Affinage

FLRT2

Leucine-rich repeat transmembrane protein FLRT2 · UniProt O43155

Length
660 aa
Mass
74.0 kDa
Annotated
2026-04-28
25 papers in source corpus 17 papers cited in narrative 17 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FLRT2 is a leucine-rich repeat transmembrane glycoprotein that functions as both a repulsive guidance ligand and a homophilic adhesion molecule, directing cell positioning during neural development, vascular morphogenesis, and synapse specificity. As a shed or membrane-bound ligand for Unc5 family receptors (Unc5B, Unc5C, Unc5D), FLRT2 mediates chemorepulsive signaling that controls cortical neuron migration timing, interneuron stream maintenance, endothelial cell alignment in the placental labyrinth, and rejection of inappropriate synaptic partners in the retina (PMID:21673655, PMID:34301831, PMID:28576770, PMID:37557174). In endothelial cells, FLRT2 forms homophilic trans-adhesions that protect tumor vasculature from oxidative stress, interacts with VE-cadherin and the adaptor Numb to regulate adherens junction morphology and blood–brain barrier integrity, and associates with ITGB4 to prevent endothelial senescence via mTORC2/AKT/p53 signaling (PMID:35104247, PMID:39609404, PMID:38587072). Intracellularly, FLRT2 binds FGFR2 through both its LRR ectodomain and cytoplasmic tail to potentiate FGF-ERK signaling in craniofacial tissues, and is subject to NEDD4-mediated ubiquitination and proteasomal degradation (PMID:21765038, PMID:39444619).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1999 Medium

    Establishing the gene product identity: FLRT2 was shown to encode a type I transmembrane glycoprotein with 10 leucine-rich repeats, cysteine-rich flanking domains, and a fibronectin-like domain — a domain architecture suggestive of adhesion/receptor function but with no known ligand or binding partner.

    Evidence Molecular cloning and heterologous expression in SF9/COS-1 cells with glycosylation analysis

    PMID:10644439

    Open questions at the time
    • No binding partner or receptor identified
    • No in vivo functional data
    • Mechanism of action entirely unknown
  2. 2011 High

    Four studies simultaneously established FLRT2's core molecular functions: it binds Unc5D to act as a repulsive cue delaying cortical neuron migration, it is essential for epicardial integrity and heart morphogenesis, it interacts with FGFR2 to potentiate FGF-ERK signaling, and it modulates N-cadherin-dependent cell aggregation during chondrogenesis — collectively revealing FLRT2 as a multifunctional regulator of cell positioning and signaling.

    Evidence Binding assays and reciprocal KO/OE in mouse cortex (PMID:21673655); conditional KO with in vivo rescue in epicardium (PMID:21350012); Co-IP/GST-pulldown/Y2H with ERK readout in craniofacial tissue (PMID:21765038); KD/OE in ATDC5 cells with proliferation and aggregation assays (PMID:21769912)

    PMID:21350012 PMID:21673655 PMID:21765038 PMID:21769912

    Open questions at the time
    • Structural basis of FLRT2-Unc5D and FLRT2-FGFR2 interfaces unresolved
    • Whether FLRT2's adhesive and repulsive functions are context-dependent or simultaneous unclear
    • Intracellular signaling downstream of FLRT2 in epicardium not defined
  3. 2014 Medium

    FLRT2 was found to associate with fibronectin in the extracellular matrix, existing in both membrane-bound and shed forms, suggesting the ECM environment regulates FLRT2 availability and function.

    Evidence Co-IP, immunolocalization, ECM fractionation, and fibronectin-blocking peptide experiments in ATDC5 cells

    PMID:24585683

    Open questions at the time
    • No reconstitution with purified proteins to confirm direct fibronectin binding
    • Shedding protease not identified
    • Functional consequence of ECM-bound FLRT2 versus shed FLRT2 not distinguished in vivo
  4. 2017 High

    The FLRT2–Unc5B repulsive axis was extended beyond the nervous system: endothelial FLRT2 signals through Unc5B to mediate inter-endothelial repulsion required for proper vessel alignment in the placental labyrinth, with endothelial-specific deletion causing embryonic lethality.

    Evidence Endothelial-specific conditional KO mouse with phenotypic analysis of placental vasculature

    PMID:28576770

    Open questions at the time
    • Downstream endothelial signaling cascades linking Unc5B activation to cytoskeletal remodeling not defined
    • Whether shed or membrane-bound FLRT2 drives the endothelial phenotype unknown
  5. 2019 Medium

    FLRT2's interaction with the Unc5B pathway was shown to regulate osteoclast multinucleation by modulating Netrin1–Unc5B crosstalk and Rac1 activation, revealing a role in bone biology.

