Affinage

LRIG1

Leucine-rich repeats and immunoglobulin-like domains protein 1 · UniProt Q96JA1

Length
1093 aa
Mass
119.1 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LRIG1 is a transmembrane negative-feedback regulator of receptor tyrosine kinase (RTK) signaling that enforces cellular quiescence and acts as a tumor suppressor across epithelial, neural, and immune tissues (PMID:15282549, PMID:22464327, PMID:12067728). It physically associates with all four ErbB/EGFR-family receptors independent of ligand, shortens their half-life, and promotes their ubiquitylation and lysosomal degradation by recruiting the E3 ligase c-Cbl, which co-ubiquitylates both the receptor and LRIG1; EGF stimulation induces LRIG1, closing a negative-feedback loop (PMID:15282549, PMID:15345710). This regulatory logic extends beyond ErbBs: LRIG1 binds and destabilizes Met (in a c-Cbl-independent manner) (PMID:17178829), suppresses GDNF/Ret signaling by blocking ligand binding and lipid-raft recruitment (PMID:18171921), attenuates BDNF/TrkB signaling (PMID:26935556), and downregulates PDGFRα through a validated interactor network (PMID:29317492). LRIG1 protein stability is set by the deubiquitinase USP8, which removes ubiquitin and protects LRIG1 from co-degradation (PMID:24828152). In vivo, loss of Lrig1 elevates ErbB receptors and expands stem/progenitor compartments, producing duodenal adenomas, intestinal stem-cell niche expansion, epidermal hyperplasia, and cortical and subventricular-zone neural stem-cell overproliferation (PMID:22464327, PMID:22388892, PMID:12067728, PMID:33053360, PMID:33972529); in neural stem cells LRIG1 raises EGFR protein levels while restraining signaling to prime cells for cell-cycle re-entry, and also binds TGFβ/BMP receptors and TGFβ1 to facilitate SMAD phosphorylation (PMID:33972529, PMID:38987622). LRIG1 additionally mediates contact inhibition via a ternary complex with EGFR and E-cadherin (PMID:23208928) and restrains STAT3-driven inflammation (PMID:24316976). In the immune system it supports Treg suppressive function through the Smad2/3/Foxp3 axis (PMID:37666819) and acts as an inhibitory checkpoint receptor by engaging VISTA to suppress TCR signaling in CD8+ T cells (PMID:38758807). LRIG1 expression is transactivated by androgen receptor (PMID:31792211) and silenced in basal/triple-negative breast cancer by CpG island promoter methylation (PMID:35440669).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2002 High

    Established the first in vivo requirement for LRIG1 in proliferation control before any molecular mechanism was known, by showing its loss causes epidermal overgrowth.

    Evidence Targeted Lrig1 knockout mouse with histology and in situ hybridization

    PMID:12067728

    Open questions at the time
    • No molecular target or pathway identified at this stage
    • Mechanism linking LRIG1 to keratinocyte proliferation undefined
  2. 2004 High

    Defined the core molecular mechanism: LRIG1 binds all ErbB receptors ligand-independently and drives their c-Cbl-dependent ubiquitylation and lysosomal degradation within an EGF-induced negative-feedback loop.

    Evidence Reciprocal Co-IP, in vitro ubiquitylation, half-life and transformation assays in transfected cells; two concurrent papers

    PMID:15282549 PMID:15345710

    Open questions at the time
    • Endogenous physiological relevance not yet shown
    • Stoichiometry and structural basis of the LRIG1-ErbB-Cbl complex unresolved
  3. 2006 High

    Extended LRIG1 regulation to loss-of-function and to a secreted modality, showing endogenous LRIG1 limits surface EGFR and that a soluble LRR ectodomain binds EGFR-expressing cells with nanomolar affinity to inhibit signaling.

    Evidence siRNA knockdown with surface EGFR/Myc-promoter readouts; recombinant ectodomain binding (Kd ~10 nM) and growth inhibition assays

    PMID:16847455 PMID:16877544

    Open questions at the time
    • Physiological source and role of a soluble ectodomain unclear
    • Direct vs indirect EGFR binding later disputed
  4. 2006 High

    Generalized LRIG1 beyond ErbBs by identifying Met as a target degraded through a c-Cbl-independent route, indicating multiple mechanistic modes.

    Evidence Co-IP, half-life, siRNA/overexpression and invasion assays in breast cancer cells

    PMID:17178829

    Open questions at the time
    • Identity of the c-Cbl-independent degradation machinery for Met unknown
  5. 2008 High

    Broadened the RTK target repertoire to Ret and clarified a non-degradative mode, showing LRIG1 blocks GDNF binding and lipid-raft recruitment to suppress neuronal differentiation signaling.

    Evidence Co-IP, GDNF binding inhibition, lipid raft fractionation, siRNA/overexpression with neurite outgrowth in neurons

    PMID:18171921

    Open questions at the time
    • Whether ligand-blocking applies to other RTK targets not tested
    • In vivo relevance addressed only later
  6. 2008 Medium

    Linked LRIG1 dysregulation to cancer feed-forward loops and trafficking, showing ErbB activation suppresses LRIG1 in tumor cells and that LRIG1 controls EGFRvIII via altered trafficking distinct from c-Cbl degradation.

    Evidence RNAi/overexpression in ErbB2+ breast and EGFRvIII+ glioblastoma cells with signaling, proliferation and trafficking readouts

    PMID:18542056 PMID:18922900

    Open questions at the time
    • Single-lab studies without independent replication
    • Trafficking machinery for EGFRvIII regulation unidentified
  7. 2012 High

    Provided definitive in vivo proof of LRIG1 as an ErbB-restraining tumor suppressor and stem-cell quiescence marker, with loss expanding the intestinal stem-cell niche and producing adenomas.

