Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation.
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Human LRIG1 associates with the four mammalian ErbB receptors and enhances EGFR ubiquitylation and degradation through recruitment of the E3 ligase c-Cbl.
"We report upregulation of LRIG1 transcript and protein upon EGF stimulation, and physical association of the encoded protein with the four EGFR orthologs of mammals. Upregulation of LRIG1 is followed by enhanced ubiquitylation and degradation of EGFR. The underlying mechanism involves recruitment of c-Cbl, an E3 ubiquitin ligase that simultaneously ubiquitylates EGFR and LRIG1 and sorts them for degradation."
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LRIG1 is an integral transmembrane protein, supporting its receptor-associated plasma-membrane state.
"Their structural relative in mammals, LRIG1, is a transmembrane protein"
The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases.
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In transfected human cells, LRIG1 formed complexes with EGFR and ERBB2-4, reduced EGFR abundance and half-life, and enhanced ligand-stimulated EGFR ubiquitination.
"LRIG1 forms a complex with each of the ErbB receptors"
LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII.
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LRIG1 retains interaction with oncogenic EGFRvIII and suppresses EGFRvIII-driven glioblastoma-cell phenotypes through a mechanism distinct from Cbl-mediated degradation.
"We find that EGFRvIII retains interaction with LRIG1 and is in fact more sensitive to LRIG1 action than wild-type receptor. We demonstrate that LRIG1 regulation of EGFRvIII is distinct from the only other known mechanism of EGFR regulation, Cbl-mediated degradation."
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).
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LRIG3 functionally opposes LRIG1 in ErbB regulation, whereas LRIG1 destabilizes LRIG3, demonstrating paralog cross-talk rather than interchangeable LRIG-family function.
"Lrig3 opposes Lrig1 negative regulatory"
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
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The LRIG1-LRIG3 association derives from cell-line-specific affinity-purification mass-spectrometry networks and is screen-level interaction evidence.
"mass spectrometry, we have created two proteome-scale, cell-line-specific"
MET binds LRIG1
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Reactome summarizes LRIG1 binding to MET, CBL-independent MET downregulation, and subsequent ubiquitination-dependent lysosomal trafficking.
"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). MET targeting by the therapeutic antibody SAIT301 leads to LRIG1-mediated MET degradation through the lysosomal route. LRIG1-mediated MET downregulation requires ubiquitination of LRIG1 by an unknown ubiquitin ligase and can be inhibited by the ubiqitin hydrolase USP8, which deubiquitinates LRIG1 (Oh et al. 2014, Lee et al. 2014). Ubiquitinated LRIG1 binds to HGS (Hrs), a protein involved in clathrin-mediated endocytosis, and LRIG1 and MET co-localize with the lysosomal marker LAMP1 (Oh et al. 2014)."
LRIG1 undergoes ubiquitination
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Reactome records ubiquitination of LRIG1 after MET binding by an unidentified ligase.
"Upon binding to MET, LRIG1 undergoes ubiquitination by an unknown ubiquitin ligase (Oh et al. 2014)."
USP8 deubiquitinates LRIG1
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Reactome records USP8-mediated deubiquitination of LRIG1 as an inhibitor of LRIG1-dependent MET downregulation.
"The ubiquitin hydrolase USP8 can deubiquitinate LRIG1, thus interfering with LRIG1-mediated MET downregulation (Oh et al. 2014)."
LRIG1 is a novel negative regulator of the Met receptor and opposes Met and Her2 synergy.
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LRIG1 binds MET without HGF stimulation, promotes CBL-independent MET destabilization, and restrains HGF responses and MET-ERBB2-driven invasion.
"We find that the Met receptor interacts with the transmembrane protein LRIG1 independent of hepatocyte growth factor (HGF) stimulation and that LRIG1 destabilizes the Met receptor in a cbl-independent manner."
Lrig1 is an endogenous inhibitor of Ret receptor tyrosine kinase activation, downstream signaling, and biological responses to GDNF.
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Lrig1 physically associates with RET and inhibits GDNF binding, RET recruitment to lipid rafts, receptor autophosphorylation, MAPK activation, and neuronal responses.
"physically interacting with Ret"
Paracrine regulation of growth factor signaling by shed leucine-rich repeats and immunoglobulin-like domains 1.
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LRIG1 ectodomains are constitutively shed, with ADAM17-sensitive modulation, and the soluble ectodomain can suppress EGF signaling in trans without detectable EGFR downregulation.
"Cells constitutively shed LRIG1 ectodomains in vitro"
The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor.
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In mouse intestinal epithelium, Lrig1 loss increases ErbB1-3/ERK signaling and causes highly penetrant duodenal adenomas, providing tissue-specific in vivo tumor-suppressor evidence.
"Notably, at five to six months of age, 14/16 (88%) Lrig1-CreERT2/CreERT2 mice developed duodenal tumors."
USP8 modulates ubiquitination of LRIG1 for Met degradation.
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In SAIT301-treated cancer cells, LRIG1 ubiquitination recruits Hrs and directs the MET-LRIG1 complex to lysosomes; USP8 counteracts this by deubiquitinating LRIG1.
"These results suggest that SAIT301-induced ubiquitination of LRIG1 promotes recruitment of Met-LRIG1 complex to the lysosome through its interaction with Hrs, resulting in lysosomal degradation of Met and LRIG1."
LRIG1 extracellular domain: structure and function analysis.
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Purified human LRIG1 ectodomain fragments yielded structural information, but this assay did not detect EGFR binding and full-length LRIG1 coexpression did not inhibit ligand-stimulated EGFR activation.
"We could not detect any binding of the LRIG1 domains"
A protein interaction network centered on leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) regulates growth factor receptors.
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Yeast two-hybrid and BioPlex-derived candidates define a hypothesis-generating LRIG1 interaction network; selected proteins were tested in HEK293 co-transfection assays for effects on growth-factor receptors.
"performed a yeast two-hybrid screen to identify novel LRIG1-interacting proteins"
LRIG1 negatively regulates RET mutants and is downregulated in thyroid cancer.
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LRIG1 binds oncogenic RET2A and RET2B and reduces their phosphorylation without reducing total receptor abundance.
"LRIG1 physically interacted with both RET2A and RET2B, as shown by the co-immunoprecipitation of LRIG1 and the RET2A and RET2B proteins"
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LRIG1 was reduced in human thyroid cancers, but the study found no survival association and Lrig1 deletion did not significantly alter lesions in its RET2B mouse model.
"However, in our mouse model of RET2B-driven MTC, no significant effect of Lrig1 gene ablation was observed."
Lrig1 and Lrig3 cooperate to control Ret receptor signaling, sensory axonal growth and epidermal innervation.
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In mouse sensory neurons, Lrig1 and Lrig3 act redundantly to constrain RET-dependent axonal growth and epidermal innervation.
"Lrig1 and Lrig3 act redundantly"