    Evidence FLRT2 KO osteoclasts with Unc5B RNAi rescue, Rac1 activation assay, Netrin1 epistasis

    PMID:31383250

    Open questions at the time
    • Whether FLRT2 competes directly with Netrin1 for Unc5B binding or acts allosterically not resolved
    • In vivo bone phenotype of FLRT2-deficient mice not characterized
  6. 2021 High

    FLRT2 and FLRT3 were shown to cooperate as non-cell-autonomous chemorepellent ligands maintaining cortical interneuron migratory streams, with double KO phenocopying loss of their receptors Unc5B/Unc5D — establishing genetic epistasis for the FLRT–Unc5 repulsion axis in interneuron guidance.

    Evidence Double conditional KO mice (FLRT2/FLRT3 and Unc5B/Unc5D), in vitro chemorepulsion assay

    PMID:34301831

    Open questions at the time
    • Source cells producing FLRT2 ligand in this context not fully defined
    • Whether FLRT2 acts as shed or membrane-bound ligand for interneurons not distinguished
  7. 2021 Medium

    Subcellular mapping showed FLRT2 is present at both pre- and postsynaptic compartments in the hippocampus and is dynamically expressed through postnatal CNS development, positioning it as a potential synaptic organizer.

    Evidence Flrt2-LacZ knock-in reporter mice with immunofluorescence and subcellular fractionation

    PMID:34744626

    Open questions at the time
    • No functional test of synaptic role in hippocampus performed
    • Synaptic binding partners at these sites not identified
    • Single reporter approach without independent antibody validation
  8. 2022 High

    FLRT2 was identified as a homophilic adhesion molecule in tumor endothelium: trans-homophilic FLRT2 interactions safeguard abnormalized vessels against oxidative stress, and endothelial-specific deletion selectively prunes these vessels, suppresses metastasis, and enhances anti-tumor immunity — revealing a druggable vascular maintenance mechanism.

    Evidence Endothelial-specific conditional KO with tumor implantation, metabolic analysis, immune checkpoint blockade, homophilic binding identification

    PMID:35104247

    Open questions at the time
    • Structural basis of homophilic versus Unc5-binding interface not compared
    • How FLRT2 switches between homophilic adhesion and Unc5-mediated repulsion in endothelium unknown
  9. 2022 High

    The cis-dimerization mechanism was resolved: FLRT2 dimerizes through two Small-X3-Small motifs in its transmembrane helix that synergize with an extracellular dimerization motif, suggesting cis/trans switching controls adhesion state.

    Evidence Molecular dynamics simulations validated by single-particle tracking and transmembrane motif mutagenesis

    PMID:35700726

    Open questions at the time
    • Functional consequence of cis versus trans states on repulsion/adhesion not tested in vivo
    • Whether cis dimerization is regulated by ligand binding or post-translational modification unknown
  10. 2023 High

    FLRT2–Unc5 signaling was shown to mediate synaptic partner rejection in the retina: FLRT2 on direction-selective neurons binds Unc5C/D on non-DS neurons to eliminate misdirected dendrites, establishing FLRT2 as a molecular determinant of synaptic specificity beyond axon guidance.

    Evidence Conditional KO, misexpression, live imaging, and synapse analysis in mouse retina

    PMID:37557174

    Open questions at the time
    • Whether FLRT2 adhesion and Unc5-mediated repulsion are simultaneously active at the same synapse not resolved
    • Downstream signaling in the eliminated dendrite not characterized
  11. 2024 High

    Three studies expanded FLRT2's endothelial roles: FLRT2 directly binds ITGB4 to prevent endothelial senescence via mTORC2/AKT/p53, interacts with VE-cadherin/Numb to regulate adherens junction morphology and blood–brain barrier integrity, and is subject to NEDD4-mediated ubiquitination controlling its protein stability.

