LRIG3

LRIG3 is a transmembrane leucine-rich repeat and immunoglobulin-domain protein that operates as a context-dependent modulator of receptor tyrosine kinase signaling and developmental patterning (PMID:18287203, PMID:23069723). In ErbB/EGFR signaling, LRIG3 physically associates with ErbB receptors and stabilizes them, acting in functional opposition to its paralog Lrig1, which destabilizes both ErbB receptors and LRIG3 itself; the two proteins interact directly (PMID:23069723, PMID:23723069). In cancer cells LRIG3 behaves as a tumor suppressor: it restrains EGFR pathway output to inhibit proliferation, invasion and migration (PMID:25708990), facilitates DUSP6-mediated dephosphorylation of ERK1/2 to downregulate the EMT regulator Slug (PMID:32107843), and inhibits PI3K/AKT signaling to reduce VEGFA expression and tumor angiogenesis (PMID:33718179). An ADAM17-shed soluble LRIG3 ectodomain engages the CUB1 domain of NETO2 on tumor-associated macrophages to block M2 polarization and suppress glioblastoma growth, defining a non-cell-autonomous signaling mode (PMID:36639372). Beyond cancer, LRIG3 binds Ret and inhibits GDNF/Ret signaling in DRG neurons, acting redundantly with Lrig1 to control cutaneous innervation and cold sensitivity (PMID:34338291). In development, LRIG3 functions downstream of Pax3/Zic1 to modulate Wnt and FGF signaling during neural crest induction and interacts with FGFR1 (PMID:18287203), and it patterns inner ear lateral semicircular canal morphogenesis through mutually antagonistic cross-repression with Netrin 1 (PMID:19004851).

1. 2008 Medium

   Established LRIG3 as a developmental signaling modulator by placing it downstream of Pax3/Zic1 in neural crest induction and linking it to Wnt/FGF pathways and FGFR1.

   Evidence Morpholino knockdown and co-injection epistasis in Xenopus with NC marker readouts, plus Co-IP with FGFR1 in cultured cells

   PMID:18287203

   Open questions at the time

   • FGFR1 interaction shown only by Co-IP in cultured cells, not reconstituted
   • Direction of FGF modulation (enhancement vs attenuation) context-dependent and not mechanistically resolved
2. 2008 Low

   Provided early evidence of reciprocal LRIG3/EGFR regulation, showing ligand-induced changes in their relative expression.

   Evidence Confocal imaging of LRIG3-EGFP fusion and EGF-treatment expression time-course in GL15 glioblastoma cells

   PMID:18925709

   Open questions at the time

   • Single localization and expression time-course without functional mutagenesis
   • Cytoplasmic localization of a fusion protein may not reflect endogenous distribution
3. 2008 High

   Defined LRIG3 as essential for inner ear lateral canal morphogenesis via cross-repression with Netrin 1, with double-mutant rescue establishing causality.

   Evidence Gene-trap mouse mutant, Lrig3 × Ntn1 heterozygous rescue, in situ hybridization and circling behavior assay

   PMID:19004851

   Open questions at the time

   • Molecular basis of the mutual repression unresolved
   • Whether LRIG3 acts cell-autonomously in the fusion plate not established
4. 2010 Medium

   Tested whether ErbB modulation underlies inner ear morphogenesis and excluded it, sharpening the mechanistic model toward Netrin.

   Evidence Co-IP with ErbB2/ErbB3 plus pharmacological ErbB inhibition in chick otic vesicle with Netrin in situ readout

   PMID:20126551

   Open questions at the time

   • Negative ErbB result is specific to inner ear and does not generalize
   • ErbB interaction characterized only in vitro
5. 2013 Medium

   Resolved the LRIG3–Lrig1 relationship, showing LRIG3 stabilizes ErbB receptors and opposes Lrig1-driven degradation while itself being destabilized by Lrig1.

   Evidence Reciprocal Co-IP, gain/loss-of-function overexpression and receptor-degradation Western blots in cells

   PMID:23069723 PMID:23723069

   Open questions at the time

   • Mechanism by which LRIG3 stabilizes ErbB receptors not defined
   • Performed in overexpression systems; endogenous stoichiometry unknown
6. 2015 Medium

   Positioned LRIG3 as a tumor suppressor acting upstream of EGFR signaling in glioblastoma.