    Evidence Lrig1-CreERT2 knockout, lineage tracing, organoids and transcriptomics; two concurrent studies

    PMID:22388892 PMID:22464327

    Open questions at the time
    • Mechanism of LRIG1-marked stem cell quiescence beyond ErbB amplitude control incomplete
  8. 2013 Medium

    Diversified LRIG1's mechanisms into contact inhibition, anti-inflammatory control, and intra-family antagonism, via an EGFR/E-cadherin ternary complex, suppression of STAT3, and degradation of Lrig3.

    Evidence Co-IP, Lrig1 knockout mice, STAT3 inhibitor/transgenic rescue, and Lrig1/Lrig3 co-expression stability assays

    PMID:23208928 PMID:23723069 PMID:24316976

    Open questions at the time
    • Single-lab findings for each mechanism
    • How LRIG1 connects to STAT3 mechanistically unclear
  9. 2014 Medium

    Identified the regulator of LRIG1's own stability, showing USP8 deubiquitinates and stabilizes LRIG1 and that disrupting this coupling triggers Met co-degradation.

    Evidence Co-IP, ubiquitination, Hrs-dependent lysosomal trafficking assays with anti-Met antibody

    PMID:24828152

    Open questions at the time
    • Whether USP8 controls LRIG1 stability in physiological/in vivo contexts untested
    • Single-lab study
  10. 2015 Medium

    Provided structural data and a rigorous negative result, solving the LRIG1 ectodomain structures while failing to detect direct ECD-EGFR binding, challenging the simplest direct-inhibition model.

    Evidence X-ray crystallography (2.3 Å), SEC, biosensor and cell-surface binding, EGFR co-expression activation assay

    PMID:25765764

    Open questions at the time
    • Conflicts with prior reports of direct ECD-EGFR binding
    • Conformation/co-factors required for functional binding undefined
  11. 2015 High

    Revealed a developmental, non-tumor lineage role, showing Lrig1+ smooth muscle progenitors give rise to interstitial cells of Cajal required for intestinal motility.

    Evidence Lineage tracing and Lrig1-null mice with immunofluorescence and transit assays

    PMID:25921371

    Open questions at the time
    • Molecular mechanism by which LRIG1 directs ICC differentiation unknown
  12. 2016 High

    Added TrkB to the RTK targets with neurodevelopmental consequences, showing LRIG1 attenuates BDNF signaling and shapes dendritic arborization and social behavior.

    Evidence Co-IP, gain/loss-of-function in hippocampal neurons, Lrig1 knockout behavioral and morphological analysis

    PMID:26935556

    Open questions at the time
    • Whether TrkB regulation uses degradation or ligand-blocking not resolved
  13. 2017 Medium

    (grouped with 2018) Defined a broad LRIG1 interactome and a PDGFRα target, identifying multiple validated modulators of LRIG1's downregulation activity.

    Evidence Yeast two-hybrid, BioPlex mining, triple co-transfection epistasis and co-localization in HEK293 cells

    PMID:29317492

    Open questions at the time
    • Most interactors lack mechanistic detail on how they modulate LRIG1
    • In vivo relevance untested
  14. 2019 High

    Identified an upstream transcriptional driver, showing androgen receptor directly transactivates LRIG1 to suppress ERBB-driven tumor growth.

    Evidence AR ChIP-seq, binding-site mutagenesis, and AR+/AR- xenograft and transgenic tumor models

    PMID:31792211

    Open questions at the time
    • Cell-type determinants of AR-LRIG1-ERBB output incompletely defined
  15. 2020 High

    Confirmed the EGFR-restraining quiescence mechanism in cortical neural stem cells, where LRIG1 loss expands the stem pool via EGFR deregulation.

    Evidence Co-IP and constitutive/conditional Lrig1 knockout mice with EGFR signaling readouts

    PMID:33053360

    Open questions at the time
    • How LRIG1 selectively limits signaling while preserving receptor protein not fully explained
  16. 2021 High

    Refined the quiescence mechanism and extended Ret regulation, showing LRIG1 primes quiescent NSCs by raising EGFR levels while limiting activation, and that Lrig1/Lrig3 redundantly inhibit GDNF/Ret in DRG neurons.

    Evidence In vivo Lrig1 disruption and NSC culture with single-cell/EGFR readouts; compound Lrig1/Lrig3 mutant mice with Co-IP and axon-growth assays

    PMID:33972529 PMID:34338291

    Open questions at the time
    • Biophysical basis for uncoupling EGFR abundance from signaling unresolved
  17. 2022 Medium

    Established epigenetic silencing of LRIG1 as a cancer mechanism, restoring expression and reducing viability via targeted CRISPR-based demethylation/activation.

    Evidence Methylation-IP, 5-aza treatment, dCas9-TET1 and dCas9-VP64 targeting in basal/triple-negative breast cancer lines

    PMID:35440669

    Open questions at the time
    • In vivo therapeutic relevance untested
    • Single-lab study
  18. 2023 High

    Defined a non-RTK immune role, showing LRIG1 is required for Treg suppressive function through the Smad2/3/Foxp3 axis.