    Evidence Co-IP identifying ITGB4 and VE-cadherin as partners, ITGB4 inhibitor rescue, expansion microscopy, conditional KO retinal/cortical phenotyping (PMID:38587072, PMID:39609404); NEDD4–FLRT2 ubiquitination assay and NSCLC xenograft epistasis (PMID:39444619)

    PMID:38587072 PMID:39444619 PMID:39609404

    Open questions at the time
    • How FLRT2 coordinates ITGB4, VE-cadherin, and Unc5B interactions at the endothelial surface not integrated
    • Whether NEDD4-mediated degradation is regulated by FLRT2 ligand engagement unknown
    • FLRT2 structural domains mediating VE-cadherin versus ITGB4 binding not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • A central unresolved question is how FLRT2 switches between its repulsive (Unc5-binding) and adhesive (homophilic, VE-cadherin, ITGB4) modes at the molecular level, and whether cis-dimerization state, shedding, or post-translational modifications control this switch in different tissues.
  • No structural model of full-length FLRT2 or its complexes with Unc5 versus homophilic partners
  • Identity of the shedding protease(s) unknown
  • Relationship between cis-dimerization state and functional output not tested in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098631 cell adhesion mediator activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 3 GO:0005886 plasma membrane 3 GO:0031012 extracellular matrix 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-1500931 Cell-Cell communication 3 R-HSA-162582 Signal Transduction 2
Partners
CDH5FGFR2FN1ITGB4NEDD4UNC5BUNC5CUNC5D

