LRIG1 is a widely expressed type I single-pass membrane glycoprotein with an extracellular leucine-rich-repeat region, three immunoglobulin-like domains and a cytoplasmic tail. At the plasma membrane it binds and inhibits several receptor tyrosine kinases through receptor- and context-dependent mechanisms. Human LRIG1 recruits c-CBL to ERBB receptors to enhance receptor ubiquitination and degradation, destabilizes MET independently of CBL, and inhibits the activation of oncogenic RET variants; neuronal experiments also show inhibition of GDNF-dependent RET activation and signaling. In an antibody-induced MET-degradation setting, ubiquitinated LRIG1 binds the endosomal sorting protein HRS and accompanies MET to lysosomes, while USP8 deubiquitinates LRIG1 and opposes this route. LRIG1 can also undergo constitutive ectodomain shedding, generating a soluble product that inhibits EGF signaling in neighboring cells without detectable EGFR downregulation. These observations establish LRIG1 as a receptor tyrosine kinase inhibitor rather than a signaling receptor, kinase, ubiquitin ligase or deubiquitinase. The strength and physical basis of LRIG1-receptor association vary among assays, and no receptor-bound or full-length experimental structure is available. Two human protein isoforms are curated, but distinct physiological functions have not been demonstrated. Its tumor-suppressive effects are tissue- and genotype-dependent rather than uniform across cancers.
Definition: Any process that stops, prevents or reduces the frequency, rate or extent of the glial cell-derived neurotrophic factor receptor signaling pathway.
Justification: Current GO provides the GDNF receptor signaling pathway but no corresponding negative-regulation child. Lrig1-RET association directly reduces GDNF binding, RET recruitment to lipid rafts, receptor autophosphorylation and MAPK activation; an exact term would represent this biology without misusing a generic signaling or kinase-regulation term. GO:2000732 is an unrelated RNA polymerase I transcription- termination term, while obsolete GO:2000734 was restricted to ureteric bud formation; neither represents general negative regulation of GDNF receptor signaling. The source cache is abstract-only, so this proposal does not assert a human-specific annotation or transfer the function from LRIG3.
Parent term: negative regulation of signaling
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: LRIG1 is a single-pass type I membrane protein experimentally localized to the human cell surface. The phylogenetic plasma-membrane inference agrees with direct human evidence. Reason: Plasma membrane is the appropriate active location for membrane-anchored LRIG1 as it binds cell-surface receptor tyrosine kinases and promotes their downregulation. This location does not by itself describe any cleaved or soluble LRIG1 product. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001224703 SUPPORTS TRANSFER The PAINT node supports plasma-membrane localization across the relevant transmembrane LRR-containing family, and the target is independently supported by direct human evidence. Supporting Evidence: PMID:15282549 The present study addressed the possible physical and functional interactions between human LRIG1 and ErbB receptors. |
| GO:0038023 signaling receptor activity | IBA GO_REF:0000033 | REMOVE | Summary: The IBA assigns autonomous signaling receptor activity to LRIG1 from a broad LRR receptor-family node. Direct human evidence instead establishes LRIG1 as a membrane regulator that binds receptor tyrosine kinases and accelerates their ubiquitination and degradation. Reason: Current GO defines signaling receptor activity as receiving a signal and transmitting it in the cell to initiate a change in cell activity. LRIG1 is experimentally a negative regulator of ErbB-family receptor abundance, not the signal-receiving receptor. Several WITH/FROM donors are genuine receptors such as TLR3, CD180, RTN4RL1, and RTN4RL2, so this is an unsafe role transfer from receptor paralog/family members to a receptor regulator. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG ROLE CONFLATION Sources checked: PANTHER:PTN002809265 SUPPORTS SOURCE BUT NOT TARGET The broad PAINT node contains bona fide signaling receptors, but direct evidence does not establish that activity for LRIG1. UniProtKB:O15455 · TLR3 SUPPORTS SOURCE BUT NOT TARGET UniProtKB:Q99467 · CD180 SUPPORTS SOURCE BUT NOT TARGET Supporting Evidence: PMID:15282549 We conclude that LRIG1 evolved in mammals as a feedback negative attenuator of signaling by receptor tyrosine kinases. |