    Evidence Lrig1-deficient mice, adoptive transfer, suppression assays, and autoimmune disease models with antibody intervention

    PMID:37666819

    Open questions at the time
    • Direct molecular link between LRIG1 and Smad2/3/Foxp3 not fully resolved
    • Single-lab study
  19. 2024 High

    Revealed two new ligand/receptor engagements: LRIG1 acts as an inhibitory checkpoint receptor binding VISTA to suppress TCR signaling, and binds TGFβ/BMP receptors and TGFβ1 to facilitate SMAD signaling in NSCs.

    Evidence Co-IP/binding assays, T-cell-specific conditional knockouts and tumor models; Lrig1 knockout NSCs with SMAD phosphorylation assays

    PMID:38758807 PMID:38987622

    Open questions at the time
    • Structural basis of LRIG1-VISTA and LRIG1-TGFβ interactions undefined
    • TGFβ/BMP finding from single lab at Medium confidence
  20. 2025 Medium

    Connected the VISTA-LRIG1 axis to tissue repair, showing macrophage VISTA engages epithelial LRIG1 to suppress PPARα and impair intestinal repair during colitis.

    Evidence Co-IP, organoid assays, Vsir-/- and Vsir-/-Rag1-/- mice, macrophage transfer in DSS colitis

    PMID:40883589

    Open questions at the time
    • Mechanism linking LRIG1 to PPARα suppression unclear
    • Single-lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How LRIG1 mechanistically reconciles its conflicting models—direct ECD-receptor binding versus indirect regulation, and degradative versus ligand-blocking versus checkpoint modes across so many partners—remains unresolved.
  • No unified structural model of LRIG1 engaging its diverse RTK and non-RTK partners
  • Direct vs indirect EGFR binding unreconciled (cf. conflicting reports)
  • Determinants selecting between degradation, ligand-blocking, and checkpoint signaling unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0140096 catalytic activity, acting on a protein 3 GO:0060090 molecular adaptor activity 2 GO:0060089 molecular transducer activity 1
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-168256 Immune System 2
Partners
CBLEGFRLRIG3METNTRK2RETUSP8VSIR
Complex memberships
LRIG1-EGFR-E-cadherin ternary complexLRIG1-ErbB-c-Cbl complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 LRIG1 physically associates with all four ErbB/EGFR family receptors (EGFR, ErbB2, ErbB3, ErbB4) and promotes their ubiquitylation and degradation via recruitment of the E3 ubiquitin ligase c-Cbl, which simultaneously ubiquitylates both EGFR and LRIG1, sorting them for lysosomal degradation. LRIG1 transcript and protein are upregulated by EGF stimulation, establishing a negative feedback loop. Co-immunoprecipitation, ubiquitylation assays, protein degradation assays, c-Cbl recruitment assays in transfected cells The EMBO journal High 15282549
2004 LRIG1 forms a complex with each ErbB receptor independent of growth factor binding, suppresses cellular receptor levels, shortens receptor half-life, and enhances ligand-stimulated receptor ubiquitination, thereby suppressing EGF-stimulated transformation and cell cycle progression. Co-transfection in 293T cells, co-immunoprecipitation, receptor half-life assays, ubiquitination assays, NIH3T3 transformation assay, inducible expression in PC3 cells The Journal of biological chemistry High 15345710
2006 LRIG1 downregulation via siRNA increases cell-surface EGF receptor levels, enhances activation of downstream signaling pathways, and stimulates keratinocyte proliferation. LRIG1 also acts in part by negatively regulating the Myc promoter. siRNA knockdown, flow cytometry for cell-surface EGFR, downstream signaling assays, clonal growth analysis, promoter regulation assay Proceedings of the National Academy of Sciences of the United States of America High 16877544
2006 A soluble ectodomain of LRIG1 containing only the leucine-rich repeat (LRR) domain inhibits both ligand-independent and ligand-dependent EGFR activation and causes growth inhibition of EGFR-expressing carcinoma cells. High-affinity binding sites (Kd = 10 nM) for the soluble ectodomain exist on EGFR-expressing cells and can be competitively displaced by excess EGF, indicating binding at or near the EGF binding site. Recombinant protein treatment, cell growth assays, biosensor binding analysis, competitive displacement with EGF, EGFR activation assays, ERK1/2 signaling assays Oncogene High 16847455
2006 LRIG1 is a novel negative regulator of the Met receptor tyrosine kinase. LRIG1 interacts with Met independent of HGF stimulation and destabilizes Met in a c-Cbl-independent manner. LRIG1 knockdown increases Met receptor half-life, and LRIG1 overexpression reduces endogenous Met in breast cancer cells and impairs HGF responsiveness. LRIG1 also opposes synergistic invasion driven by Met and ErbB2. Co-immunoprecipitation, receptor half-life assays, siRNA knockdown, overexpression in breast cancer cells, invasion assays Molecular and cellular biology High 17178829
2008 Lrig1 physically interacts with the Ret receptor tyrosine kinase, and this association inhibits GDNF binding to Ret, prevents Ret recruitment to lipid rafts, and suppresses Ret autophosphorylation and MAPK activation in response to GDNF. Lrig1 overexpression inhibits GDNF/Ret-induced neurite outgrowth, while Lrig1 siRNA knockdown potentiates neuronal differentiation and MAPK activation. Co-immunoprecipitation, GDNF binding assay, lipid raft fractionation, receptor autophosphorylation assays, MAPK activation assays, siRNA knockdown, neurite outgrowth assay The Journal of neuroscience High 18171921