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 FLRT2 is a type I transmembrane protein containing 10 leucine-rich repeats flanked by cysteine-rich regions, a fibronectin/collagen-like domain, and an intracellular tail; when expressed in SF9 and COS-1 cells it migrates as an ~85-kDa glycoprotein, consistent with a role in cell adhesion and/or receptor signaling. Heterologous expression in SF9 and COS-1 cells, molecular cloning, glycosylation analysis Genomics Medium 10644439
2011 The shed FLRT2 ectodomain binds specifically to the Unc5D receptor and acts as a repulsive guidance cue for Unc5D-positive neurons; in the developing neocortex, FLRT2/Unc5D signaling delays migration of SVZ-derived neurons toward the cortical plate, as shown by premature migration upon deletion of either FLRT2 or Unc5D and delayed migration upon Unc5D overexpression. Binding assays (ectodomain-receptor interaction), mouse genetic deletion, overexpression in vivo, neuronal migration assays The EMBO journal High 21673655
2011 FLRT2 is required in the epicardium for heart morphogenesis; loss of FLRT2 disrupts epicardial sheet integrity and basement membrane organization, leading to mid-gestation cardiac lethality; FLRT2 and FLRT3 are functionally interchangeable in both the epicardium and the AVE, as demonstrated by in vitro and in vivo reconstitution assays. Gene targeting (conditional KO), in vitro and in vivo reconstitution assays, histological analysis Development (Cambridge, England) High 21350012
2011 FLRT2 interacts with both the extracellular and intracellular regions of FGFR2; the LRR domain of FLRT2 mediates interaction with the extracellular region of FGFR2, and the C-tail of FLRT2 interacts with the intracellular region of FGFR2; FLRT2 positively regulates FGF signaling (FGFR2 protein/mRNA levels and ERK phosphorylation) in craniofacial tissues. Co-immunoprecipitation from embryonic craniofacial tissue lysates, GST pulldown, yeast two-hybrid, stable shRNA knockdown and cDNA overexpression with ERK phosphorylation readout Journal of dental research High 21765038
2011 FLRT2 promotes cell proliferation and inhibits cell-cell adhesion (reducing N-cadherin-mediated aggregation) during early chondrogenesis; FLRT2 knockdown slows proliferation and increases PNA-stained cell aggregates, while overexpression accelerates proliferation and reduces aggregation. Stable knockdown and overexpression in ATDC5 chondroprogenitor cells, proliferation assays, PNA staining, N-cadherin immunostaining, wound-healing migration assay Journal of cellular biochemistry Medium 21769912
2014 FLRT2 interacts with fibronectin in the extracellular matrix of ATDC5 chondroprogenitor cells; FLRT2 co-localizes with fibronectin fibrils, is found in ECM fractions, and co-immunoprecipitates with fibronectin; disruption of fibronectin fibril formation reduces extracellular FLRT2 accumulation; FLRT2 exists in both membrane-bound and shed forms. Co-immunoprecipitation, immunolocalization, ECM fractionation, fibronectin-coated bead binding, fibronectin-blocking peptide experiments, Western blot with domain-specific antibodies Journal of cellular physiology Medium 24585683
2017 FLRT2 expressed on endothelial cells in the placental labyrinth signals through the UNC5B receptor to mediate inter-endothelial repulsion, which is required for proper alignment of endothelial cells and feto-maternal circulation; endothelial-specific deletion of FLRT2 causes aberrant endothelial layering and embryonic lethality. Endothelial cell-specific conditional KO mouse, phenotypic analysis of placental labyrinth, receptor-ligand interaction with UNC5B Development (Cambridge, England) High 28576770
2019 FLRT2 regulates osteoclast multinucleation by interfering with Netrin1-Unc5B interaction; FLRT2 deficiency reduces hyper-multinucleation and attenuates RANKL-induced Rac1 activation, effects rescued by Unc5B knockdown; Netrin1 inhibitory effects on multinucleation are abolished in FLRT2-deficient cells. Genetic KO in osteoclasts, RNAi knockdown of Unc5B, Rac1 activation assay, Netrin1 treatment, osteoclast differentiation assays BMB reports Medium 31383250
2021 FLRT2 and FLRT3 cooperate in a non-cell-autonomous repulsive mechanism to maintain tangential migratory streams of cortical interneurons; double KO of FLRT2/FLRT3 phenocopies double KO of their repulsive receptors Unc5B/Unc5D; FLRT proteins act as chemorepellent ligands for interneurons in vitro, partially dependent on FLRT-Unc5 interaction. Double conditional KO mice (FLRT2/FLRT3 and Unc5B/Unc5D), in vitro chemorepulsion assay, immunostaining of interneuron streams The Journal of neuroscience High 34301831
2021 FLRT2 is localized to pre- and postsynapses in the CA1 region of the adult hippocampus and is upregulated in reactive astrocytes around spinal cord injury lesion sites; its expression is dynamic across postnatal CNS development. Flrt2-LacZ knock-in reporter mice, immunofluorescence, subcellular fractionation analysis Frontiers in molecular neuroscience Medium 34744626
2022 FLRT2 forms homophilic (in trans) interendothelial adhesions in tumor vasculature that safeguard endothelial cells against oxidative stress; endothelial-specific Flrt2 deletion selectively prunes abnormalized vessels, induces oxygen-glucose uncoupling, suppresses tumor metastasis, and enhances responses to immune checkpoint blockers. Endothelial-specific conditional KO mouse, tumor implantation models, metabolic analysis, immune checkpoint blockade experiments, mechanistic identification of homophilic binding The Journal of clinical investigation High 35104247
2022 FLRT2 dimerizes in cis via two Small-X3-Small motifs in its transmembrane helix, which synergize with a third dimerization motif in the extracellular domain to permit cis association and co-diffusion on the cell surface; this cis dimerization may compete with in trans interactions, suggesting a switching mechanism between adhesion states. Molecular dynamics simulations, single particle tracking (SPT) experiments, transmembrane motif mutagenesis Structure (London, England : 1993) High 35700726
2023 FLRT2-UNC5 transcellular signaling mediates rejection of inappropriate synaptic partners in the mouse retina; FLRT2 expressed by direction-selective (DS) circuit neurons binds UNC5C/D on non-DS neurons, causing elimination of misdirected dendrites; loss of FLRT2-UNC5 binding allows mistargeted arbors to persist and acquire synapses from wrong partners, while UNC5 misexpression drives arbors into adjacent sublayers; mechanistically, UNC5s promote dendrite elimination by interfering with FLRT2-mediated adhesion. In vivo gain- and loss-of-function (conditional KO, misexpression), live imaging, synapse analysis Developmental cell High 37557174
2023 FLRT2 elevates ACSL4 expression to increase lipid peroxidation and trigger ferroptosis in bladder cancer cells, thereby suppressing tumor cell growth and migration. Overexpression and knockdown in bladder cancer cell lines, lipid peroxidation assays, ferroptosis markers, ACSL4 expression analysis Journal of cellular and molecular medicine Medium 37480224
2024 FLRT2 directly associates with integrin subunit beta 4 (ITGB4) and promotes ITGB4 phosphorylation; this interaction mediates prevention of endothelial cell senescence via the mTORC2/AKT/p53 signaling pathway; FLRT2 silencing in mice promotes vascular aging, and FLRT2 overexpression rescues premature vascular aging. Co-immunoprecipitation (direct association with ITGB4), ITGB4 inhibition rescue experiments, mTORC2/AKT/p53 pathway analysis, in vivo FLRT2 silencing and overexpression mouse models JCI insight High 38587072
2024 NEDD4 (E3 ubiquitin ligase) binds FLRT2, ubiquitinates it, and promotes its proteasomal degradation; NEDD4 overexpression abolishes FLRT2-mediated suppression of NSCLC stem cell proliferation and sphere formation. Co-immunoprecipitation (NEDD4-FLRT2 binding), ubiquitination assay, overexpression/knockdown in NSCLC cells and xenograft mouse models Frontiers in pharmacology Medium 39444619
2024 FLRT2 interacts with VE-cadherin and, together with the endocytic adaptor Numb, modulates adherens junction morphology in retinal and cortical vessels; endothelial FLRT2 deletion in postnatal mice causes defects in retinal vein endothelial cell proliferation, sprouting, and polarity, reduces tip cells, and disrupts blood-brain barrier development by altering crosstalk between adherens and tight junctions. Endothelial-specific conditional KO, expansion microscopy of VE-cadherin distribution, Co-immunoprecipitation (FLRT2-VE-cadherin), in vivo retinal and cortical vascular phenotyping Nature communications High 39609404

