{"gene":"PLXNB1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2010,"finding":"Crystal structures of the PLXNB1 sema domain (residues 1-2) in complex with SEMA4D ectodomain revealed that semaphorin dimers bind two plexin molecules independently, forming a 2:2 bivalent complex. Monomeric semaphorin binds PLXNB1 but fails to trigger signaling, demonstrating that signaling requires avidity of the bivalent complex. The interaction is mediated through conserved contacts of the N-terminal seven-bladed β-propeller (sema) domains of both semaphorin and plexin, suggesting semaphorin-stabilized plexin dimerization as the activation mechanism.","method":"X-ray crystallography, biophysical assays, cellular signaling assays with wild-type and mutant proteins","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation by mutagenesis and cellular assays in a single rigorous study","pmids":["20877282"],"is_preprint":false},{"year":2011,"finding":"Binding of Sema4D (secreted by osteoclasts) to its receptor Plexin-B1 on osteoblasts activates the small GTPase RhoA, which suppresses bone formation by inhibiting IGF-1 signaling and modulating osteoblast motility. Plxnb1-/- mice display an osteosclerotic phenotype due to augmented bone formation, placing PLXNB1 in the Sema4D-RhoA-IGF-1 signaling axis in bone homeostasis.","method":"Genetic knockout mouse models (Plxnb1-/-, Sema4d-/-, dominant-negative RhoA transgenic in osteoblasts), bone phenotype analysis, IGF-1 signaling assays","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models with defined phenotypic readouts, replicated across multiple knockout lines","pmids":["22019888"],"is_preprint":false},{"year":2013,"finding":"Sema4D promotes rapid GABAergic synapse formation in rodent hippocampus via its receptor PlexinB1; this effect is dependent on PlexinB1 as it is abolished in PlxnB1-/- mice. Sema4D-PlexinB1 signaling initiates synapse formation by recruiting synaptic proteins to both presynaptic and postsynaptic terminals within 10-30 minutes.","method":"Loss-of-function genetic screen, immunocytochemistry, live imaging in cultured hippocampal neurons and PlxnB1-/- mice, organotypic slice electrophysiology","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout validation combined with live imaging and electrophysiology, multiple orthogonal methods","pmids":["23699507"],"is_preprint":false},{"year":2016,"finding":"A high-affinity macrocyclic peptide PB1m6 (KD = 3.5 nM) binds PLXNB1 at a groove between the fifth and sixth blades of the sema domain, distant from the Sema4D-binding site. This allosteric binding competitively inhibits Sema4D binding in vitro and completely suppresses Sema4D-induced cell collapse, identifying a novel allosteric site on PLXNB1.","method":"In vitro binding assay, cell collapse assay, X-ray crystallography of PB1m6-PlxnB1 complex","journal":"Cell chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus functional in vitro and cellular assays, single lab but multiple orthogonal methods","pmids":["27984026"],"is_preprint":false},{"year":2017,"finding":"Sema4D binding to PlexinB1 on retinal pigment epithelium (RPE) cells attenuates photoreceptor outer segment (POS) phagocytosis by decreasing GTP-loading of Rac1. PlexinB1 phosphorylation and Sema4D levels are reduced at the peak of diurnal phagocytosis after light onset in vivo; plxnb1-/- or sema4d-/- mice show increased POS phagosome content after light onset.","method":"In vitro Rac1 GTP-loading assay in differentiated RPE cells, in situ analysis in wild-type and mutant rat/mouse retina, genetic knockout models","journal":"Molecular neurobiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (in vitro Rac1 assay, in vivo knockout phenotype, in situ phosphorylation analysis) in a single study","pmids":["28624895"],"is_preprint":false},{"year":2018,"finding":"Plexin-B1 requires its presence in both the presynaptic axon of inhibitory interneurons and the postsynaptic dendrites of excitatory neurons for Sema4D-dependent inhibitory synapse development in rodent hippocampus. Sema4A also signals through postsynaptic PlexinB1 to promote inhibitory synapse development, using the same pathway as Sema4D.","method":"Compartment-specific loss-of-function experiments in cultured hippocampal neurons, immunocytochemistry, genetic approaches","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — compartment-specific functional dissection but single lab, methods partially inferred from abstract","pmids":["29981480"],"is_preprint":false},{"year":2019,"finding":"Soluble CD100 (Sema4D) induces epithelial-mesenchymal transition (EMT) in head and neck squamous cell carcinoma through its receptor Plexin-B1, and promotes metastasis in a xenograft mouse model. The signaling mechanism involves the Vav1-Rac1/RhoA-p21-activated kinase pathway leading to Snail stabilization.","method":"Xenograft mouse model, cell migration/invasion assays, western blot, siRNA knockdown, anti-CD100 antibody treatment","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — xenograft model combined with mechanistic pathway dissection (Vav1-Rac1/RhoA-PAK-Snail), single lab","pmids":["30981760"],"is_preprint":false},{"year":2022,"finding":"A PLXNB1 variant (p.R1031H) identified in normosmic IHH patients shows reduced membrane expression and impaired cell migration in GnRH neuronal cell lines compared to wild-type PlexinB1, implicating PLXNB1 in GnRH cell migration during development.","method":"Boyden chamber migration assay, flow cytometry/western blot for membrane expression, bioinformatic modeling","journal":"Journal of neuroendocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional assays in GnRH cell line with a clinically identified variant, single lab, two methods","pmids":["35170806"],"is_preprint":false},{"year":2022,"finding":"Rnd1 (a constitutively active Rho GTPase) facilitates pro-inflammatory cytokine (IL-6 and TNF-α) production during bacterial infection through PlexinB1, providing a Rnd1-PLXNB1-mediated innate immune defense mechanism against intracellular bacterial infections.","method":"In vitro infection assays, cytokine measurements, functional assays with Rnd1 and Plxnb1","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional mechanistic link between Rnd1, Plxnb1, and cytokine production established, single lab","pmids":["35654795"],"is_preprint":false},{"year":2022,"finding":"De novo Fc-based receptor dimerizers grafted with different PLXNB1-binding peptides can act as either agonists or antagonists of PlexinB1. Structural analysis revealed that the agonistic Fc dimerizes PlxnB1 in a face-to-face fashion similar to that induced by Sema4D, whereas the antagonistic Fc induces a signaling-incompetent dimer conformation, demonstrating that plexin activation is controlled by receptor orientation within the dimer.","method":"Structural analysis of peptide-PlxnB1 complexes, cell-based signaling assays with Fc