2008 LRIG1 protein levels are suppressed by ErbB receptor activation in breast tumor cells but not in normal breast epithelial cells, creating a feed-forward loop: aberrant ErbB2 signaling suppresses LRIG1, which in turn contributes to ErbB2 overexpression. RNAi knockdown of endogenous LRIG1 elevates ErbB2 and augments proliferation in ErbB2+ breast tumor cell lines. RNAi knockdown, ectopic LRIG1 expression, western blotting, ErbB receptor activation experiments, proliferation assays Cancer research Medium 18922900
2008 EGFRvIII, despite its extracellular deletion, retains interaction with LRIG1 and is more sensitive to LRIG1-mediated downregulation than wild-type EGFR. LRIG1 regulation of EGFRvIII is mechanistically distinct from c-Cbl-mediated degradation. RNAi-mediated silencing of LRIG1 alters EGFRvIII intracellular trafficking and leads to enhanced EGFRvIII expression. Co-immunoprecipitation, RNAi knockdown, receptor trafficking assays, proliferation/survival/motility/invasion assays in glioblastoma cells Oncogene Medium 18542056
2012 Loss of Lrig1 in mice results in heightened ErbB1-3 expression and development of duodenal adenomas, establishing Lrig1 as an in vivo tumor suppressor functioning through ErbB regulation. Lrig1 marks predominantly noncycling intestinal stem cells at the crypt base that can replenish damaged crypts upon injury. Genetic knockout (Lrig1-CreERT2/CreERT2), lineage tracing, transcriptome profiling, immunohistochemistry Cell High 22464327
2012 Lrig1 controls the size of the intestinal stem cell niche by regulating the amplitude of ErbB growth factor signaling. Loss of Lrig1 leads to expansion of the intestinal stem cell compartment through increased ErbB-driven proliferation. Genetic knockout, intestinal organoid culture, ErbB signaling assays, immunostaining of intestinal crypts Nature cell biology High 22388892
2013 LRIG1 regulates contact inhibition by forming a ternary complex with EGFR and E-cadherin, modulating EGFR activity in a contact-dependent manner. Deletion of Lrig1 is sufficient to promote murine airway hyperplasia through loss of contact inhibition. Co-immunoprecipitation (ternary complex), Lrig1 knockout mouse model, re-expression in human lung cancer cells, airway hyperplasia assay The Journal of pathology Medium 23208928
2013 LRIG1 inhibits STAT3-dependent inflammatory signaling in the cornea. Deletion of Lrig1 promotes a cell-fate switch from transparent epithelium to keratinized epidermis. Inhibition of STAT3 in Lrig1-/- mice rescues pathological phenotypes, placing LRIG1 upstream of STAT3 in corneal homeostasis. Bone marrow chimera experiments indicate LRIG1 also coordinates bone marrow-derived inflammatory cell function. Genetic knockout mouse model (Lrig1-/-), STAT3 inhibitor rescue experiments, transgenic STAT3-CA mice, bone marrow chimera experiments The Journal of clinical investigation High 24316976
2013 Lrig3 functionally opposes Lrig1: Lrig3 stabilizes ErbB receptors and counteracts Lrig1 negative regulatory activity, while Lrig1 destabilizes Lrig3 itself, identifying Lrig3 as a new target of Lrig1-mediated degradation. Co-expression studies, receptor stability assays, co-immunoprecipitation, ErbB receptor level measurement The Journal of biological chemistry Medium 23723069
2014 USP8 acts as a LRIG1-specific deubiquitinating enzyme: USP8 interacts with LRIG1 and stabilizes it by removing ubiquitin modifications. An anti-Met antibody (SAIT301) triggers LRIG1 ubiquitination by inhibiting the LRIG1-USP8 interaction, leading to LRIG1-mediated Met and LRIG1 co-degradation via lysosomal targeting through Hrs. Co-immunoprecipitation (USP8-LRIG1 interaction), ubiquitination assays, lysosomal trafficking assay, siRNA knockdown, anti-Met antibody treatment Scientific reports Medium 24828152
2015 Crystal structures of the LRIG1 extracellular domain were determined at 2.3 Å resolution for the LRR domain and 3Ig domain. The LRR domain and LRR-1Ig fragment are monomers in solution, while the 3Ig domain is dimeric. Notably, no detectable direct binding of isolated LRIG1 ECD domains to EGFR was observed in solution or on the cell surface, and co-expression of full-length LRIG1 in HEK293 cells did not inhibit ligand-stimulated EGFR activation. X-ray crystallography (2.3 Å), biosensor binding analysis, size-exclusion chromatography, cell-surface binding assays, co-expression EGFR activation assay Journal of molecular biology Medium 25765764
2015 Lrig1 regulates the postnatal development of smooth muscle-derived subsets of interstitial cells of Cajal (ICC-DMP and ICC-SMP) in the intestine. Lineage tracing demonstrates that ICC-DMP and ICC-SMP arise from Lrig1-positive smooth muscle progenitors, and loss of Lrig1 results in loss of KIT, anoctamin-1, and neurokinin 1 receptor expression in these ICC populations and impaired intestinal transit. Lineage tracing (Lrig1-CreERT2 x Rosa26-LSL-YFP), Lrig1-null mouse model, immunofluorescence, intestinal transit assay Gastroenterology High 25921371
2016 Lrig1 physically interacts with TrkB and attenuates BDNF signaling. Loss of Lrig1 enhances primary dendrite formation and proximal dendritic branching of hippocampal neurons, phenocopying BDNF effects. Lrig1-deficient mice display morphological changes in dendrite arborization and defects in social interaction. Co-immunoprecipitation (Lrig1-TrkB), gain- and loss-of-function in hippocampal neurons, in vivo knockout mouse behavioral analysis, dendritic morphology quantification EMBO reports High 26935556
2019 Androgen receptor (AR) directly transactivates LRIG1 by binding to multiple AR-binding sites in the LRIG1 locus. LRIG1 in turn dampens ERBB expression in a cell type-dependent manner and inhibits ERBB2-driven tumor growth, establishing LRIG1 as a pleiotropic AR-regulated feedback tumor suppressor. AR ChIP-seq, AR binding site mutagenesis, LRIG1 expression assays upon AR activation, xenograft tumor models (AR+ and AR-), Hi-Myc and TRAMP transgenic models Nature communications High 31792211