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 FLRT2 and FLRT3 act as repulsive guidance cues for Unc5-positive neurons. The EMBO journal 122 21673655
1999 Identification of FLRT1, FLRT2, and FLRT3: a novel family of transmembrane leucine-rich repeat proteins. Genomics 102 10644439
2011 The fibronectin leucine-rich repeat transmembrane protein Flrt2 is required in the epicardium to promote heart morphogenesis. Development (Cambridge, England) 42 21350012
2016 Methylation profiling identified novel differentially methylated markers including OPCML and FLRT2 in prostate cancer. Epigenetics 40 26890304
2017 Epigenetically regulated Fibronectin leucine rich transmembrane protein 2 (FLRT2) shows tumor suppressor activity in breast cancer cells. Scientific reports 27 28325946
2017 Placental labyrinth formation in mice requires endothelial FLRT2/UNC5B signaling. Development (Cambridge, England) 27 28576770
2009 Flrt2 and Flrt3 have overlapping and non-overlapping expression during craniofacial development. Gene expression patterns : GEP 26 19635589
2011 Mouse FLRT2 interacts with the extracellular and intracellular regions of FGFR2. Journal of dental research 22 21765038
2022 Tumor-specific interendothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness. The Journal of clinical investigation 21 35104247
2011 FLRT2 promotes cellular proliferation and inhibits cell adhesion during chondrogenesis. Journal of cellular biochemistry 18 21769912
2021 FLRT2 and FLRT3 Cooperate in Maintaining the Tangential Migratory Streams of Cortical Interneurons during Development. The Journal of neuroscience : the official journal of the Society for Neuroscience 16 34301831
2023 FLRT2 suppresses bladder cancer progression through inducing ferroptosis. Journal of cellular and molecular medicine 14 37480224
2020 FLRT2 functions as Tumor Suppressor gene inactivated by promoter methylation in Colorectal Cancer. Journal of Cancer 13 33193897
2018 Enhanced synaptic plasticity and spatial memory in female but not male FLRT2-haplodeficient mice. Scientific reports 13 29487336
2014 FLRT2 interacts with fibronectin in the ATDC5 chondroprogenitor cells. Journal of cellular physiology 13 24585683
2022 The guidance and adhesion protein FLRT2 dimerizes in cis via dual small-X3-small transmembrane motifs. Structure (London, England : 1993) 10 35700726
2024 FLRT2 prevents endothelial cell senescence and vascular aging by regulating the ITGB4/mTORC2/p53 signaling pathway. JCI insight 9 38587072
2023 Rejection of inappropriate synaptic partners in mouse retina mediated by transcellular FLRT2-UNC5 signaling. Developmental cell 8 37557174
2021 Expression of FLRT2 in Postnatal Central Nervous System Development and After Spinal Cord Injury. Frontiers in molecular neuroscience 8 34744626
2019 Flrt2 is involved in fine-tuning of osteoclast multinucleation. BMB reports 7 31383250
2023 LncRNA ZFAS1 protects chondrocytes from IL-1β-induced apoptosis and extracellular matrix degradation via regulating miR-7-5p/FLRT2 axis. Journal of orthopaedic surgery and research 6 37098630
2024 FLRT2 mediates chondrogenesis of nasal septal cartilage and mandibular condyle cartilage. Open medicine (Warsaw, Poland) 3 38584835
2024 Vascular FLRT2 regulates venous-mediated angiogenic expansion and CNS barriergenesis. Nature communications 3 39609404
2023 Loss of flrt2 gene leads to microphthalmia in zebrafish. Biology open 2 37259881
2024 The NEDD4/FLRT2 axis regulates NSCLC cell stemness. Frontiers in pharmacology 1 39444619