   Evidence Lentiviral overexpression, siRNA knockdown, EGFR-inhibitor epistasis, proliferation/invasion assays and xenografts

   PMID:25708990

   Open questions at the time

   • Does not distinguish direct receptor effects from downstream pathway modulation
   • Single cancer-cell context
7. 2020 Medium

   Identified a mechanism for LRIG3 suppression of cancer cell motility via DUSP6-mediated ERK1/2 dephosphorylation and Slug downregulation.

   Evidence LRIG3 knockout/re-introduction, Co-IP of DUSP6 with ERK1/2, p-ERK1/2 and Slug Western blots, Transwell assays in CRC cells

   PMID:32107843

   Open questions at the time

   • How LRIG3 promotes DUSP6–ERK association not structurally defined
   • Single lab and cancer type
8. 2020 Medium

   Established post-transcriptional control of LRIG3 by miR-196a, linking its loss to cervical cancer aggressiveness.

   Evidence Dual-luciferase reporter validation, si-LRIG3 rescue, Transwell and CCK-8 assays

   PMID:33287939

   Open questions at the time

   • Downstream signaling effectors in this context not mapped
   • In vivo relevance not tested
9. 2021 High

   Extended LRIG3's RTK regulatory role to the nervous system, showing it binds Ret and inhibits GDNF signaling redundantly with Lrig1 to control innervation and cold sensitivity.

   Evidence Co-IP with Ret, GDNF time-course, Lrig1-haploinsufficient × Lrig3-knockout genetic analysis, axon growth and behavioral cold tests

   PMID:34338291

   Open questions at the time

   • Mechanism of Ret inhibition (degradation vs sequestration) not defined
   • Relative contributions of Lrig1 and Lrig3 not fully separated
10. 2021 High

    Defined a non-cell-autonomous mechanism in which ADAM17-shed soluble LRIG3 binds the NETO2 CUB1 domain on macrophages to block M2 polarization and suppress tumor growth.

    Evidence Mass spectrometry, Co-IP, NETO2 knockout and CUB1-deletion mutagenesis, conditioned-medium and in vivo tumor models; ADAM17–sLRIG3 correlation

    PMID:36639372

    Open questions at the time

    • ADAM17 cleavage site not mapped by reconstitution (correlational shedding evidence)
    • NETO2 downstream signaling in TAMs not detailed
11. 2021 Medium

    Showed LRIG3 inhibits PI3K/AKT signaling to reduce VEGFA and tumor angiogenesis.

    Evidence Gain/loss-of-function, PI3K/AKT Western blots, VEGFA measurement, tube-formation and in vivo angiogenesis assays

    PMID:33718179

    Open questions at the time

    • Link between LRIG3 and proximal PI3K/AKT regulators not defined
    • Whether this is downstream of EGFR not resolved
12. 2025 Low

    Broadened the in vivo phenotypic landscape of LRIG3 loss across metabolic, intestinal and inflammatory tissues and implicated BMP signaling.

    Evidence Histopathology of 42 tissues from Lrig3-deficient mice on two backgrounds with high-fat diet challenge

    PMID:40320098

    Open questions at the time

    • BMP signaling link stated without detailed mechanistic experiment
    • Strain-dependent phenotypes complicate interpretation
13. 2026 Low

    Demonstrated that LRIG3 gain-of-function in skin disrupts hair follicle homeostasis with upregulation of ErbB, PI3K/AKT and NOTCH1 pathways.

    Evidence Tet-Off transgenic overexpression in mouse skin with proteome profiling and pathway analysis

    PMID:42218262

    Open questions at the time

    • No direct binding or reconstitution experiments
    • Pathway changes correlative at the proteome level

• How LRIG3 mechanistically stabilizes ErbB receptors and inhibits Ret, and how its dual cell-autonomous (receptor-modulating) and ectodomain (NETO2-binding) activities are coordinated, remains unresolved.
• No structural model of LRIG3 receptor engagement
• Endogenous shedding regulation and balance between membrane-bound and soluble pools unknown