2021 LRIG1 is a gatekeeper for neural stem cell (NSC) exit from quiescence. BMP-4 signaling induces dormant quiescence while combined BMP-4/FGF-2 induces a primed quiescent state with high LRIG1 levels. Mechanistically, LRIG1 enables EGFR protein levels to increase while limiting signaling activation, priming quiescent NSCs for cell cycle re-entry. Genetic disruption of Lrig1 in the SVZ leads to enhanced NSC proliferation. In vitro NSC culture, genetic Lrig1 disruption in vivo, single-cell analysis, EGFR protein and signaling assays, SVZ engraftment experiments Nature communications High 33972529
2021 LRIG1 is expressed on Ret-positive DRG neurons and cooperates with Lrig3 to inhibit GDNF/Ret signaling. Lrig3 also interacts with Ret and inhibits GDNF/Ret signaling. Single deletion of Lrig1 or Lrig3 does not promote axonal growth, but haploinsufficiency of Lrig1 on a Lrig3 mutant background significantly potentiates Ret signaling and axonal growth, demonstrating redundant genetic interaction. Genetic compound mutant mouse models, Co-immunoprecipitation (Lrig3-Ret), GDNF-stimulated signaling assays, axonal growth assays, behavioral testing Development (Cambridge, England) High 34338291
2023 Lrig1 is required for the suppressive function of regulatory T cells (Tregs). Within CD4+ T cells, Tregs express the highest levels of Lrig1; Lrig1 deficiency impairs Treg suppressive function without affecting naïve T cell differentiation into other subsets. Mechanistically, Lrig1 controls suppressive function via the Smad2/3/Foxp3 axis. Adoptive transfer of CD4+Lrig1+ T cells alleviates autoimmune symptoms in colitis and lupus nephritis models. Lrig1-deficient mouse models, adoptive transfer experiments, Treg suppression assays, Smad2/3/Foxp3 pathway analysis, autoimmune disease models (EAE, colitis, lupus nephritis), anti-Lrig1 monoclonal antibody treatment Nature communications High 37666819
2024 LRIG1 functions as an inhibitory immune checkpoint receptor by engaging VISTA (V-domain immunoglobulin suppressor of T cell activation) as a binding partner on CD8+ T cells, suppressing TCR signaling pathways. T cell-specific LRIG1 deletion leads to expansion of tumor-specific cytotoxic T cells with increased effector function. Co-immunoprecipitation/binding assays (LRIG1-VISTA interaction), T cell-specific conditional knockout mouse models, tumor models, TCR signaling assays, flow cytometry of T cell subsets Science immunology High 38758807
2024 LRIG1 binds to TGFβ/BMP receptors and the TGFβ1 ligand, and facilitates SMAD phosphorylation downstream. Loss of LRIG1 in adult neural stem cells impairs TGFβ and BMP signaling activation, causing hyperproliferation that is not solely attributable to EGFR activation. Co-immunoprecipitation (LRIG1-TGFβ/BMP receptors, LRIG1-TGFβ1 ligand), Lrig1 knockout mouse models, SMAD phosphorylation assays, EGFR and TGFβ/BMP signaling assays Communications biology Medium 38987622
2025 Macrophage-derived VISTA interacts with LRIG1 in intestinal stem cells and suppresses PPARα signaling, leading to impeded intestinal organoid growth and increased epithelial damage. This VISTA/LRIG1 interaction hinders gut epithelial repair during colitis. Co-immunoprecipitation (macrophage VISTA-epithelial LRIG1), intestinal organoid growth assays, Vsir-/- and Vsir-/-Rag1-/- mouse models, macrophage transfer experiments, DSS colitis model Cellular & molecular immunology Medium 40883589
2018 A protein interaction network centered on LRIG1 was identified through yeast two-hybrid screening and BioPlex data mining. Functionally validated interactors that modulate LRIG1's ability to downregulate PDGFRα include RAB4A, PON2, GAL3ST1, ZBTB16, LRIG2, CNPY3, HLA-DRA, GML, CNPY4, LRRC40, LRIG3, GLRX3, and PTPRK. PON2 co-localizes with LRIG1 in LRIG1-transfected cells. Yeast two-hybrid screen, BioPlex data mining, triple co-transfection functional validation (HEK293 cells), co-localization by microscopy The Journal of biological chemistry Medium 29317492
2002 Targeted disruption of the Lig-1 (Lrig1) gene in mice results in psoriasiform epidermal hyperplasia, demonstrating that Lrig1 is required for normal epidermal proliferation control. Lrig1 is expressed in basal cells of the epidermis and outer root sheath cells of hair follicles. Gene targeting/knockout mouse model, histological analysis, in situ hybridization FEBS letters High 12067728
2022 LRIG1 expression in basal/triple-negative breast cancer is silenced by CpG island promoter methylation. Global demethylation with 5-aza-2'-deoxycytidine restores LRIG1 expression in basal/triple-negative but not luminal cell lines. Targeted TET1-mediated demethylation and VP64-mediated transcriptional activation using CRISPR/dCas9 at the CpG island restores LRIG1 expression and reduces cancer cell viability. Methylation immunoprecipitation, 5-aza-2'-deoxycytidine treatment, CRISPR/dCas9-TET1 targeted demethylation, dCas9-VP64 transcriptional activation, RT-PCR, immunoblotting, viability assays British journal of cancer Medium 35440669
2020 LRIG1-mediated inhibition of EGFR controls neural precursor cell proliferation during cortical development. Loss of Lrig1 in cortical NSCs causes stem cell expansion due to increased proliferation via EGFR deregulation. LRIG1 associates with and negatively regulates EGFR in cortical NSCs. Co-immunoprecipitation (LRIG1-EGFR), constitutive and conditional Lrig1 knockout mice, stem cell expansion quantification, EGFR signaling assays Cell reports High 33053360