| GO:0007605 sensory perception of sound | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Mouse Lrig1 loss directly impairs auditory sensitivity, while Lrig2 has a distinct contribution to the subsequent neuronal response. Transfer to human LRIG1 is biologically defensible through the direct mouse orthologue but remains an organism-level, tissue-specific role rather than the protein's general core molecular function. Reason: The IBA includes the exact mouse Lrig1 orthologue as a source, and mouse genetics places Lrig1 upstream of normal sound perception. There is no direct human LRIG1 auditory experiment in the supplied evidence, so this is retained as a phylogenetically supported non-core process with an explicit species boundary; the mouse Lrig2 paralog alone would not license transfer. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:107935 · mouse Lrig1 SUPPORTS TRANSFER The exact mouse orthologue has direct loss-of-function evidence for impaired auditory sensitivity. MGI:MGI:2443718 · mouse Lrig2 SUPPORTS SOURCE BUT NOT TARGET This paralog contributes to auditory neural responses but is not needed to justify transfer from mouse Lrig1 to human LRIG1. PANTHER:PTN009094493 SUPPORTS TRANSFER |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: The electronic mapping from the reviewed UniProt cell-membrane location to plasma membrane is correct and independently supported by experimental human LRIG1 evidence. Reason: LRIG1 is a single-pass type I cell-membrane protein. The IEA is broad but accurate for the membrane-anchored product and does not imply that every processed LRIG1 form remains at the plasma membrane. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0039 · Cell membrane SUPPORTS TRANSFER Supporting Evidence: PMID:15282549 Their structural relative in mammals, LRIG1, is a transmembrane protein whose inactivation in rodents promotes skin hyperplasia, suggesting involvement in EGFR regulation. |
| GO:0005515 protein binding | IPI PMID:15282549 LRIG1 restricts growth factor signaling by enhancing recepto... | MODIFY | Summary: Human LRIG1 physically associates with the four ErbB receptor tyrosine kinases and recruits the E3 ubiquitin ligase CBL. Generic protein binding obscures these mechanistically informative partner classes. Reason: Replace the undifferentiated binding term with receptor tyrosine kinase binding for EGFR, ERBB2, ERBB3, and ERBB4, and ubiquitin protein ligase binding for CBL. The paper demonstrates association coupled to receptor ubiquitination and degradation; it does not make LRIG1 itself a receptor or ubiquitin ligase. Proposed replacements: receptor tyrosine kinase binding ubiquitin protein ligase binding Supporting Evidence: PMID:15282549 We report direct ErbB–LRIG1 interactions, which inhibit ErbB signaling through a mechanism that involves enhancement of receptor ubiquitylation and accelerated intracellular degradation. PMID:15282549 The underlying mechanism involves recruitment of c-Cbl, an E3 ubiquitin ligase that simultaneously ubiquitylates EGFR and LRIG1 and sorts them for degradation. |
| GO:0005515 protein binding | IPI PMID:15345710 The leucine-rich repeat protein LRIG1 is a negative regulato... | MODIFY | Summary: LRIG1 forms complexes with ErbB receptor tyrosine kinases and reduces their abundance and signaling. A receptor-class binding term is more informative than generic protein binding. Reason: The ordered WITH/FROM partners are EGFR, ERBB2, and ERBB4, all receptor tyrosine kinases. The evidence therefore licenses receptor tyrosine kinase binding, while the negative-regulatory consequence belongs in biological-process annotations rather than being recast as autonomous receptor activity. Proposed replacements: receptor tyrosine kinase binding Supporting Evidence: PMID:15345710 co-transfected 293T cells, LRIG1 forms a complex with each of the ErbB receptors |
| GO:0005515 protein binding | IPI PMID:18542056 LRIG1 negatively regulates the oncogenic EGF receptor mutant... | MODIFY | Summary: LRIG1 interacts with the oncogenic EGFRvIII receptor and destabilizes it. The canonical EGFR WITH/FROM identifier represents the receptor partner, while the tested mutant context is described by the paper. Reason: Receptor tyrosine kinase binding captures the demonstrated LRIG1–EGFRvIII interaction more precisely than protein binding. The evidence concerns an oncogenic EGFR deletion mutant in glioblastoma cells and should not be generalized into an LRIG1 catalytic or receptor activity. Proposed replacements: receptor tyrosine kinase binding Supporting Evidence: PMID:18542056 We find that EGFRvIII retains interaction with LRIG1 and is in fact more sensitive to LRIG1 action than wild-type receptor. |
| GO:0005515 protein binding | IPI PMID:23723069 Leucine-rich repeat and immunoglobulin domain-containing pro... | MODIFY | Summary: The curated IPI identifies ERBB2 as an LRIG1 partner in a study of LRIG-family regulation of ERBB receptor tyrosine kinases. Reason: Receptor tyrosine kinase binding captures the ERBB2-directed association more precisely than generic protein binding. The cache is abstract-only, so the experimental IPI is retained with curator deference and is not expanded into an autonomous receptor, kinase or catalytic activity for LRIG1. Proposed replacements: receptor tyrosine kinase binding Supporting Evidence: PMID:23723069 Lrig3 opposes Lrig1 negative regulatory |
