GLIPR1 is a type-I single-pass membrane member of the CAP/CRISP superfamily, produced with an N-terminal signal peptide and a large extracellular CAP domain; soluble or released ectodomain forms can also act on cells. Its direct physiological ligand and biochemical activity are unresolved. In prostate cancer cells, GLIPR1 restoration promotes ROS-JNK-dependent apoptosis and suppresses proliferation through CK1alpha/c-Myc and Hsc70-AURKA/TPX2-linked pathways. In glioma cells and glioma stem cells it has the opposite, context-specific effect of promoting N-WASP-dependent spreading, migration, invasion, and matrix degradation while weakening the inhibitory association between N-WASP and hnRNPK. GLIPR1 is therefore a context-dependent membrane and extracellular regulatory protein rather than a demonstrated enzyme or a universally acting tumor suppressor.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT places GLIPR1 activity in the extracellular region, consistent with its signal peptide, extracellular CAP domain, type-I membrane topology, and biologically active soluble ectodomain. Reason: Extracellular exposure is broadly conserved among CAP-family proteins and is independently supported for human GLIPR1 by the crystal-structure study and reviewed sequence topology. The term accommodates both the extracellular-facing membrane pool and released or soluble forms. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000036124 · broad PTHR10334 ancestral node SUPPORTS TRANSFER Multiple extracellular CAP-family seeds support this conserved localization, and GLIPR1's own signal peptide and topology provide independent corroboration. Supporting Evidence: PMID:21931216 GLIPR1 is composed of a signal peptide that directs its secretion, a conserved cysteine-rich CAP (cysteine-rich secretory proteins, antigen 5 and pathogenesis-related 1 proteins) domain and a transmembrane domain. |
| GO:0060090 molecular adaptor activity | IBA GO_REF:0000033 | REMOVE | Summary: PAINT propagated molecular adaptor activity from mouse Glipr1l1 across a broad CAP-family ancestral node to GLIPR1. Reason: Mouse Glipr1l1 is a specialized sperm/acrosomal paralog, and the CAP family has strongly diversified functions. Human GLIPR1 interacts with N-WASP, hnRNPK, and Hsc70, but no study shows it bringing molecules together as required by the GO definition. In the best-defined glioma mechanism, GLIPR1 instead decreases the N-WASP-hnRNPK association. The sole Glipr1l1-derived seed therefore does not support adaptor activity in GLIPR1. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG CONTEXT OR TISSUE MISMATCH ROLE CONFLATION Sources checked: MGI:MGI:1916536 · mouse Glipr1l1 SUPPORTS SOURCE BUT NOT TARGET The source activity belongs to a sperm/acrosomal GLIPR1-like paralog functioning in IZUMO1 localization during the acrosome reaction. gomodel:62f58d8800005094/62f58d8800005346 · mouse Glipr1l1 GO-CAM adaptor activity SUPPORTS SOURCE BUT NOT TARGET The production model places the activity at the outer acrosomal membrane in protein localization during the acrosome reaction, a sperm-specific context not shared by GLIPR1. PANTHER:PTN000036124 · broad PTHR10334 ancestral node UNRESOLVED This node spans many functionally divergent CAP-family subfamilies and is too broad for propagation of the Glipr1l1-specific adaptor role. Supporting Evidence: PMID:26305187 overexpression of RTVP-1 decreased the association of N-WASP and hnRNPK. file:human/GLIPR1/GLIPR1-deep-research-manual.md Human GLIPR1's own interactions do not demonstrate the GO-defined activity of bringing two molecules together. |
| GO:0005576 extracellular region | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro maps the CAP-family signature to the broad extracellular region. The canonical human protein is more precisely an extracellular-facing type-I plasma-membrane protein, while soluble forms can also be released. Reason: The broad localization is correct for both the extracellular-facing membrane pool and released or soluble GLIPR1. A separate proposed annotation to GO:0009897 captures the more precise topology of the canonical membrane-bound pool without invalidating this broader term. Supporting Evidence: PMID:21931216 A model is also proposed for the structure of full-length membrane-bound GLIPR1. |
| GO:0016020 membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping assigns the canonical single-pass membrane protein to membrane. Reason: The reviewed human sequence contains a C-terminal transmembrane helix, and the human structural study explicitly models full-length membrane-bound GLIPR1. The term is broad but correct and independently supported. Supporting Evidence: PMID:21931216 Human glioma pathogenesis-related protein 1 (GLIPR1) is a membrane protein |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: BioPlex 2.0 AP-MS reports an association between GLIPR1 and ALOXE3. Reason: The high-throughput interaction may be real and is repeated in BioPlex 3.0, but generic protein binding does not identify GLIPR1's molecular activity. The cached article does not establish a GLIPR1-specific functional consequence for the ALOXE3 association, so it should not be treated as core function. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: A neurodegeneration-focused interaction map reports GLIPR1 association with HTT. Reason: The interaction is retained in IntAct and UniProt, but generic protein binding is uninformative and the abstract-only cached paper does not establish a GLIPR1-specific consequence of HTT association. It should not define GLIPR1's molecular or biological core. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: BioPlex 3.0 independently reports the GLIPR1-ALOXE3 association seen in BioPlex 2.0. Reason: Replication strengthens confidence in co-association but does not convert the generic protein-binding term into an informative molecular function. ALOXE3-dependent consequences for GLIPR1 have not been demonstrated. |