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell 583 22464327
2009 Lrig1 expression defines a distinct multipotent stem cell population in mammalian epidermis. Cell stem cell 426 19427292
2012 Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling. Nature cell biology 342 22388892
2006 Single-cell expression profiling of human epidermal stem and transit-amplifying cells: Lrig1 is a regulator of stem cell quiescence. Proceedings of the National Academy of Sciences of the United States of America 254 16877544
2004 LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. The EMBO journal 237 15282549
2004 The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases. The Journal of biological chemistry 193 15345710
2006 LRIG1 is a novel negative regulator of the Met receptor and opposes Met and Her2 synergy. Molecular and cellular biology 107 17178829
2002 Targeted disruption of LIG-1 gene results in psoriasiform epidermal hyperplasia. FEBS letters 96 12067728
2008 Lrig1 is an endogenous inhibitor of Ret receptor tyrosine kinase activation, downstream signaling, and biological responses to GDNF. The Journal of neuroscience : the official journal of the Society for Neuroscience 94 18171921
2008 Suppression of the negative regulator LRIG1 contributes to ErbB2 overexpression in breast cancer. Cancer research 93 18922900
2013 The interfollicular epidermis of adult mouse tail comprises two distinct cell lineages that are differentially regulated by Wnt, Edaradd, and Lrig1. Stem cell reports 91 24052938
2002 Is LRIG1 a tumour suppressor gene at chromosome 3p14.3? Acta oncologica (Stockholm, Sweden) 77 12234026
2021 LRIG1 is a gatekeeper to exit from quiescence in adult neural stem cells. Nature communications 72 33972529
1996 cDNA cloning of a novel membrane glycoprotein that is expressed specifically in glial cells in the mouse brain. LIG-1, a protein with leucine-rich repeats and immunoglobulin-like domains. The Journal of biological chemistry 72 8798419
2013 LRIG1 is a triple threat: ERBB negative regulator, intestinal stem cell marker and tumour suppressor. British journal of cancer 71 23558895
2003 LRIG1 and epidermal growth factor receptor in renal cell carcinoma: a quantitative RT--PCR and immunohistochemical analysis. British journal of cancer 65 14520461
2008 LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII. Oncogene 64 18542056
2006 A soluble ectodomain of LRIG1 inhibits cancer cell growth by attenuating basal and ligand-dependent EGFR activity. Oncogene 59 16847455
2003 LRIG1 protein in human cells and tissues. Cell and tissue research 58 12684867
2013 LRIG1 inhibits STAT3-dependent inflammation to maintain corneal homeostasis. The Journal of clinical investigation 56 24316976
2017 Lrig1+ gastric isthmal progenitor cells restore normal gastric lineage cells during damage recovery in adult mouse stomach. Gut 53 28814482
2014 Inducible loss of one Apc allele in Lrig1-expressing progenitor cells results in multiple distal colonic tumors with features of familial adenomatous polyposis. American journal of physiology. Gastrointestinal and liver physiology 52 24833705
2013 LRIG1 modulates aggressiveness of head and neck cancers by regulating EGFR-MAPK-SPHK1 signaling and extracellular matrix remodeling. Oncogene 52 23624915
2013 The soluble form of the tumor suppressor Lrig1 potently inhibits in vivo glioma growth irrespective of EGF receptor status. Neuro-oncology 52 23723255
2016 Lrig1 is a cell-intrinsic modulator of hippocampal dendrite complexity and BDNF signaling. EMBO reports 46 26935556
2024 LRIG1 engages ligand VISTA and impairs tumor-specific CD8+ T cell responses. Science immunology 42 38758807
2009 Upregulation of LRIG1 suppresses malignant glioma cell growth by attenuating EGFR activity. Journal of neuro-oncology 42 19300910
2018 Isoliquiritigenin suppresses human melanoma growth by targeting miR-301b/LRIG1 signaling. Journal of experimental & clinical cancer research : CR 41 30081934
2011 LRIG1 and the liar paradox in prostate cancer: a study of the expression and clinical significance of LRIG1 in prostate cancer. International journal of cancer 39 21128282
2015 LRIG1 inhibits hypoxia-induced vasculogenic mimicry formation via suppression of the EGFR/PI3K/AKT pathway and epithelial-to-mesenchymal transition in human glioma SHG-44 cells. Cell stress & chaperones 35 25860915
2012 Downregulation of LRIG1 expression by RNA interference promotes the aggressive properties of glioma cells via EGFR/Akt/c-Myc activation. Oncology reports 35 23124613
2012 Expression of LRIG1 and LRIG3 correlates with human papillomavirus status and patient survival in cervical adenocarcinoma. International journal of oncology 35 23165628
2015 LRIG1 opposes epithelial-to-mesenchymal transition and inhibits invasion of basal-like breast cancer cells. Oncogene 33 26387542
2013 LRIG1 regulates cadherin-dependent contact inhibition directing epithelial homeostasis and pre-invasive squamous cell carcinoma development. The Journal of pathology 33 23208928
2018 Lrig1 is a haploinsufficient tumor suppressor gene in malignant glioma. Oncogenesis 32 29391393