dimerizers","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures of agonist and antagonist complexes combined with functional cellular assays revealing mechanistic basis of dimer orientation in signaling","pmids":["35981535"],"is_preprint":false},{"year":2023,"finding":"A rare homozygous loss-of-function PLXNB1 variant (p.Ser454Arg) causes neurite outgrowth deficits in patient iPSC-derived cortical neurons. Expression of wild-type PLXNB1, but not the variant, rescued neurite outgrowth in patient neurons; expression of the variant caused neurite outgrowth deficits in cortical neurons from PlxnB1 knockout mice, establishing PLXNB1 as a regulator of neurite outgrowth.","method":"iPSC-derived cortical neurons from patient and controls, rescue experiments with wild-type vs. variant PLXNB1, PlxnB1 knockout mouse neurons, transcriptomic profiling of organoids","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss-of-function patient variant with rescue experiment in patient neurons and validation in knockout mouse neurons; multiple orthogonal approaches in single study","pmids":["37032361"],"is_preprint":false},{"year":2023,"finding":"Prostate epithelial cell-specific expression of a clinically identified mutant Plexin-B1 (P1597L) significantly increases metastasis in two transgenic prostate cancer mouse models, whereas wild-type Plexin-B1 expression suppresses metastasis, demonstrating that P1597L converts PLXNB1 from a metastasis suppressor to a metastasis promoter. Deletion of RhoA/C or PDZRhoGEF suppressed metastasis in this context, implicating the Rho/ROCK pathway in the phenotypic switch.","method":"Transgenic mouse models (PbCre), germline and conditional deletion, RhoA/C and PDZRhoGEF deletion, metastasis quantification, invasion assays","journal":"Cancer research communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple transgenic and knockout mouse models with clear metastasis quantification and pathway identification (Rho/ROCK)","pmids":["36936664"],"is_preprint":false},{"year":2024,"finding":"Plexin-B1 is upregulated in plaque-associated astrocytes in Alzheimer's disease and governs cell distancing in peri-plaque glial nets. Plexin-B1 deletion in a mouse AD model reduced the number of reactive astrocytes and microglia in peri-plaque nets but increased glial process coverage of plaques, reduced overall plaque burden, shifted plaques toward dense-core type, and reduced neuritic dystrophy and neuroinflammatory transcriptional signatures.","method":"Conditional knockout in AD mouse model, histology, transcriptomics, plaque morphology analysis","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type-specific knockout with multiple quantitative phenotypic readouts and transcriptional analysis in a rigorous AD mouse model study","pmids":["38802590"],"is_preprint":false},{"year":2024,"finding":"PlexinB1 inactivation in the tumor microenvironment (TME) of triple-negative murine breast carcinoma reduces primary tumor growth and metastatic dissemination, associated with a switch of tumor-associated macrophages toward a pro-inflammatory M1 phenotype, enhanced CD8+ T lymphocyte infiltration, and upregulation of anti-tumor genes (Icos, Perforin-1, Stat3, Ccl5) in TILs. Pharmacological PLXNB1 blockade phenocopied genetic deletion and enhanced anti-PD-1 immunotherapy efficacy.","method":"PLXNB1-deficient mouse model, flow cytometry, gene expression profiling of TILs, pharmacological inhibition, anti-PD-1 combination treatment","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological targeting with multiple immune phenotyping methods; functional consequences in vivo established","pmids":["38874583"],"is_preprint":false},{"year":2024,"finding":"Sema4D secreted by osteoclast-like cells induces sympathetic nerve diffusion and hyperinnervation through binding to Plxnb1, contributing to abdominal aortic aneurysm development. This was identified by single-cell RNA sequencing and validated in Sema4D-deficient mice showing reduced AAA progression.","method":"Single-cell RNA sequencing, Sema4D knockout mouse model, immunostaining","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — scRNA-seq identification with in vivo genetic validation (Sema4D KO), single lab","pmids":["38821358"],"is_preprint":false},{"year":2025,"finding":"Genetic ablation of PLXNB1 in murine and human iPSC-derived astrocytes decreased the Ast10 (SLC38A2-high) pathologic astrocyte state signature in Alzheimer's disease, confirming PLXNB1 as a regulator of this disease-associated astrocyte state that contributes to cognitive decline through synaptic loss.","method":"Genetic ablation in murine astrocytes and human iPSC-derived astrocytes, single-nucleus RNA-seq meta-analysis, spatial transcriptomics validation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic ablation in two model systems with transcriptomic validation; preprint, not yet peer-reviewed","pmids":["40060644"],"is_preprint":true},{"year":2016,"finding":"CRISPR-mediated knockout of Plxnb1 in p53-null/Myc-overexpressing mouse hepatocytes increased liver tumor formation and was associated with increased MAPK phosphorylation, identifying PLXNB1 as a suppressor of liver tumor formation that acts upstream of the MAPK pathway.","method":"Genome-wide CRISPR/Cas9 knockout screen, subcutaneous and orthotopic transplantation in mice, immunohistochemistry for MAPK phosphorylation","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genome-wide screen with validation of Plxnb1-specific MAPK phosphorylation; single lab, limited mechanistic follow-up for PLXNB1 specifically","pmids":["27956228"],"is_preprint":false},{"year":2016,"finding":"PLXNB1 expression is regulated by the TMPRSS2-ERG fusion gene in prostate cancer cells, and PLXNB1 (but not MMP-9) contributes to TMPRSS2-ERG-mediated enhancement of cancer cell migration and invasion in VCaP cells, placing PLXNB1 downstream of ERG as a mediator of invasion.","method":"siRNA knockdown of ERG, MMP-9, and PLXNB1; MTT and Transwell invasion assays; qRT-PCR and western blot","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — siRNA epistasis with invasion assays establishes pathway position; single lab, single cell line model","pmids":["28004109"],"is_preprint":false},{"year":2022,"finding":"miR-362-5p directly targets PLXNB1 mRNA (confirmed by luciferase reporter assay), suppressing PLXNB1 expression and thereby inhibiting chondrogenic differentiation of bone marrow mesenchymal stem cells; PLXNB1 overexpression promotes chondrogenic differentiation and alleviates joint injury in an in vivo OA rat model.","method":"Luciferase reporter assay, RT-qPCR, western blot, chondrogenic differentiation assays, micro-CT in OA rat model","journal":"Journal of orthopaedic surgery (Hong Kong)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct miRNA-target relationship confirmed by luciferase assay with in vivo phenotypic validation; single lab","pmids":["36523183"],"is_preprint":false},{"year":2026,"finding":"ALDH1A3 