on the outer face of the plasma membrane and can be released by GPI-anchor cleavage. It is expressed in placenta, suprabasal keratinocytes of skin and urothelium, is upregulated in migrating keratinocytes during wound re-epithelialization, and is overexpressed in many carcinomas and metastases. Unlike uPAR it does not bind urokinase; reported partners include laminins and galectin-3 (from rat studies) and the ER folding factors AGR2 and AGR3. Its molecular function is poorly defined, but it is thought to support cell-matrix interactions and cell migration.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:31040128 Control of anterior GRadient 2 (AGR2) dimerization links end... | REMOVE | Summary: AGR2-LYPD3 association detected by the ERMIT assay in the ER of HEK293T cells. Reason: Bare protein binding is uninformative under the protein-binding policy. The AGR2 interaction is real (also found by yeast two-hybrid, PMID:12592373) but reflects LYPD3 acting as a client of the ER folding/quality-control protein AGR2, not a specific LYPD3 molecular function. Removal does not dispute the interaction. Supporting Evidence: PMID:31040128 proteins CD59 and LYPD3, that were reported in proteomics studies, were confirmed using ERMIT with the monomeric AGR2 E60A used as bait |
| GO:0005576 extracellular region | HDA PMID:16502470 Human colostrum: identification of minor proteins in the aqu... | KEEP AS NON CORE | Summary: LYPD3 detected among minor proteins of human colostrum by proteomics. Reason: LYPD3 is a GPI-anchored surface protein whose ectodomain can be released by GPI-anchor hydrolysis (Reactome GPLD1 reaction), so detection of soluble LYPD3 in a secretion is plausible. The extracellular pool is a secondary, shed form; the functional location is the outer face of the plasma membrane. Supporting Evidence: PMID:16502470 One hundred and fifty-one proteins were identified, 83 of which have not been previously reported in human colostrum, or milk. Reactome:R-HSA-8940388 Some proteins function at the cell's surface, attached to the plasma membrane via GPI (glycosylphosphatidylinositol) anchors |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8940388 | KEEP AS NON CORE | Summary: Reactome places the GPLD1-released form of LYPD3 in the extracellular region. Reason: The Reactome reaction depicts GPLD1 cleaving the GPI anchor and releasing the protein; this is a valid but secondary shed pool, not the principal site of LYPD3 action. Supporting Evidence: Reactome:R-HSA-8940388 Some proteins function at the cell's surface, attached to the plasma membrane via GPI (glycosylphosphatidylinositol) anchors |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane localization inherited across the uPAR/Ly6 family node. Reason: Consistent with the GPI anchor and direct surface staining of human C4.4A; the PAINT node includes LYPD3 itself and PLAUR among experimental descendants, which is expected rather than circular. Supporting Evidence: PMID:15012588 By immunohistochemistry we observed a pronounced surface staining for C4.4A in suprabasal keratinocytes of chronic human wounds file:human/LYPD3/LYPD3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor, GPI-anchor. |
| GO:0005886 plasma membrane | IDA PMID:31040128 Control of anterior GRadient 2 (AGR2) dimerization links end... | ACCEPT | Summary: The study treats LYPD3 as a plasma-membrane GPI-anchored protein while testing its interaction with AGR2. Reason: Plasma membrane is correct for LYPD3 and agrees with independent immunohistochemical surface staining and GPI-anchored expression on MCF7 cells; the curator read the full text, so the experimental annotation is retained. Supporting Evidence: PMID:31040128 proteins CD59 and LYPD3, that were reported in proteomics studies, were confirmed using ERMIT PMID:15012588 By immunohistochemistry we observed a pronounced surface staining for C4.4A in suprabasal keratinocytes of chronic human wounds |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location (Cell membrane; GPI-anchor) maps to plasma membrane. Reason: Correct mapping; LYPD3 is a GPI-anchored cell-surface glycoprotein. Supporting Evidence: file:human/LYPD3/LYPD3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor, GPI-anchor. PMID:15012588 MCF 7 cells, which express significant amounts of GPI-anchored C4.4A |