| GO:0005515 protein binding | IPI PMID:23723069 Leucine-rich repeat and immunoglobulin domain-containing pro... | MARK AS OVER ANNOTATED | Summary: The curated IPI identifies LRIG3 as an LRIG1 partner in a study that demonstrates functional opposition and cross-talk between these paralogs. Reason: The experimental association is retained with curator deference, but generic protein binding is uninformative and no more specific molecular-function term captures LRIG1 association with another LRIG-family regulator. This row should not be used to infer interchangeable receptor-regulatory roles or a stable obligate LRIG1-LRIG3 complex. Supporting Evidence: PMID:23723069 Conversely, Lrig1 destabilizes Lrig3, |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: A proteome-scale AP-MS network reports an LRIG1–LRIG3 association in a cell-line screen, but the paper does not establish a specific molecular function for LRIG1 from this pair. Reason: The physical association may be valid, but generic protein binding is uninformative and the screen-only result does not license a more specific LRIG3-directed molecular function. It should not be promoted to a core activity or used to infer that LRIG1 and LRIG3 have interchangeable receptor-regulatory roles. Supporting Evidence: PMID:33961781 mass spectrometry, we have created two proteome-scale, cell-line-specific |
| GO:0005886 plasma membrane | EXP PMID:15282549 LRIG1 restricts growth factor signaling by enhancing recepto... | ACCEPT | Summary: Direct human experimental evidence places full-length LRIG1 at the cell membrane as a single-pass transmembrane protein. Reason: Plasma membrane accurately captures the location at which membrane-anchored LRIG1 associates with ErbB receptors. This localization is distinct from the subsequent endocytic trafficking/degradation of receptor complexes and does not assert a location for any shed ectodomain. Supporting Evidence: PMID:15282549 Their structural relative in mammals, LRIG1, is a transmembrane protein whose inactivation in rodents promotes skin hyperplasia, suggesting involvement in EGFR regulation. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8875431 | ACCEPT | Summary: The Reactome event models ubiquitination of membrane LRIG1 after MET binding; plasma membrane is a valid starting location for this human signaling event. Reason: LRIG1 ubiquitination in the MET-downregulation pathway occurs after receptor association and does not turn LRIG1 into an ubiquitin ligase. The event context is compatible with the independently demonstrated plasma-membrane location. Supporting Evidence: Reactome:R-HSA-8875431 Upon binding to MET, LRIG1 undergoes ubiquitination by an unknown ubiquitin ligase (Oh et al. 2014). |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8875443 | ACCEPT | Summary: The Reactome event places membrane LRIG1 in the USP8-regulated MET-downregulation pathway; plasma membrane is consistent with its receptor-associated state. Reason: USP8-mediated deubiquitination regulates LRIG1 and MET downregulation, while the GO row records LRIG1's plasma-membrane location rather than the later intracellular trafficking destination. Supporting Evidence: Reactome:R-HSA-8875443 The ubiquitin hydrolase USP8 can deubiquitinate LRIG1, thus interfering with LRIG1-mediated MET downregulation (Oh et al. 2014). |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8875374 | ACCEPT | Summary: Human LRIG1 binds cell-surface MET before their lysosomal trafficking; the Reactome statement therefore supports plasma membrane for the receptor-associated LRIG1 state. Reason: The reaction describes MET binding and subsequent downregulation. Plasma membrane is appropriate for the initial LRIG1–MET interaction, whereas later colocalization with LAMP1 concerns downstream lysosomal trafficking and should not replace the source location in this row. Supporting Evidence: Reactome:R-HSA-8875374 LRIG1 can bind the MET receptor in the absence of HGF-mediated MET activation and trigger MET downregulation in a CBL-independent manner (Shattuck et al. 2007). |
| GO:0030293 transmembrane receptor protein tyrosine kinase inhibitor activity | IDA PMID:29436694 LRIG1 negatively regulates RET mutants and is downregulated ... | NEW | Summary: Human LRIG1 physically interacts with the oncogenic RET2A and RET2B receptor tyrosine kinases and inhibits their constitutive activation. Reason: Direct RET phosphorylation assays establish transmembrane receptor protein tyrosine kinase inhibitor activity rather than binding alone. Human ERBB and MET studies provide additional receptor-specific support, but their distinct ubiquitination and degradation mechanisms are not generalized to RET. This term does not assign LRIG1 autonomous receptor, kinase or ubiquitin-ligase activity. Supporting Evidence: PMID:29436694 LRIG1 physically interacted with both RET2A and RET2B, as well as inhibited their constitutive activation PMID:15282549 We report direct ErbB–LRIG1 interactions, which inhibit ErbB signaling through a mechanism that involves enhancement of receptor ubiquitylation and accelerated intracellular degradation. PMID:17178829 We conclude that LRIG1 is a novel suppressor of Met function, serving to regulate cellular receptor levels by promoting Met degradation in a ligand- and cbl-independent manner. |