2013 Gambogic acid induces EGFR degradation and Akt/mTORC1 inhibition through AMPK dependent-LRIG1 upregulation in cultured U87 glioma cells. Biochemical and biophysical research communications 32 23665322
2013 Leucine-rich repeat and immunoglobulin domain-containing protein-1 (Lrig1) negative regulatory action toward ErbB receptor tyrosine kinases is opposed by leucine-rich repeat and immunoglobulin domain-containing protein 3 (Lrig3). The Journal of biological chemistry 32 23723069
2018 Downregulation of microRNA-4295 enhances cisplatin-induced gastric cancer cell apoptosis through the EGFR/PI3K/Akt signaling pathway by targeting LRIG1. International journal of oncology 30 30320337
2013 LRIG1 dictates the chemo-sensitivity of temozolomide (TMZ) in U251 glioblastoma cells via down-regulation of EGFR/topoisomerase-2/Bcl-2. Biochemical and biophysical research communications 30 23850692
2012 LRIG1 modulates cancer cell sensitivity to Smac mimetics by regulating TNFα expression and receptor tyrosine kinase signaling. Cancer research 30 22241084
2021 LRIG1, a regulator of stem cell quiescence and a pleiotropic feedback tumor suppressor. Seminars in cancer biology 29 33476721
2020 LncRNA MAGI2-AS3 inhibits the self-renewal of leukaemic stem cells by promoting TET2-dependent DNA demethylation of the LRIG1 promoter in acute myeloid leukaemia. RNA biology 29 32174258
2019 Targeted mobilization of Lrig1+ gastric epithelial stem cell populations by a carcinogenic Helicobacter pylori type IV secretion system. Proceedings of the National Academy of Sciences of the United States of America 28 31488717
2019 LRIG1 is a pleiotropic androgen receptor-regulated feedback tumor suppressor in prostate cancer. Nature communications 28 31792211
2018 A protein interaction network centered on leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) regulates growth factor receptors. The Journal of biological chemistry 28 29317492
2017 Overexpressed miR-183 promoted glioblastoma radioresistance via down-regulating LRIG1. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 28 29793318
2014 Loss of LRIG1 locus increases risk of early and late relapse of stage I/II breast cancer. Cancer research 28 24879564
2007 LRIG1 expression in colorectal cancer. Acta oncologica (Stockholm, Sweden) 28 17851870
2014 USP8 modulates ubiquitination of LRIG1 for Met degradation. Scientific reports 27 24828152
2021 microRNA-1246-containing extracellular vesicles from acute myeloid leukemia cells promote the survival of leukemia stem cells via the LRIG1-meditated STAT3 pathway. Aging 26 33893245
2015 LRIG1 Regulates Ontogeny of Smooth Muscle-Derived Subsets of Interstitial Cells of Cajal in Mice. Gastroenterology 26 25921371
2017 HPV8 Field Cancerization in a Transgenic Mouse Model Is due to Lrig1+ Keratinocyte Stem Cell Expansion. The Journal of investigative dermatology 25 28595997
2015 miR-20a mediates temozolomide-resistance in glioblastoma cells via negatively regulating LRIG1 expression. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 25 25960225
2006 LRIG1, a candidate tumour-suppressor gene in human bladder cancer cell line BIU87. BJU international 24 16978290
2019 LRIG1 acts as a critical regulator of melanoma cell invasion, migration, and vasculogenic mimicry upon hypoxia by regulating EGFR/ERK-triggered epithelial-mesenchymal transition. Bioscience reports 23 30487162
2013 A role for LRIG1 in the regulation of malignant glioma aggressiveness. International journal of oncology 23 23337938
2015 Loss of Lrig1 leads to expansion of Brunner glands followed by duodenal adenomas with gastric metaplasia. The American journal of pathology 22 25794708
2015 LRIG1, human EGFR inhibitor, reverses multidrug resistance through modulation of ABCB1 and ABCG2. Brain research 22 25801120
2020 Lrig1 expression prospectively identifies stem cells in the ventricular-subventricular zone that are neurogenic throughout adult life. Neural development 20 32183906
2018 Tumor-suppressive effect of LRIG1, a negative regulator of ErbB, in non-small cell lung cancer harboring mutant EGFR. Carcinogenesis 20 29546323
2017 Harnessing LRIG1-mediated inhibition of receptor tyrosine kinases for cancer therapy. Biochimica et biophysica acta. Reviews on cancer 20 28259645
2022 Aberrant promoter methylation contributes to LRIG1 silencing in basal/triple-negative breast cancer. British journal of cancer 19 35440669
2015 LRIG1 enhances the radiosensitivity of radioresistant human glioblastoma U251 cells via attenuation of the EGFR/Akt signaling pathway. International journal of clinical and experimental pathology 19 26097540
2012 Lrig1: a new master regulator of epithelial stem cells. The EMBO journal 19 22433838
2015 LRIG1, a 3p tumor suppressor, represses EGFR signaling and is a novel epigenetic silenced gene in colorectal cancer. Biochemical and biophysical research communications 18 26159916
2013 Restoration of LRIG1 suppresses bladder cancer cell growth by directly targeting EGFR activity. Journal of experimental & clinical cancer research : CR 18 24314030
2020 LRIG1-Mediated Inhibition of EGF Receptor Signaling Regulates Neural Precursor Cell Proliferation in the Neocortex. Cell reports 17 33053360