promotes acetyl-CoA production and enhances H3K9/K14 histone acetylation at the PLXNB1 promoter, activating PLXNB1 transcription in pancreatic ductal adenocarcinoma. This sensitizes PDAC cells to SEMA4D from lung epithelial cells, driving SEMA4D-PLXNB1 signaling-mediated lung metastatic colonization.","method":"RNA sequencing, ChIP for histone acetylation at PLXNB1 promoter, in vitro and in vivo metastasis assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP establishes epigenetic mechanism at PLXNB1 promoter with functional in vivo metastasis readout; single lab","pmids":["42221815"],"is_preprint":false},{"year":2026,"finding":"PLXNB1 knockdown in human nasal epithelial cells increases expression of inflammatory cytokines (IL-4, IL-6), likely via activation of the MAPK/p38 signaling pathway, while PLXNB1 overexpression suppresses inflammation, indicating PLXNB1 negatively regulates MAPK/p38-driven inflammation in epithelial cells.","method":"In vitro PLXNB1 knockdown and overexpression in nasal epithelial cells, cytokine assays, in vivo AR mouse model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional gain/loss of function with pathway identification (MAPK/p38), single lab","pmids":["42224190"],"is_preprint":false}],"current_model":"PLXNB1 encodes a transmembrane semaphorin receptor (primarily for Sema4D) that signals through RhoA/ROCK and Rac1 GTPase pathways to regulate diverse cellular processes including cytoskeletal remodeling, cell migration, neurite outgrowth, synapse formation, bone homeostasis, and immune cell behavior; structurally, signaling requires semaphorin-induced dimerization of PLXNB1 in a specific face-to-face orientation, and allosteric sites on its sema domain can modulate this activation."},"narrative":{"mechanistic_narrative":"PLXNB1 encodes a transmembrane semaphorin receptor that transduces extracellular cues into cytoskeletal and transcriptional responses governing cell migration, neural connectivity, bone homeostasis, and tumor/immune behavior [PMID:20877282, PMID:22019888]. Activation requires that the semaphorin ligand Sema4D (and also Sema4A) bridge two receptor molecules into a 2:2 bivalent complex through conserved contacts of the N-terminal seven-bladed sema (β-propeller) domains; monomeric ligand binds but cannot signal, establishing ligand-stabilized receptor dimerization as the activation switch [PMID:20877282, PMID:29981480]. Signaling output is dictated by dimer geometry: a face-to-face orientation matching that induced by Sema4D is agonistic, whereas an alternative orientation yields a signaling-incompetent dimer, and an allosteric groove between the fifth and sixth blades of the sema domain, distinct from the ligand site, can be exploited to block activation [PMID:27984026, PMID:35981535]. Downstream, PLXNB1 couples to Rho-family GTPase signaling—activating RhoA (via PDZRhoGEF and the RhoA/ROCK axis) and modulating Rac1 GTP-loading—to control diverse outputs including suppression of osteoblast bone formation through inhibition of IGF-1 signaling [PMID:22019888], attenuation of photoreceptor outer-segment phagocytosis in retinal pigment epithelium [PMID:28624895], and EMT and invasion in cancer via a Vav1-Rac1/RhoA-PAK-Snail cascade [PMID:30981760, PMID:36936664]. In the nervous system, PLXNB1 is required both pre- and postsynaptically for Sema4D/Sema4A-dependent GABAergic synapse formation and for cortical neurite outgrowth [PMID:23699507, PMID:29981480, PMID:37032361]. Rare loss-of-function PLXNB1 variants cause neurite outgrowth deficits in patient iPSC-derived neurons (p.Ser454Arg) and impair GnRH neuronal migration (p.R1031H, in normosmic idiopathic hypogonadotropic hypogonadism) [PMID:35170806, PMID:37032361]. PLXNB1 also shapes Alzheimer's disease pathology by governing peri-plaque glial distancing and a pathologic astrocyte state [PMID:38802590], and modulates the tumor immune microenvironment, where its blockade reprograms macrophages toward M1, boosts CD8+ T-cell infiltration, and enhances anti-PD-1 efficacy [PMID:38874583].","teleology":[{"year":2010,"claim":"Resolved how a semaphorin engages PLXNB1 to switch it on, establishing that ligand-stabilized receptor dimerization—not mere binding—is the activation mechanism.","evidence":"X-ray crystallography of the PLXNB1 sema domain–SEMA4D ectodomain complex with mutagenesis and cellular signaling assays","pmids":["20877282"],"confidence":"High","gaps":["Does not resolve how dimerization is propagated across the membrane to the intracellular GAP domain","No structure of the full-length receptor or intracellular signaling complex"]},{"year":2011,"claim":"Defined a physiological role for PLXNB1 in skeletal homeostasis, placing it in a Sema4D-RhoA-IGF-1 axis that restrains bone formation.","evidence":"Plxnb1-/-, Sema4d-/-, and osteoblast dominant-negative RhoA mouse models with bone phenotyping and IGF-1 signaling assays","pmids":["22019888"],"confidence":"High","gaps":["Effector linking RhoA to IGF-1 pathway suppression not fully resolved","Cell-autonomous vs systemic contributions not dissected"]},{"year":2013,"claim":"Showed PLXNB1 is the receptor mediating rapid Sema4D-induced GABAergic synapse formation, extending plexin function to synaptic assembly.","evidence":"Loss-of-function in PlxnB1-/- mice, immunocytochemistry, live imaging, and slice electrophysiology in hippocampal neurons","pmids":["23699507"],"confidence":"High","gaps":["Intracellular effectors recruiting synaptic proteins not identified","Whether RhoA or Rac mediate this synaptic effect unclear"]},{"year":2016,"claim":"Identified PLXNB1 as a context-dependent tumor suppressor acting upstream of MAPK in liver and downstream of ERG in prostate, framing dual roles in cancer.","evidence":"Genome-wide CRISPR knockout screen with transplantation and MAPK phosphorylation readout in hepatocytes; siRNA epistasis with invasion assays in prostate VCaP cells","pmids":["27956228","28004109"],"confidence":"Medium","gaps":["Mechanism linking PLXNB1 loss to MAPK activation not defined","Single cell-line/model contexts limit generality"]},{"year":2016,"claim":"Discovered a druggable allosteric site on PLXNB1 distinct from the ligand site, providing a pharmacological route to block activation.","evidence":"High-affinity macrocyclic peptide PB1m6 binding assay, cell collapse assay, and X-ray crystallography of the PB1m6-PlxnB1 complex","pmids":["27984026"],"confidence":"High","gaps":["In vivo efficacy of allosteric inhibition not tested in this study","How allosteric occupancy translates structurally to blocked dimerization unresolved"]},{"year":2017,"claim":"Linked PLXNB1 to Rac1-dependent regulation of a phagocytic process, showing it tunes RPE photoreceptor outer-segment clearance diurnally.","evidence":"In vitro Rac1 GTP-loading assays in differentiated RPE cells plus in situ phosphorylation analysis and knockout retina