| GO:0005886 plasma membrane | TAS PMID:15012588 Structural analysis and tissue localization of human C4.4A: ... | ACCEPT | Summary: Biochemical/immunohistochemical characterization of glycolipid-anchored human C4.4A. Reason: The paper shows surface staining and a GPI-anchored native protein; plasma membrane is correct. Supporting Evidence: PMID:15012588 By immunohistochemistry we observed a pronounced surface staining for C4.4A in suprabasal keratinocytes of chronic human wounds PMID:15012588 MCF 7 cells, which express significant amounts of GPI-anchored C4.4A |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8940388 | ACCEPT | Summary: Reactome places GPI-anchored LYPD3 at the plasma membrane as GPLD1 substrate. Reason: Consistent with the GPI anchor and direct surface staining. Supporting Evidence: Reactome:R-HSA-8940388 Some proteins function at the cell's surface, attached to the plasma membrane via GPI (glycosylphosphatidylinositol) anchors PMID:15012588 By immunohistochemistry we observed a pronounced surface staining for C4.4A in suprabasal keratinocytes of chronic human wounds |
| GO:0016020 membrane | IEA GO_REF:0000120 | MODIFY | Summary: Generic membrane annotation from combined automated methods. Reason: True but too general: the evidence places LYPD3 specifically in the plasma membrane (outer leaflet, GPI-anchored), a term LYPD3 already carries. Proposed replacements: plasma membrane Supporting Evidence: file:human/LYPD3/LYPD3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor, GPI-anchor. PMID:15012588 By immunohistochemistry we observed a pronounced surface staining for C4.4A in suprabasal keratinocytes of chronic human wounds |
| GO:0034392 negative regulation of smooth muscle cell apoptotic process | IGI PMID:32151690 CircCBFB-mediated miR-28-5p facilitates abdominal aortic ane... | KEEP AS NON CORE | Summary: In a miR-28-5p/circCBFB axis study, LYPD3 knockdown/rescue affected vascular smooth muscle cell apoptosis. Reason: Abstract-only access; the study shows an anti-apoptotic effect of LYPD3 in cultured VSMCs within a miRNA-target framework. No mechanism links a cell-surface GPI-anchored protein directly to the apoptotic machinery, so this is at best an indirect, context-specific phenotype. Retained as non-core, deferring to the curator who read the full text. Supporting Evidence: PMID:32151690 MiR-28-5p acted as an apoptosis driver while circCBFB, GRIA4 and |
| GO:0043236 laminin binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Laminin binding transferred from rat C4.4A via Ensembl Compara orthology. Reason: Rat C4.4A was reported to bind laminin-1 and laminin-5, and UniProt records this for human LYPD3 only by similarity. Direct evidence for the human protein was not found; the binding is plausible for an adhesion-associated surface protein but not established as its core activity. Supporting Evidence: file:human/LYPD3/LYPD3-uniprot.txt SUBUNIT: Binds laminin-1 and laminin-5. Interacts with LGALS3 (By similarity). |
| GO:0009897 external side of plasma membrane | IDA PMID:15012588 Structural analysis and tissue localization of human C4.4A: ... | NEW | Summary: GPI-anchored LYPD3 resides in the outer leaflet with its full ectodomain exposed at the cell surface. Reason: A GPI anchor attaches the protein to the extracellular leaflet; human C4.4A shows pronounced surface staining in keratinocytes and is GPI-anchored on MCF7 cells. This term captures the cell-surface exposure more precisely than plasma membrane alone. Supporting Evidence: PMID:15012588 By immunohistochemistry we observed a pronounced surface staining for C4.4A in suprabasal keratinocytes of chronic human wounds PMID:15012588 MCF 7 cells, which express significant amounts of GPI-anchored C4.4A file:human/LYPD3/LYPD3-uniprot.txt SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor, GPI-anchor. |
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Download this section (compressed HTML)Q: Does human LYPD3 bind laminin-332 or laminin-111 directly, and is this binding required for its pro-migratory effect on keratinocytes?
Q: What fraction of LYPD3 is shed from the cell surface in vivo (by GPLD1 or proteases at the Tyr200-Arg204 site), and does soluble LYPD3 have its own activity?
Q: Is the AGR2/AGR3 interaction a chaperone-client relationship in the ER, or does it also occur extracellularly?
Experiment: Surface plasmon resonance or solid-phase binding of purified human LYPD3 ectodomain to laminin isoforms, galectin-3 and AGR2, coupled with keratinocyte scratch-wound migration assays in LYPD3-knockout cells rescued with wild-type or binding-deficient mutants.
Experiment: PI-PLC release and surface biotinylation of endogenous LYPD3 in keratinocytes to quantify the GPI-anchored versus shed pools.
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