| GO:1901185 negative regulation of ERBB signaling pathway | IDA PMID:15282549 LRIG1 restricts growth factor signaling by enhancing recepto... | NEW | Summary: Human LRIG1 inhibits signaling by the ERBB receptor family through physical association, c-CBL recruitment, enhanced receptor ubiquitination and accelerated degradation. Reason: Direct human experiments address multiple ERBB-family receptors, making the family-level negative-regulation term an exact fit. The annotation is restricted to ERBB signaling and does not imply that every LRIG1 target uses c-CBL. Supporting Evidence: PMID:15282549 We report direct ErbB–LRIG1 interactions, which inhibit ErbB signaling through a mechanism that involves enhancement of receptor ubiquitylation and accelerated intracellular degradation. PMID:15345710 LRIG1 forms a complex with each of the ErbB receptors |
| GO:1902203 negative regulation of hepatocyte growth factor receptor signaling pathway | IMP PMID:17178829 LRIG1 is a novel negative regulator of the Met receptor and ... | NEW | Summary: Endogenous human LRIG1 restrains MET abundance and HGF responsiveness; LRIG1 depletion increases MET half-life, whereas LRIG1 expression destabilizes MET independently of ligand and c-CBL. Reason: The loss- and gain-of-function evidence directly supports the current MET/HGF-receptor negative-regulation term. This annotation is kept distinct from the c-CBL-dependent ERBB mechanism and from the SAIT301-induced lysosomal route. Supporting Evidence: PMID:17178829 We conclude that LRIG1 is a novel suppressor of Met function, serving to regulate cellular receptor levels by promoting Met degradation in a ligand- and cbl-independent manner. |
| GO:0042059 negative regulation of epidermal growth factor receptor signaling pathway | IDA PMID:21087604 Paracrine regulation of growth factor signaling by shed leuc... | NEW | Summary: Shed LRIG1 ectodomain inhibits EGF signaling in neighboring cells without detectable reduction of EGFR abundance. Reason: This process annotation captures the direct paracrine effect of the soluble ectodomain while avoiding an unsupported claim that it binds EGFR directly or uses the degradation mechanism established for membrane LRIG1. Supporting Evidence: PMID:21087604 Purified LRIG1 ectodomains suppressed EGF signaling without |
| GO:0005764 lysosome | IDA PMID:24828152 USP8 modulates ubiquitination of LRIG1 for Met degradation. | NEW | Summary: In SAIT301-treated human cancer cells, LRIG1 and MET co-localize with LAMP1 as the ubiquitinated LRIG1-MET complex undergoes lysosomal degradation. Reason: Direct immunofluorescence and lysosomal-inhibitor experiments support lysosome for this induced trafficking state. This annotation does not replace plasma membrane as LRIG1's basal active location or imply constitutive lysosomal residence. Supporting Evidence: PMID:24828152 Subsequent lysosomal degradation of Met/LRIG1 complex was verified by co-localization of LRIG1 and Met with a lysosomal marker (Lamp1) (Figure 2f). |
| GO:0005576 extracellular region | IDA PMID:21087604 Paracrine regulation of growth factor signaling by shed leuc... | NEW | Summary: Proteolytic shedding releases the LRIG1 ectodomain outside the producing cell, where it acts on neighboring cells in a paracrine manner. Reason: Extracellular region is directly implied by recovery and functional testing of the shed ectodomain and applies to the processed soluble product, not to the membrane-anchored precursor. The evidence does not establish a narrower stable extracellular compartment or an isoform-specific location. Supporting Evidence: PMID:21087604 Cells constitutively shed LRIG1 ectodomains in vitro |
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Download this section (compressed HTML)Q: Which ubiquitin ligase and degradation-machinery components mediate basal, c-CBL-independent LRIG1-dependent MET destabilization, and how do they differ from the SAIT301-induced HRS/USP8 route?
Q: What are the affinity, stoichiometry and receptor-contact surfaces of endogenous full-length LRIG1 complexes with EGFR/ERBB, MET and RET, and which contacts explain their distinct inhibitory mechanisms?
Q: Which protease and cleavage site generate soluble LRIG1 in vivo, what receptor or co-receptor does the ectodomain engage, and does either curated isoform differ in shedding or paracrine activity?