phenotyping","pmids":["28624895"],"confidence":"High","gaps":["GEF/GAP intermediaries controlling Rac1 loading not identified","Mechanism of diurnal Sema4D/receptor phosphorylation regulation unclear"]},{"year":2018,"claim":"Refined the synaptic model by showing PLXNB1 is required in both pre- and postsynaptic compartments and serves as a shared receptor for Sema4D and Sema4A.","evidence":"Compartment-specific loss-of-function and immunocytochemistry in cultured hippocampal neurons","pmids":["29981480"],"confidence":"Medium","gaps":["Methods partially inferred from abstract","Distinct downstream signaling for Sema4A vs Sema4D not resolved"]},{"year":2019,"claim":"Mapped a cancer signaling cascade downstream of PLXNB1, connecting Sema4D engagement to EMT and metastasis via Vav1-Rac1/RhoA-PAK-Snail.","evidence":"Xenograft mouse model, migration/invasion assays, siRNA knockdown, and anti-CD100 antibody treatment in head and neck squamous carcinoma","pmids":["30981760"],"confidence":"Medium","gaps":["Single-lab pathway dissection","Relative contributions of Rac1 vs RhoA to Snail stabilization not quantified"]},{"year":2022,"claim":"Established the structural rule that dimer orientation, not just dimerization, dictates PLXNB1 signaling competence, using engineered agonist/antagonist dimerizers.","evidence":"Structural analysis of peptide-PlxnB1 complexes and cell-based signaling assays with Fc-based receptor dimerizers","pmids":["35981535"],"confidence":"High","gaps":["Structural basis for how orientation alters intracellular GAP activity not shown","In vivo applicability of engineered dimerizers untested"]},{"year":2022,"claim":"Implicated PLXNB1 in human developmental and innate-immune phenotypes, tying a patient variant to GnRH neuron migration and Rnd1-PLXNB1 signaling to antibacterial cytokine production.","evidence":"Boyden chamber migration and membrane-expression assays for the p.R1031H IHH variant in GnRH cell lines; infection and cytokine assays with Rnd1 and Plxnb1","pmids":["35170806","35654795"],"confidence":"Medium","gaps":["Single variant/single-lab functional support for IHH link","How Rnd1 engages PLXNB1 to drive IL-6/TNF-α mechanistically unclear"]},{"year":2023,"claim":"Demonstrated that point mutation can invert PLXNB1's function in cancer and confirmed causal roles in neurodevelopment via patient cells.","evidence":"Transgenic prostate cancer mouse models with Rho/ROCK and PDZRhoGEF deletion; patient iPSC-derived cortical neurons with rescue and PlxnB1 knockout-mouse neuron validation","pmids":["36936664","37032361"],"confidence":"High","gaps":["How P1597L structurally rewires Rho/ROCK output not resolved","Generalizability of the metastasis-suppressor-to-promoter switch beyond prostate models unknown"]},{"year":2024,"claim":"Extended PLXNB1 function to disease-relevant glial and immune cell organization—governing peri-plaque glial distancing in Alzheimer's disease and shaping the tumor immune microenvironment.","evidence":"Cell-type-specific conditional knockout in an AD mouse model with histology/transcriptomics; PLXNB1-deficient and pharmacologically blocked breast carcinoma models with immune phenotyping and anti-PD-1 combination; scRNA-seq with Sema4D KO in aortic aneurysm","pmids":["38802590","38874583","38821358"],"confidence":"High","gaps":["Cell-autonomous signaling effectors in astrocytes/macrophages not defined","Whether canonical Rho/Rac signaling underlies these cell-distancing and immune effects untested"]},{"year":2026,"claim":"Defined upstream regulatory inputs to PLXNB1 expression—epigenetic activation by ALDH1A3 and an opposing role in epithelial inflammation—broadening its regulatory and pathophysiological context.","evidence":"ChIP for H3K9/K14 acetylation at the PLXNB1 promoter with metastasis assays in PDAC; knockdown/overexpression with MAPK/p38 cytokine readouts in nasal epithelial cells; luciferase-validated miR-362-5p targeting in chondrogenic MSCs","pmids":["42221815","42224190","36523183"],"confidence":"Medium","gaps":["Single-lab/single-model support for each regulatory axis","How PLXNB1 negatively regulates MAPK/p38 inflammation mechanistically unresolved"]},{"year":null,"claim":"How the extracellular dimerization/orientation switch is mechanically transmitted to the intracellular GAP domain to selectively activate RhoA versus Rac1 in different cell types remains the central open question.","evidence":"","pmids":[],"confidence":"High","gaps":["No full-length structure linking ectodomain orientation to intracellular GAP state","Determinants of cell-type-specific RhoA vs Rac1 output unknown","Identity of GEFs/GAPs coupling PLXNB1 to GTPases across tissues incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,4,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,7,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,11,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,13]}],"complexes":[],"partners":["SEMA4D","SEMA4A","RHOA","RAC1","RND1","ARHGEF11"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43157","full_name":"Plexin-B1","aliases":["Semaphorin receptor SEP"],"length_aa":2135,"mass_kda":232.3,"function":"Receptor for SEMA4D (PubMed:19843518, PubMed:20877282, PubMed:21912513). Plays a role in GABAergic synapse development (By similarity). Mediates SEMA4A- and SEMA4D-dependent inhibitory synapse development (By similarity). Plays a role in RHOA activation and subsequent changes of the actin cytoskeleton (PubMed:12196628, PubMed:15210733). Plays a role in axon guidance, invasive growth and cell migration (PubMed:12198496)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/O43157/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLXNB1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PLXNB1","total_profiled":1310},"omim":[{"mim_id":"605885","title":"SEMAPHORIN 6A; SEMA6A","url":"https://www.omim.org/entry/605885"},{"mim_id":"604293","title":"PLEXIN B2; PLXNB2","url":"https://www.omim.org/entry/604293"},{"mim_id":"601866","title":"SEMAPHORIN 4D; SEMA4D","url":"https://www.omim.org/entry/601866"},{"mim_id":"601054","title":"PLEXIN A2; PLXNA2","url":"https://www.omim.org/entry/601054"},{"mim_id":"601053","title":"PLEXIN B1; PLXNB1","url":"https://www.omim.org/entry/601053"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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Monomeric semaphorin binds PLXNB1 but fails to trigger signaling, demonstrating that signaling requires avidity of the bivalent complex. The interaction is mediated through conserved contacts of the N-terminal seven-bladed β-propeller (sema) domains of both semaphorin and plexin, suggesting semaphorin-stabilized plexin dimerization as the activation mechanism.