LRIG3

LRIG3 is a transmembrane leucine-rich repeat and immunoglobulin-like domain protein that functions as a context-dependent modulator of receptor tyrosine kinase signaling and intercellular communication during development and in cancer. It directly interacts with FGFR1, ErbB receptors, and the Ret receptor to attenuate their downstream signaling, and opposes the action of its paralog LRIG1 by stabilizing ErbB receptors against LRIG1-induced degradation (PMID:18287203, PMID:23723069, PMID:34338291). In the inner ear, LRIG3 establishes mutually antagonistic expression domains with Netrin1 to control basement membrane breakdown during lateral semicircular canal morphogenesis (PMID:19004851). LRIG3 also suppresses cancer cell motility by scaffolding a DUSP6–ERK1/2 complex that promotes ERK dephosphorylation and EMT inhibition, and its ADAM17-shed soluble ectodomain interacts with the CUB1 domain of NETO2 on tumor-associated macrophages to block M2 polarization (PMID:32107843, PMID:36639372).

1. 2008 High

   Establishing LRIG3 as a signaling modulator in neural crest development resolved the question of where in the FGF/Wnt hierarchy this LRR protein operates: it acts downstream of Pax3/Zic1, attenuates FGF signaling via direct FGFR1 interaction, and positively modulates Wnt signaling.

   Evidence Morpholino knockdown, animal cap epistasis assays, and co-immunoprecipitation with FGFR1 in Xenopus

   PMID:18287203

   Open questions at the time

   • Mechanism by which LRIG3 attenuates FGFR1 signaling (degradation vs. inhibition of activation) not determined
   • Wnt modulation mechanism not defined at molecular level
2. 2008 High

   Genetic epistasis in mice revealed that LRIG3 controls lateral semicircular canal morphogenesis by antagonizing Netrin1 expression, with Ntn1 haploinsufficiency rescuing the canal defect and circling behavior of Lrig3 mutants.

   Evidence Gene trap mutagenesis, Lrig3 × Ntn1 genetic crosses, behavioral assay, in situ hybridization in mouse inner ear

   PMID:19004851

   Open questions at the time

   • Molecular mechanism by which LRIG3 represses Netrin1 transcription is unknown
   • Whether LRIG3 acts cell-autonomously in the otic epithelium was not resolved
3. 2010 Medium

   Although LRIG3 binds ErbB2/ErbB3 in vitro, pharmacological ErbB inhibition in chick otic vesicle did not phenocopy Lrig3 loss, dissociating ErbB modulation from the inner ear morphogenesis function.

   Evidence Co-immunoprecipitation of LRIG3 with ErbB2/ErbB3; pharmacological ErbB inhibition in chick otic vesicle explants

   PMID:20126551

   Open questions at the time

   • The relevant in vivo receptor target in the inner ear remains unidentified
   • Single-lab finding without genetic ErbB loss-of-function
4. 2013 Medium

   Defining the LRIG3–LRIG1 functional antagonism showed that LRIG3 stabilizes ErbB receptors and counteracts LRIG1-mediated degradation, while LRIG1 reciprocally destabilizes LRIG3 protein—establishing a paralog-level regulatory circuit.

   Evidence Co-immunoprecipitation, receptor stability assays, gain- and loss-of-function in cell lines

   PMID:23723069

   Open questions at the time

   • Whether LRIG3–LRIG1 antagonism occurs in vivo in specific tissues is untested
   • Whether LRIG1-induced LRIG3 destabilization is ubiquitin-dependent is unknown
5. 2015 Medium

   Extending LRIG3's RTK-inhibitory role to cancer, LRIG3 overexpression in glioblastoma cells suppressed proliferation and invasion via EGFR pathway downregulation, confirmed by EGFR inhibitor epistasis.

   Evidence Lentiviral overexpression and siRNA knockdown in glioma cells, EGFR inhibitor rescue, xenograft assays

   PMID:25708990

   Open questions at the time

   • Whether LRIG3 directly binds EGFR or acts indirectly through other ErbB family members not resolved
   • Mechanism of EGFR downregulation (degradation, internalization, or transcriptional) not defined
6. 2020 Medium

   Identifying LRIG3 as a scaffold that bridges DUSP6 to ERK1/2 provided a mechanism for its anti-migratory function: LRIG3 facilitates ERK dephosphorylation and consequent Slug downregulation, suppressing EMT-driven motility in colorectal cancer cells.

   Evidence Co-immunoprecipitation of LRIG3–DUSP6–ERK1/2 ternary complex, knockout and re-expression rescue, Transwell assays

   PMID:32107843

   Open questions at the time

   • Structural basis for LRIG3 scaffolding of DUSP6 and ERK1/2 is unknown
   • Whether this mechanism operates in non-cancer contexts not tested
7. 2021 High

   Demonstration that LRIG3 directly interacts with the Ret receptor and inhibits GDNF/Ret signaling in DRG neurons, with LRIG1 and LRIG3 acting redundantly to control cutaneous innervation and cold sensitivity, extended the RTK-regulatory function to the peripheral nervous system.

   Evidence Co-immunoprecipitation of Lrig3–Ret, single and compound Lrig1/Lrig3 mutant mice, behavioral cold-sensitivity assay, skin innervation immunostaining

   PMID:34338291

   Open questions at the time

   • Whether LRIG3 promotes Ret degradation or blocks ligand binding is not determined
   • Relative contributions of LRIG1 vs. LRIG3 to Ret regulation in different DRG neuron subtypes are unclear
8. 2023 High

   Discovery that ADAM17-shed soluble LRIG3 interacts with the CUB1 domain of NETO2 on tumor-associated macrophages to suppress M2 polarization revealed a non-cell-autonomous, paracrine tumor-suppressive mechanism distinct from its RTK-modulatory roles.

   Evidence Mass spectrometry identification of sLRIG3–NETO2 interaction, Co-IP, NETO2 ΔCUB1 domain-deletion abolishes effect, in vivo tumor assay

   PMID:36639372

   Open questions at the time

   • Signaling pathway downstream of NETO2 that mediates M2 suppression is not identified
   • Physiological relevance of sLRIG3-NETO2 interaction outside the tumor microenvironment is unknown

• The structural basis for LRIG3's receptor selectivity, the mechanism by which it simultaneously scaffolds phosphatases and modulates RTKs, and whether its paracrine (sLRIG3–NETO2) and cell-autonomous (RTK-inhibitory) functions are coordinated remain unresolved.
• No structural or cryo-EM model of LRIG3 in complex with any partner
• In vivo relevance of LRIG3–DUSP6–ERK scaffolding outside colorectal cancer not tested
• Whether ADAM17-mediated shedding is regulated and how it partitions LRIG3 between cell-autonomous and paracrine functions is unknown