| GO:0035577 azurophil granule membrane | TAS Reactome:R-HSA-6798739 | KEEP AS NON CORE | Summary: Reactome places GLIPR1 among azurophil-granule membrane proteins released during neutrophil degranulation. Reason: This is a plausible specialized localization for a single-pass membrane protein expressed in blood cells, and it should not be overruled from the summary-level Reactome cache. It represents a neutrophil trafficking context rather than the general site or defining function of GLIPR1. Supporting Evidence: Reactome:R-HSA-6798739 Exocytosis of azurophil granule membrane proteins |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | ACCEPT | Summary: High-throughput proteomics identified GLIPR1 in the membrane preparation of the YTS NK-like cell line. Reason: Although the cached abstract does not enumerate individual proteins, the curated HDA assignment agrees with GLIPR1's transmembrane helix and independent human structural evidence. Membrane localization is a core property of the canonical isoform. Supporting Evidence: PMID:19946888 The present study was initiated to define the composition of the membrane proteome of the Natural Killer (NK) like cell line YTS. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1989772 | ACCEPT | Summary: Reactome models expressed GLIPR1 protein at the plasma membrane. Reason: The Reactome event is sparse, but plasma-membrane placement is independently supported by the signal peptide plus C-terminal transmembrane topology and the human structure-based model of full-length membrane-bound GLIPR1. Supporting Evidence: PMID:21931216 A model is also proposed for the structure of full-length membrane-bound GLIPR1. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6798739 | ACCEPT | Summary: Reactome assigns plasma-membrane localization after exocytosis of GLIPR1-containing azurophil granules in neutrophils. Reason: Plasma-membrane localization is compatible with canonical GLIPR1 topology, and independent structural evidence establishes this as a general core location. This particular Reactome evidence describes a specialized neutrophil degranulation route, but the term itself is correct and core. Supporting Evidence: Reactome:R-HSA-6798739 Azurophil granules undergo limited exocytosis in response to stimulation |
| GO:0009897 external side of plasma membrane | IC PMID:21931216 Structural studies of human glioma pathogenesis-related prot... | NEW | Summary: Proposed topology-based human annotation. The canonical precursor has an N-terminal signal peptide, an extracellular CAP domain, and a C-terminal transmembrane helix, placing the mature CAP domain on the external side of the plasma membrane. Reason: External side of plasma membrane is more precise than the existing broad membrane and extracellular-region terms for the canonical membrane-bound protein. IC reflects curator inference from the experimentally solved human ectodomain and the structure-based full-length topology model. Supporting Evidence: PMID:21931216 A model is also proposed for the structure of full-length membrane-bound GLIPR1. |
| GO:0043065 positive regulation of apoptotic process | IMP PMID:18199537 Glioma pathogenesis-related protein 1 exerts tumor suppresso... | NEW | Summary: Proposed direct human-cell annotation. GLIPR1 restoration or overexpression promotes apoptosis through ROS production and sustained JNK signaling in several cancer-cell models. Reason: Gain-of-function experiments in human cancer cells and genetic loss in mouse provide causal support for a pro-apoptotic role. The annotation is context-dependent and does not imply that GLIPR1 promotes apoptosis in every cell type. Supporting Evidence: PMID:18199537 Overexpression of GLIPR1 in cancer cells leads to suppression of colony growth and induction of apoptosis. |
| GO:0008285 negative regulation of cell population proliferation | IMP PMID:22025562 GLIPR1 suppresses prostate cancer development through target... | NEW | Summary: Proposed direct human-cell annotation. Restoring GLIPR1 in prostate cancer cells decreases c-MYC expression and inhibits cell-cycle progression. Reason: GLIPR1 perturbation changes CK1alpha localization, beta-catenin/TCF4-driven c-MYC transcription, c-Myc turnover, and prostate-cell proliferation. This supports negative regulation of proliferation in the experimentally defined prostate context. Supporting Evidence: PMID:22025562 Restoration of GLIPR1 expression in prostate cancer cells downregulated c-myc levels, inhibiting cell-cycle progression. |
| GO:0030335 positive regulation of cell migration | IMP PMID:26305187 RTVP-1 regulates glioma cell migration and invasion via inte... | NEW | Summary: Proposed direct human-cell annotation. GLIPR1 gain and loss alter glioma cell and glioma-stem-cell spreading, migration, invasion, and matrix degradation through an N-WASP-dependent mechanism. Reason: Overexpression increases migration whereas GLIPR1 silencing decreases it, and N-WASP depletion attenuates the phenotype. The term captures the demonstrated glioma-cell process without asserting an unproven catalytic activity or universal effect across tissues. Supporting Evidence: PMID:26305187 We found that RTVP-1 increased cell spreading, migration and invasion and these effects were at least partly mediated by N-WASP. |
Loading supporting content…
Download this section (compressed HTML)Q: What physiological extracellular ligand, receptor, lipid, or substrate engages the GLIPR1 CAP-domain cavity, and is zinc coordination required?