Q: In which human tissues and tumor genotypes is endogenous LRIG1 quantitatively rate-limiting for receptor signaling or tumor suppression, rather than merely correlated with disease state?
Experiment: Endogenously tag LRIG1 and selected ERBB, MET and RET receptors in human epithelial and neuronal cell models, then combine ligand time courses, quantitative surface proteomics, receptor half-life measurements, phosphosignaling and acute LRIG1 degradation/rescue to compare receptor inhibition without overexpression.
Hypothesis: Endogenous LRIG1 inhibits each receptor family with distinct dependencies on receptor activation, ubiquitination and degradation.
Type: endogenous quantitative receptor-trafficking and signaling analysis
Experiment: Perform a focused CRISPR screen of E3 ligases and endosomal-sorting factors in LRIG1-positive MET cells, followed by ubiquitin-remnant proteomics and rescue with catalytic-dead candidates under basal, HGF and SAIT301 conditions.
Hypothesis: A non-CBL E3 ligase ubiquitinates LRIG1 or an associated factor to drive basal MET destabilization, while HRS and USP8 specifically tune the induced lysosomal route.
Type: genetic interaction screen and ubiquitin proteomics
Experiment: Reconstitute full-length glycosylated LRIG1 with EGFR, MET or RET in defined membranes and use cryo-EM, crosslinking mass spectrometry and quantitative binding assays, validating candidate interfaces with separation-of-function mutants at endogenous expression levels.
Hypothesis: LRIG1 uses partly distinct ectodomain contacts for different receptor families, explaining both low apparent affinity and receptor-specific inhibitory mechanisms.
Type: structural and quantitative interaction analysis
Experiment: Map LRIG1 cleavage by N-terminomics and secretome proteomics after ADAM17 knockout or inhibition, then compare cleavage-resistant full-length LRIG1 and purified isoform-specific ectodomains in receptor-panel binding, signaling and co-culture assays.
Hypothesis: A defined metalloprotease cleavage event releases a soluble LRIG1 ectodomain whose paracrine target and mechanism differ from membrane LRIG1-driven receptor degradation.
Type: protease mapping and isoform-resolved paracrine signaling assay
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The E3 ligase and degradation machinery that execute basal, c-CBL-independent LRIG1-mediated MET destabilization are unresolved, and it is not known whether the SAIT301-induced HRS/USP8 pathway is used during unperturbed MET regulation.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Endogenous LRIG1 binds and destabilizes MET independently of HGF and c-CBL. In SAIT301-treated cancer cells, LRIG1 ubiquitination recruits HRS and targets the LRIG1-MET complex to lysosomes, while USP8 counteracts this process.
Significance: Identifying the basal machinery is required to distinguish LRIG1's physiological MET-regulatory mechanism from a therapeutic-antibody-specific trafficking route.
What would resolve it: Combine endogenous LRIG1/MET perturbation with E3-ligase and sorting-factor screens, ubiquitin-site mapping and rescue under basal, HGF and SAIT301 conditions.
Provenance (the field's own admissions):
Gap: The direct structural interface, affinity and stoichiometry of full-length LRIG1 with its receptor targets remain unresolved, and positive cell-based association results have not been reconciled with failure to detect EGFR binding in purified ectodomain assays.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Human cell studies demonstrate LRIG1 association with ERBB receptors, MET and RET, but the two experimental structures cover isolated ectodomain fragments and no LRIG1-receptor complex or full-length LRIG1 structure is available.
Significance: Resolving the interface would distinguish direct low-affinity recognition from avidity, membrane-context or cofactor-dependent association and enable rigorous separation-of-function tests.
What would resolve it: Determine structures and binding kinetics of full-length, glycosylated LRIG1 with ERBB, MET and RET in membrane contexts, followed by endogenous interface-mutant rescue.
Provenance (the field's own admissions):
Gap: The physiological protease, cleavage site and direct signaling target of the shed LRIG1 ectodomain are unknown, as is whether the two curated human isoforms differ in production or activity of the soluble product.
OPEN BIOLOGY MF_DARK
What is known: LRIG1 ectodomains are constitutively shed, shedding is modulated by ADAM17 perturbation, and purified ectodomain suppresses EGF signaling without detectable EGFR downregulation.
Significance: Closing this gap would define a mechanistically distinct non-cell-autonomous LRIG1 activity and prevent unsupported assignment of the membrane-form degradation mechanism to soluble LRIG1 or to a specific isoform.
What would resolve it: Map endogenous cleavage products and protease dependence, then identify direct ectodomain targets with quantitative binding and receptor-panel signaling assays.
Provenance (the field's own admissions):
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