\",\n \"method\": \"X-ray crystallography, biophysical assays, cellular signaling assays with wild-type and mutant proteins\",\n \"journal\": \"Nature\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation by mutagenesis and cellular assays in a single rigorous study\",\n \"pmids\": [\"20877282\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2011,\n \"finding\": \"Binding of Sema4D (secreted by osteoclasts) to its receptor Plexin-B1 on osteoblasts activates the small GTPase RhoA, which suppresses bone formation by inhibiting IGF-1 signaling and modulating osteoblast motility. Plxnb1-/- mice display an osteosclerotic phenotype due to augmented bone formation, placing PLXNB1 in the Sema4D-RhoA-IGF-1 signaling axis in bone homeostasis.\",\n \"method\": \"Genetic knockout mouse models (Plxnb1-/-, Sema4d-/-, dominant-negative RhoA transgenic in osteoblasts), bone phenotype analysis, IGF-1 signaling assays\",\n \"journal\": \"Nature medicine\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models with defined phenotypic readouts, replicated across multiple knockout lines\",\n \"pmids\": [\"22019888\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2013,\n \"finding\": \"Sema4D promotes rapid GABAergic synapse formation in rodent hippocampus via its receptor PlexinB1; this effect is dependent on PlexinB1 as it is abolished in PlxnB1-/- mice. Sema4D-PlexinB1 signaling initiates synapse formation by recruiting synaptic proteins to both presynaptic and postsynaptic terminals within 10-30 minutes.\",\n \"method\": \"Loss-of-function genetic screen, immunocytochemistry, live imaging in cultured hippocampal neurons and PlxnB1-/- mice, organotypic slice electrophysiology\",\n \"journal\": \"The Journal of neuroscience\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — knockout validation combined with live imaging and electrophysiology, multiple orthogonal methods\",\n \"pmids\": [\"23699507\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2016,\n \"finding\": \"A high-affinity macrocyclic peptide PB1m6 (KD = 3.5 nM) binds PLXNB1 at a groove between the fifth and sixth blades of the sema domain, distant from the Sema4D-binding site. This allosteric binding competitively inhibits Sema4D binding in vitro and completely suppresses Sema4D-induced cell collapse, identifying a novel allosteric site on PLXNB1.\",\n \"method\": \"In vitro binding assay, cell collapse assay, X-ray crystallography of PB1m6-PlxnB1 complex\",\n \"journal\": \"Cell chemical biology\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus functional in vitro and cellular assays, single lab but multiple orthogonal methods\",\n \"pmids\": [\"27984026\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2017,\n \"finding\": \"Sema4D binding to PlexinB1 on retinal pigment epithelium (RPE) cells attenuates photoreceptor outer segment (POS) phagocytosis by decreasing GTP-loading of Rac1. PlexinB1 phosphorylation and Sema4D levels are reduced at the peak of diurnal phagocytosis after light onset in vivo; plxnb1-/- or sema4d-/- mice show increased POS phagosome content after light onset.\",\n \"method\": \"In vitro Rac1 GTP-loading assay in differentiated RPE cells, in situ analysis in wild-type and mutant rat/mouse retina, genetic knockout models\",\n \"journal\": \"Molecular neurobiology\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (in vitro Rac1 assay, in vivo knockout phenotype, in situ phosphorylation analysis) in a single study\",\n \"pmids\": [\"28624895\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2018,\n \"finding\": \"Plexin-B1 requires its presence in both the presynaptic axon of inhibitory interneurons and the postsynaptic dendrites of excitatory neurons for Sema4D-dependent inhibitory synapse development in rodent hippocampus. Sema4A also signals through postsynaptic PlexinB1 to promote inhibitory synapse development, using the same pathway as Sema4D.\",\n \"method\": \"Compartment-specific loss-of-function experiments in cultured hippocampal neurons, immunocytochemistry, genetic approaches\",\n \"journal\": \"Molecular and cellular neurosciences\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Weak — compartment-specific functional dissection but single lab, methods partially inferred from abstract\",\n \"pmids\": [\"29981480\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2019,\n \"finding\": \"Soluble CD100 (Sema4D) induces epithelial-mesenchymal transition (EMT) in head and neck squamous cell carcinoma through its receptor Plexin-B1, and promotes metastasis in a xenograft mouse model. The signaling mechanism involves the Vav1-Rac1/RhoA-p21-activated kinase pathway leading to Snail stabilization.\",\n \"method\": \"Xenograft mouse model, cell migration/invasion assays, western blot, siRNA knockdown, anti-CD100 antibody treatment\",\n \"journal\": \"Cancer letters\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — xenograft model combined with mechanistic pathway dissection (Vav1-Rac1/RhoA-PAK-Snail), single lab\",\n \"pmids\": [\"30981760\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2022,\n \"finding\": \"A PLXNB1 variant (p.R1031H) identified in normosmic IHH patients shows reduced membrane expression and impaired cell migration in GnRH neuronal cell lines compared to wild-type PlexinB1, implicating PLXNB1 in GnRH cell migration during development.\",\n \"method\": \"Boyden chamber migration assay, flow cytometry/western blot for membrane expression, bioinformatic modeling\",\n \"journal\": \"Journal of neuroendocrinology\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Weak — functional assays in GnRH cell line with a clinically identified variant, single lab, two methods\",\n \"pmids\": [\"35170806\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2022,\n \"finding\": \"Rnd1 (a constitutively active Rho GTPase) facilitates pro-inflammatory cytokine (IL-6 and TNF-α) production during bacterial infection through PlexinB1, providing a Rnd1-PLXNB1-mediated innate immune defense mechanism against intracellular bacterial infections.\",\n \"method\": \"In vitro infection assays, cytokine measurements, functional assays with Rnd1 and Plxnb1\",\n \"journal\": \"Cell death & disease\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Weak — functional mechanistic link between Rnd1, Plxnb1, and cytokine production established, single lab\",\n \"pmids\": [\"35654795\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2022,\n \"finding\": \"De novo Fc-based receptor dimerizers grafted with different PLXNB1-binding peptides can act as either agonists or antagonists of PlexinB1. Structural analysis revealed that the agonistic Fc dimerizes PlxnB1 in a face-to-face fashion similar to that induced by Sema4D, whereas the antagonistic Fc induces a signaling-incompetent dimer conformation, demonstrating that plexin activation is controlled by receptor orientation within the dimer.