Suggested experts: CAP-superfamily structural biologists, extracellular signaling biochemists
Q: Which normal human cell types use the prostate-like pro-apoptotic output, the glioma-like pro-migratory output, or a distinct GLIPR1 function?
Suggested experts: human tissue and single-cell biologists, cancer signaling specialists
Q: How does an extracellular-facing protein with a very short cytoplasmic tail control or contact cytosolic N-WASP, hnRNPK, Hsc70, and CK1alpha?
Suggested experts: membrane-trafficking and proteolysis specialists, cytoskeletal signaling biologists
Experiment: Purify full-length nanodisc-embedded GLIPR1 and its soluble CAP ectodomain, then perform quantitative ligand, lipid, protease, and metal-binding screens with CAP-cavity and zinc-coordinating residue mutants.
Hypothesis: GLIPR1 binds a restricted extracellular ligand or lipid through its CAP cavity, and this binding supplies the missing initiating molecular activity.
Type: biochemical activity and ligand-discovery profiling
Experiment: Endogenously tag GLIPR1 in primary prostate epithelial cells, macrophages, and patient-derived glioma cells; map topology, shedding, internalization, and proximity partners before and after defined stimuli.
Hypothesis: Cell-type-specific cleavage or internalization determines whether GLIPR1 engages extracellular, membrane, or cytosolic regulatory partners.
Type: endogenous topology, trafficking, and proximity proteomics
Experiment: Create GLIPR1-null human prostate epithelial and glioma organoid models and rescue them with full-length, cleavage-resistant, transmembrane-deleted, cytoplasmic-tail-deleted, and CAP-cavity mutant proteins while measuring ROS-JNK apoptosis, proliferation, N-WASP activity, migration, and invasion.
Hypothesis: Distinct GLIPR1 structural modules and trafficking states drive the pro-apoptotic prostate and pro-migratory glioma outputs.
Type: CRISPR genetics and separation-of-function rescue
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The direct physiological molecular activity, ligand, receptor, lipid, or substrate of human GLIPR1 is unknown.
OPEN BIOLOGY MF_DARK
What is known: The extracellular CAP-domain structure, zinc-coordinating cavity, single-pass topology, soluble ectodomain activity, and several downstream signaling consequences are established, but none identifies the initiating biochemical action.
Significance: Resolving this is necessary for a defensible molecular-function annotation and for distinguishing receptor, ligand, competitor, and catalytic models.
What would resolve it: Direct binding and activity screens with purified full-length and ectodomain protein, followed by cellular rescue with cavity mutants, should identify the initiating activity.
Provenance (the field's own admissions):
Gap: The normal physiological context and direction of GLIPR1 action are not established beyond disease-cell models.
OPEN BIOLOGY BP_DARK
What is known: Direct experiments show pro-apoptotic and antiproliferative effects in prostate cancer cells but pro-migratory and pro-invasive effects in glioma cells, while normal-tissue expression studies also disagree.
Significance: Without a normal-cell context, disease phenotypes cannot be safely treated as a single universal evolved core process.
What would resolve it: Conditional loss-of-function and endogenous rescue across primary human epithelial, immune, and neural-lineage systems should reveal which outputs are physiological and which are tumor-state adaptations.
Provenance (the field's own admissions):
Gap: The topology and trafficking step that permit GLIPR1 to regulate cytosolic N-WASP, hnRNPK, Hsc70, and CK1alpha are unknown.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Canonical GLIPR1 has a large extracellular CAP domain, a C-terminal transmembrane helix, and a very short cytoplasmic tail, while soluble ectodomain can be internalized and full-length constructs yield cytosolic interaction phenotypes.
Significance: This mechanistic gap determines whether the reported partners are contacted at the cell surface, after cleavage/internalization, or indirectly.
What would resolve it: Endogenous topology mapping, pulse-chase shedding/internalization assays, compartment-resolved proximity labeling, and tail/cleavage mutants should establish the causal trafficking route.
Provenance (the field's own admissions):
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)