2017 From the Cover: High Susceptibility of Lrig1 Sebaceous Stem Cells to TCDD in Mice. Toxicological sciences : an official journal of the Society of Toxicology 17 28973660
2014 Using a new Lrig1 reporter mouse to assess differences between two Lrig1 antibodies in the intestine. Stem cell research 17 25460603
2017 MicroRNA-590-3p enhances the radioresistance in glioblastoma cells by targeting LRIG1. Experimental and therapeutic medicine 16 28810655
2021 LRIG1 is a conserved EGFR regulator involved in melanoma development, survival and treatment resistance. Oncogene 14 33947959
2018 Expression of LRIG1, a Negative Regulator of EGFR, Is Dynamically Altered during Different Stages of Gastric Carcinogenesis. The American journal of pathology 14 30248341
2015 Decreased LRIG1 in fulvestrant-treated luminal breast cancer cells permits ErbB3 upregulation and increased growth. Oncogene 14 26148232
2014 LRIG1 as a potential novel marker for neoplastic transformation in ocular surface squamous neoplasia. PloS one 13 24709893
2015 Adenovirus-mediated LRIG1 expression enhances the chemosensitivity of bladder cancer cells to cisplatin. Oncology reports 12 25695283
2015 LRIG1 extracellular domain: structure and function analysis. Journal of molecular biology 12 25765764
2018 Resveratrol inhibits glioma cell growth via targeting LRIG1. Journal of B.U.ON. : official journal of the Balkan Union of Oncology 11 29745084
2017 Senescent Atrophic Epidermis Retains Lrig1+ Stem Cells and Loses Wnt Signaling, a Phenotype Shared with CD44KO Mice. PloS one 11 28099467
2011 Suppression of bladder cancer cell tumorigenicity in an athymic mouse model by adenoviral vector-mediated transfer of LRIG1. Oncology reports 11 21567105
2024 Dysregulation and antimetastatic function of circLRIG1 modulated by miR-214-3p/LRIG1 axis in bladder carcinoma. Biology direct 10 38454507
2022 Lrig1 expression identifies airway basal cells with high proliferative capacity and restricts lung squamous cell carcinoma growth. The European respiratory journal 10 34385275
2022 Lrig1 regulates the balance between proliferation and quiescence in glioblastoma stem cells. Frontiers in cell and developmental biology 10 36420140
2020 MicroRNA Expression Profiling of Normal and Malignant Human Colonic Stem Cells Identifies miRNA92a as a Regulator of the LRIG1 Stem Cell Gene. International journal of molecular sciences 10 32316543
2012 LRIG1 enhances cisplatin sensitivity of glioma cell lines. Oncology research 10 23581227
2011 LRIG1 combined with cisplatin enhances bladder cancer lesions via a novel pathway. Oncology reports 10 21431282
2023 A member of the immunoglobulin superfamily lrig-1 might be involved in the immune priming of Scylla paramamosain in response to the infection and re-infection by Vibrio parahaemolyticus. Developmental and comparative immunology 9 37302729
2023 Lrig1-expression confers suppressive function to CD4+ cells and is essential for averting autoimmunity via the Smad2/3/Foxp3 axis. Nature communications 9 37666819
2014 LRIG1 enhances chemosensitivity by modulating BCL-2 expression and receptor tyrosine kinase signaling in glioma cells. Yonsei medical journal 9 25048475
2007 Down-regulation of leucine-rich repeats and immunoglobulin-like domain proteins (LRIG1-3) in HP75 pituitary adenoma cell line. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 9 17393120
2021 hsa_circ_0000006 induces tumorigenesis through miR-361-3p targeting immunoglobulin-like domains protein 1 (LRIG1) in osteosarcoma. Annals of translational medicine 8 34532379
2016 Over-expression of LRIG1 suppresses biological function of pituitary adenoma via attenuation of PI3K/AKT and Ras/Raf/ERK pathways in vivo and in vitro. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 8 27465333
2016 Investigation of the association between miR‑181b, Bcl‑2 and LRIG1 in oral verrucous carcinoma. Molecular medicine reports 8 27509922
2016 Overexpression of LRIG1 regulates PTEN via MAPK/MEK signaling pathway in esophageal squamous cell carcinoma. Experimental and therapeutic medicine 8 27698691
2020 LRIG1 gene copy number analysis by ddPCR and correlations to clinical factors in breast cancer. BMC cancer 7 32448168
2014 MicroRNA-19a promotes glioma cell growth by repressing LRIG1. International journal of clinical and experimental medicine 7 25664006
2012 Effects of RNAi-mediated gene silencing of LRIG1 on proliferation and invasion of glioma cells. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 7 22528225
2024 LRIG1 controls proliferation of adult neural stem cells by facilitating TGFβ and BMP signalling pathways. Communications biology 6 38987622
2017 Role and mechanism of action of LRIG1 in ovarian cancer cell line and VP16 drug-resistant cell line. Oncology letters 6 28943962
2025 Macrophage-derived VISTA engages with LRIG1 and hinders gut epithelial repair in colitis. Cellular & molecular immunology 5 40883589
2021 Lrig1 and Lrig3 cooperate to control Ret receptor signaling, sensory axonal growth and epidermal innervation. Development (Cambridge, England) 5 34338291

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