\",\n \"method\": \"Structural analysis of peptide-PlxnB1 complexes, cell-based signaling assays with Fc dimerizers\",\n \"journal\": \"Structure\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures of agonist and antagonist complexes combined with functional cellular assays revealing mechanistic basis of dimer orientation in signaling\",\n \"pmids\": [\"35981535\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2023,\n \"finding\": \"A rare homozygous loss-of-function PLXNB1 variant (p.Ser454Arg) causes neurite outgrowth deficits in patient iPSC-derived cortical neurons. Expression of wild-type PLXNB1, but not the variant, rescued neurite outgrowth in patient neurons; expression of the variant caused neurite outgrowth deficits in cortical neurons from PlxnB1 knockout mice, establishing PLXNB1 as a regulator of neurite outgrowth.\",\n \"method\": \"iPSC-derived cortical neurons from patient and controls, rescue experiments with wild-type vs. variant PLXNB1, PlxnB1 knockout mouse neurons, transcriptomic profiling of organoids\",\n \"journal\": \"Molecular psychiatry\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function patient variant with rescue experiment in patient neurons and validation in knockout mouse neurons; multiple orthogonal approaches in single study\",\n \"pmids\": [\"37032361\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2023,\n \"finding\": \"Prostate epithelial cell-specific expression of a clinically identified mutant Plexin-B1 (P1597L) significantly increases metastasis in two transgenic prostate cancer mouse models, whereas wild-type Plexin-B1 expression suppresses metastasis, demonstrating that P1597L converts PLXNB1 from a metastasis suppressor to a metastasis promoter. Deletion of RhoA/C or PDZRhoGEF suppressed metastasis in this context, implicating the Rho/ROCK pathway in the phenotypic switch.\",\n \"method\": \"Transgenic mouse models (PbCre), germline and conditional deletion, RhoA/C and PDZRhoGEF deletion, metastasis quantification, invasion assays\",\n \"journal\": \"Cancer research communications\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — multiple transgenic and knockout mouse models with clear metastasis quantification and pathway identification (Rho/ROCK)\",\n \"pmids\": [\"36936664\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2024,\n \"finding\": \"Plexin-B1 is upregulated in plaque-associated astrocytes in Alzheimer's disease and governs cell distancing in peri-plaque glial nets. Plexin-B1 deletion in a mouse AD model reduced the number of reactive astrocytes and microglia in peri-plaque nets but increased glial process coverage of plaques, reduced overall plaque burden, shifted plaques toward dense-core type, and reduced neuritic dystrophy and neuroinflammatory transcriptional signatures.\",\n \"method\": \"Conditional knockout in AD mouse model, histology, transcriptomics, plaque morphology analysis\",\n \"journal\": \"Nature neuroscience\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific knockout with multiple quantitative phenotypic readouts and transcriptional analysis in a rigorous AD mouse model study\",\n \"pmids\": [\"38802590\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2024,\n \"finding\": \"PlexinB1 inactivation in the tumor microenvironment (TME) of triple-negative murine breast carcinoma reduces primary tumor growth and metastatic dissemination, associated with a switch of tumor-associated macrophages toward a pro-inflammatory M1 phenotype, enhanced CD8+ T lymphocyte infiltration, and upregulation of anti-tumor genes (Icos, Perforin-1, Stat3, Ccl5) in TILs. Pharmacological PLXNB1 blockade phenocopied genetic deletion and enhanced anti-PD-1 immunotherapy efficacy.\",\n \"method\": \"PLXNB1-deficient mouse model, flow cytometry, gene expression profiling of TILs, pharmacological inhibition, anti-PD-1 combination treatment\",\n \"journal\": \"Cancer immunology research\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological targeting with multiple immune phenotyping methods; functional consequences in vivo established\",\n \"pmids\": [\"38874583\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2024,\n \"finding\": \"Sema4D secreted by osteoclast-like cells induces sympathetic nerve diffusion and hyperinnervation through binding to Plxnb1, contributing to abdominal aortic aneurysm development. This was identified by single-cell RNA sequencing and validated in Sema4D-deficient mice showing reduced AAA progression.\",\n \"method\": \"Single-cell RNA sequencing, Sema4D knockout mouse model, immunostaining\",\n \"journal\": \"Journal of advanced research\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Weak — scRNA-seq identification with in vivo genetic validation (Sema4D KO), single lab\",\n \"pmids\": [\"38821358\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2025,\n \"finding\": \"Genetic ablation of PLXNB1 in murine and human iPSC-derived astrocytes decreased the Ast10 (SLC38A2-high) pathologic astrocyte state signature in Alzheimer's disease, confirming PLXNB1 as a regulator of this disease-associated astrocyte state that contributes to cognitive decline through synaptic loss.\",\n \"method\": \"Genetic ablation in murine astrocytes and human iPSC-derived astrocytes, single-nucleus RNA-seq meta-analysis, spatial transcriptomics validation\",\n \"journal\": \"bioRxiv\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — genetic ablation in two model systems with transcriptomic validation; preprint, not yet peer-reviewed\",\n \"pmids\": [\"40060644\"],\n \"is_preprint\": true\n },\n {\n \"year\": 2016,\n \"finding\": \"CRISPR-mediated knockout of Plxnb1 in p53-null/Myc-overexpressing mouse hepatocytes increased liver tumor formation and was associated with increased MAPK phosphorylation, identifying PLXNB1 as a suppressor of liver tumor formation that acts upstream of the MAPK pathway.\",\n \"method\": \"Genome-wide CRISPR/Cas9 knockout screen, subcutaneous and orthotopic transplantation in mice, immunohistochemistry for MAPK phosphorylation\",\n \"journal\": \"Gastroenterology\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Weak — genome-wide screen with validation of Plxnb1-specific MAPK phosphorylation; single lab, limited mechanistic follow-up for PLXNB1 specifically\",\n \"pmids\": [\"27956228\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2016,\n \"finding\": \"PLXNB1 expression is regulated by the TMPRSS2-ERG fusion gene in prostate cancer cells, and PLXNB1 (but not MMP-9) contributes to TMPRSS2-ERG-mediated enhancement of cancer cell migration and invasion in VCaP cells, placing PLXNB1 downstream of ERG as a mediator of invasion.\",\n \"method\": \"siRNA knockdown of ERG, MMP-9, and PLXNB1; MTT and Transwell invasion assays; qRT-PCR and western blot\",\n \"journal\": \"Oncology reports\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Weak — siRNA epistasis with invasion assays establishes pathway position; single lab, single cell line model\",\n \"pmids\": [\"28004109\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2022,\n \"finding\": \"miR-362-5p directly targets PLXNB1 mRNA (confirmed by luciferase reporter assay), suppressing PLXNB1 expression and thereby inhibiting chondrogenic differentiation of bone marrow mesenchymal stem cells; PLXNB1 overexpression promotes chondrogenic differentiation and alleviates joint injury in an in vivo OA rat model.\",\n \"method\": \"Luciferase reporter assay, RT-qPCR, western blot, chondrogenic differentiation assays, micro-CT in OA rat model\",\n \"journal\": \"Journal of orthopaedic surgery (Hong Kong)\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Weak — direct miRNA-target relationship confirmed by luciferase assay with in vivo phenotypic validation; single lab\",\n \"pmids\": [\"36523183\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2026,\n \"finding\": \"ALDH1A3 promotes acetyl-CoA production and enhances H3K9/K14 histone acetylation at the PLXNB1 promoter, activating PLXNB1 transcription in pancreatic ductal adenocarcinoma. This sensitizes PDAC cells to SEMA4D from lung epithelial cells, driving SEMA4D-PLXNB1 signaling-mediated lung metastatic colonization.\",\n \"method\": \"RNA sequencing, ChIP for histone acetylation at PLXNB1 promoter, in vitro and in vivo metastasis assays\",\n \"journal\": \"iScience\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Weak — ChIP establishes epigenetic mechanism at PLXNB1 promoter with functional in vivo metastasis readout; single lab\",\n \"pmids\": [\"42221815\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2026,\n \"finding\": \"PLXNB1 knockdown in human nasal epithelial cells increases expression of inflammatory cytokines (IL-4, IL-6), likely via activation of the MAPK/p38 signaling pathway, while PLXNB1 overexpression suppresses inflammation, indicating PLXNB1 negatively regulates MAPK/p38-driven inflammation in epithelial cells.\",\n \"method\": \"In vitro PLXNB1 knockdown and overexpression in nasal epithelial cells, cytokine assays, in vivo AR mouse model\",\n \"journal\": \"PloS one\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Weak — functional gain/loss of function with pathway identification (MAPK/p38), single lab\",\n \"pmids\": [\"42224190\"],\n \"is_preprint\": false\n }\n ],\n \"current_model\": \"PLXNB1 encodes a transmembrane semaphorin receptor (primarily for Sema4D) that signals through RhoA/ROCK and Rac1 GTPase pathways to regulate diverse cellular processes including cytoskeletal remodeling, cell migration, neurite outgrowth, synapse formation, bone homeostasis, and immune cell behavior; structurally, signaling requires semaphorin-induced dimerization of PLXNB1 in a specific face-to-face orientation, and allosteric sites on its sema domain can modulate this activation.\"\n}\n```","stage2_raw":"{\n \"mechanistic_narrative\": \"PLXNB1 encodes a transmembrane semaphorin receptor that transduces extracellular cues into cytoskeletal and transcriptional responses governing cell migration, neural connectivity, bone homeostasis, and tumor/immune behavior [#0, #1]. Activation requires that the semaphorin ligand Sema4D (and also Sema4A) bridge two receptor molecules into a 2:2 bivalent complex through conserved contacts of the N-terminal seven-bladed sema (\\u03b2-propeller) domains; monomeric ligand binds but cannot signal, establishing ligand-stabilized receptor dimerization as the activation switch [#0, #5]. Signaling output is dictated by dimer geometry: a face-to-face orientation matching that induced by Sema4D is agonistic, whereas an alternative orientation yields a signaling-incompetent dimer, and an allosteric groove between the fifth and sixth blades of the sema domain, distinct from the ligand site, can be exploited to block activation [#3, #9]. Downstream, PLXNB1 couples to Rho-family GTPase signaling\\u2014activating RhoA (via PDZRhoGEF and the RhoA/ROCK axis) and modulating Rac1 GTP-loading\\u2014to control diverse outputs including suppression of osteoblast bone formation through inhibition of IGF-1 signaling [#1], attenuation of photoreceptor outer-segment phagocytosis in retinal pigment epithelium [#4], and EMT and invasion in cancer via a Vav1-Rac1/RhoA-PAK-Snail cascade [#6, #11]. In the nervous system, PLXNB1 is required both pre- and postsynaptically for Sema4D/Sema4A-dependent GABAergic synapse formation and for cortical neurite outgrowth [#2, #5, #10]. Rare loss-of-function PLXNB1 variants cause neurite outgrowth deficits in patient iPSC-derived neurons (p.Ser454Arg) and impair GnRH neuronal migration (p.R1031H, in normosmic idiopathic hypogonadotropic hypogonadism) [#7, #10]. PLXNB1 also shapes Alzheimer's disease pathology by governing peri-plaque glial distancing and a pathologic astrocyte state [#12], and modulates the tumor immune microenvironment, where its blockade reprograms macrophages toward M1, boosts CD8+ T-cell infiltration, and enhances anti-PD-1 efficacy [#13].\",\n \"teleology\": [\n {\n \"year\": 2010,\n \"claim\": \"Resolved how a semaphorin engages PLXNB1 to switch it on, establishing that ligand-stabilized receptor dimerization\\u2014not mere binding\\u2014is the activation mechanism.\",\n \"evidence\": \"X-ray crystallography of the PLXNB1 sema domain\\u2013SEMA4D ectodomain complex with mutagenesis and cellular signaling assays\",\n \"pmids\": [\"20877282\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Does not resolve how dimerization is propagated across the membrane to the intracellular GAP domain\", \"No structure of the full-length receptor or intracellular signaling complex\"]\n },\n {\n \"year\": 2011,\n \"claim\": \"Defined a physiological role for PLXNB1 in skeletal homeostasis, placing it in a Sema4D-RhoA-IGF-1 axis that restrains bone formation.\",\n \"evidence\": \"Plxnb1-/-, Sema4d-/-, and osteoblast dominant-negative RhoA mouse models with bone phenotyping and IGF-1 signaling assays\",\n \"pmids\": [\"22019888\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Effector linking RhoA to IGF-1 pathway suppression not fully resolved\", \"Cell-autonomous vs systemic contributions not dissected\"]\n },\n {\n \"year\": 2013,\n \"claim\": \"Showed PLXNB1 is the receptor mediating rapid Sema4D-induced GABAergic synapse formation, extending plexin function to synaptic assembly.\",\n \"evidence\": \"Loss-of-function in PlxnB1-/- mice, immunocytochemistry, live imaging, and slice electrophysiology in hippocampal neurons\",\n \"pmids\": [\"23699507\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Intracellular effectors recruiting synaptic proteins not identified\", \"Whether RhoA or Rac mediate this synaptic effect unclear\"]\n },\n {\n \"year\": 2016,\n \"claim\": \"Identified PLXNB1 as a context-dependent tumor suppressor acting upstream of MAPK in liver and downstream of ERG in prostate, framing dual roles in cancer.\",\n \"evidence\": \"Genome-wide CRISPR knockout screen with transplantation and MAPK phosphorylation readout in hepatocytes; siRNA epistasis with invasion assays in prostate VCaP cells\",\n \"pmids\": [\"27956228\", \"28004109\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Mechanism linking PLXNB1 loss to MAPK activation not defined\", \"Single cell-line/model contexts limit generality\"]\n },\n {\n \"year\": 2016,\n \"claim\": \"Discovered a druggable allosteric site on PLXNB1 distinct from the ligand site, providing a pharmacological route to block activation.\",\n \"evidence\": \"High-affinity macrocyclic peptide PB1m6 binding assay, cell collapse assay, and X-ray crystallography of the PB1m6-PlxnB1 complex\",\n \"pmids\": [\"27984026\"],\n \"confidence\": \"High\",\n \"gaps\": [\"In vivo efficacy of allosteric inhibition not tested in this study\", \"How allosteric occupancy translates structurally to blocked dimerization unresolved\"]\n },\n {\n \"year\": 2017,\n \"claim\": \"Linked PLXNB1 to Rac1-dependent regulation of a phagocytic process, showing it tunes RPE photoreceptor outer-segment clearance diurnally.\",\n \"evidence\": \"In vitro Rac1 GTP-loading assays in differentiated RPE cells plus in situ phosphorylation analysis and knockout retina phenotyping\",\n \"pmids\": [\"28624895\"],\n \"confidence\": \"High\",\n \"gaps\": [\"GEF/GAP intermediaries controlling Rac1 loading not identified\", \"Mechanism of diurnal Sema4D/receptor phosphorylation regulation unclear\"]\n },\n {\n \"year\": 2018,\n \"claim\": \"Refined the synaptic model by showing PLXNB1 is required in both pre- and postsynaptic compartments and serves as a shared receptor for Sema4D and Sema4A.\",\n \"evidence\": \"Compartment-specific loss-of-function and immunocytochemistry in cultured hippocampal neurons\",\n \"pmids\": [\"29981480\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Methods partially inferred from abstract\", \"Distinct downstream signaling for Sema4A vs Sema4D not resolved\"]\n },\n {\n \"year\": 2019,\n \"claim\": \"Mapped a cancer signaling cascade downstream of PLXNB1, connecting Sema4D engagement to EMT and metastasis via Vav1-Rac1/RhoA-PAK-Snail.\",\n \"evidence\": \"Xenograft mouse model, migration/invasion assays, siRNA knockdown, and anti-CD100 antibody treatment in head and neck squamous carcinoma\",\n \"pmids\": [\"30981760\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Single-lab pathway dissection\", \"Relative contributions of Rac1 vs RhoA to Snail stabilization not quantified\"]\n },\n {\n \"year\": 2022,\n \"claim\": \"Established the structural rule that dimer orientation, not just dimerization, dictates PLXNB1 signaling competence, using engineered agonist/antagonist dimerizers.\",\n \"evidence\": \"Structural analysis of peptide-PlxnB1 complexes and cell-based signaling assays with Fc-based receptor dimerizers\",\n \"pmids\": [\"35981535\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Structural basis for how orientation alters intracellular GAP activity not shown\", \"In vivo applicability of engineered dimerizers untested\"]\n },\n {\n \"year\": 2022,\n \"claim\": \"Implicated PLXNB1 in human developmental and innate-immune phenotypes, tying a patient variant to GnRH neuron migration and Rnd1-PLXNB1 signaling to antibacterial cytokine production.\",\n \"evidence\": \"Boyden chamber migration and membrane-expression assays for the p.R1031H IHH variant in GnRH cell lines; infection and cytokine assays with Rnd1 and Plxnb1\",\n \"pmids\": [\"35170806\", \"35654795\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Single variant/single-lab functional support for IHH link\", \"How Rnd1 engages PLXNB1 to drive IL-6/TNF-\\u03b1 mechanistically unclear\"]\n },\n {\n \"year\": 2023,\n \"claim\": \"Demonstrated that point mutation can invert PLXNB1's function in cancer and confirmed causal roles in neurodevelopment via patient cells.\",\n \"evidence\": \"Transgenic prostate cancer mouse models with Rho/ROCK and PDZRhoGEF deletion; patient iPSC-derived cortical neurons with rescue and PlxnB1 knockout-mouse neuron validation\",\n \"pmids\": [\"36936664\", \"37032361\"],\n \"confidence\": \"High\",\n \"gaps\": [\"How P1597L structurally rewires Rho/ROCK output not resolved\", \"Generalizability of the metastasis-suppressor-to-promoter switch beyond prostate models unknown\"]\n },\n {\n \"year\": 2024,\n \"claim\": \"Extended PLXNB1 function to disease-relevant glial and immune cell organization\\u2014governing peri-plaque glial distancing in Alzheimer's disease and shaping the tumor immune microenvironment.\",\n \"evidence\": \"Cell-type-specific conditional knockout in an AD mouse model with histology/transcriptomics; PLXNB1-deficient and pharmacologically blocked breast carcinoma models with immune phenotyping and anti-PD-1 combination; scRNA-seq with Sema4D KO in aortic aneurysm\",\n \"pmids\": [\"38802590\", \"38874583\", \"38821358\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Cell-autonomous signaling effectors in astrocytes/macrophages not defined\", \"Whether canonical Rho/Rac signaling underlies these cell-distancing and immune effects untested\"]\n },\n {\n \"year\": 2026,\n \"claim\": \"Defined upstream regulatory inputs to PLXNB1 expression\\u2014epigenetic activation by ALDH1A3 and an opposing role in epithelial inflammation\\u2014broadening its regulatory and pathophysiological context.\",\n \"evidence\": \"ChIP for H3K9/K14 acetylation at the PLXNB1 promoter with metastasis assays in PDAC; knockdown/overexpression with MAPK/p38 cytokine readouts in nasal epithelial cells; luciferase-validated miR-362-5p targeting in chondrogenic MSCs\",\n \"pmids\": [\"42221815\", \"42224190\", \"36523183\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Single-lab/single-model support for each regulatory axis\", \"How PLXNB1 negatively regulates MAPK/p38 inflammation mechanistically unresolved\"]\n },\n {\n \"year\": null,\n \"claim\": \"How the extracellular dimerization/orientation switch is mechanically transmitted to the intracellular GAP domain to selectively activate RhoA versus Rac1 in different cell types remains the central open question.\",\n \"evidence\": \"\",\n \"pmids\": [],\n \"confidence\": \"High\",\n \"gaps\": [\"No full-length structure linking ectodomain orientation to intracellular GAP state\", \"Determinants of cell-type-specific RhoA vs Rac1 output unknown\", \"Identity of GEFs/GAPs coupling PLXNB1 to GTPases across tissues incomplete\"]\n }\n ],\n \"mechanism_profile\": {\n \"molecular_activity\": [\n {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0, 2, 5]},\n {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 4]},\n {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 4, 11]}\n ],\n \"localization\": [\n {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 7]}\n ],\n \"pathway\": [\n {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 6]},\n {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 7, 10]},\n {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 11, 12]},\n {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 13]}\n ],\n \"complexes\": [],\n \"partners\": [\"SEMA4D\", \"SEMA4A\", \"RHOA\", \"RAC1\", \"RND1\", \"ARHGEF11\"]\n }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}