Affinage

PLXNB3

Plexin-B3 · UniProt Q9ULL4

Length
1909 aa
Mass
206.8 kDa
Annotated
2026-06-10
25 papers in source corpus 7 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PLXNB3 is a transmembrane semaphorin receptor that drives tumor cell migration, invasion, and growth across multiple cancer types (PMID:36857181, PMID:37768037, PMID:35981243). It functions as a cell-surface receptor for Sema5A, as defined by the R538H extracellular-domain mutation that abolishes ligand binding (PMID:19462467). In breast cancer, PLXNB3 is a direct HIF-1 transcriptional target induced under hypoxia, and it is required for hypoxia-driven MET/SRC/FAK signaling (promoting migration and invasion) and MET/SRC/STAT3/NANOG signaling (promoting cancer stem cell specification), as well as for tumor formation and lung metastasis in vivo (PMID:36857181, PMID:37768037). PLXNB3 is enriched as a cell-surface glycoprotein in triple-negative breast cancer, where its depletion impairs growth, invasion, and migration (PMID:35981243). In pancreatic adenocarcinoma, tumor-associated macrophage-derived SEMA5A engages tumor-cell PLXNB3 to enhance aerobic glycolysis and tumor outgrowth (PMID:36741230). A pathogenic missense variant (p.E1440V) links PLXNB3 to congenital heart disease with neurodevelopmental disability through effects on cell migration and proliferation (PMID:36506778). Beyond these receptor and signaling roles, the biochemical mechanism by which PLXNB3 couples to MET remains uncharacterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2009 Medium

    Establishing what ligand PLXNB3 recognizes, this work showed it acts as a receptor for Sema5A by identifying an extracellular missense mutation that blocks ligand binding.

    Evidence Functional ligand-receptor binding assay in cellular models using a cancer-associated R538H mutation

    PMID:19462467

    Open questions at the time
    • Single lab, single binding method reported in abstract
    • Downstream signaling consequences of Sema5A binding not addressed here
    • Sema4D as an alternative ligand not tested
  2. 2015 Low

    An early attempt to place PLXNB3 in a signaling axis proposed a KIAA1199/PLXNB3/SEMA5A/CTGF pathway promoting proliferation and angiogenesis in synoviocytes.

    Evidence KIAA1199 knockdown/overexpression with MTT proliferation and tube-formation assays, western blot, qPCR

    PMID:26022278

    Open questions at the time
    • Pathway placement is proposed from expression/knockdown correlation, not direct mechanism
    • PLXNB3-specific molecular detail is limited
    • Direct PLXNB3-CTGF link not demonstrated
  3. 2022 High

    To define PLXNB3's role in aggressive breast cancer, glycoproteomics and genetic depletion established it as a cell-surface glycoprotein enriched in TNBC and functionally required for tumor cell growth and invasion.

    Evidence N-glycoproteomics, siRNA and CRISPR-Cas9 depletion, in vitro invasion/migration assays and in vivo models

    PMID:35981243

    Open questions at the time
    • Receptor ligand and downstream effectors not resolved in this study
    • Single lab
    • Mechanism of growth/invasion control not detailed
  4. 2022 Medium

    Extending PLXNB3 beyond cancer, a pathogenic p.E1440V variant was linked to congenital heart disease with neurodevelopmental disability through impaired migration and proliferation.

    Evidence Scratch wound and Ki-67 assays in AC16/HEK293T cells, RT-qPCR of pathway genes, whole-exome sequencing, computational structural modeling

    PMID:36506778

    Open questions at the time
    • Structural impact is computationally modeled, not experimentally resolved
    • Causality in disease rests on exome association plus cell assays
    • Notch/myocardial pathway effects are correlative readouts
  5. 2023 High

    Defining the upstream regulation and downstream signaling of PLXNB3, this work showed it is a direct HIF-1 target required for hypoxia-driven MET/SRC/FAK and MET/SRC/STAT3/NANOG cascades and for metastasis and cancer stem cell specification.

    Evidence siRNA knockdown, HIF-1 reporter target validation, pathway signaling assays, orthotopic breast cancer mouse models

    PMID:36857181 PMID:37768037

    Open questions at the time
    • Biochemical mechanism coupling PLXNB3 to MET activation not defined
    • Role of Sema5A/Sema4D ligand in this hypoxic context not established
    • Direct physical PLXNB3-MET interaction not shown
  6. 2023 Medium

    Identifying a tumor-microenvironment ligand source, this work showed macrophage-derived SEMA5A engages tumor PLXNB3 to drive pancreatic cancer outgrowth via enhanced aerobic glycolysis.

    Evidence Intrasplenic injection and KPC mouse models plus in vitro glycolysis assays of the SEMA5A-PLXNB3 axis

    PMID:36741230

    Open questions at the time
    • Signaling intermediates linking PLXNB3 to glycolytic reprogramming not mapped
    • Single lab
    • Direct SEMA5A-PLXNB3 binding not re-demonstrated in this context

Open questions

Synthesis pass · forward-looking unresolved questions
  • The proximal biochemical mechanism by which PLXNB3 transduces semaphorin binding into MET activation and metabolic reprogramming remains unresolved.
  • No structural model of the PLXNB3-MET interface
  • No identified GAP/effector activity for PLXNB3 intracellular domain in the corpus
  • Mechanism linking receptor activation to glycolysis unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-162582 Signal Transduction 2
Partners
METSEMA5A

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 PLXNB3 expression is induced by hypoxia and is a direct transcriptional target gene of hypoxia-inducible factor 1 (HIF-1) in human breast cancer cells. PLXNB3 protein is required for hypoxia-induced MET/SRC/focal adhesion kinase (FAK) signaling and MET/SRC/STAT3/NANOG signaling cascades, and for hypoxia-induced breast cancer cell migration, invasion, cancer stem cell specification, tumor formation, and lung metastasis in orthotopic mouse models. siRNA knockdown, orthotopic breast cancer mouse models, reporter assays for HIF-1 target gene validation, pathway analysis of MET/SRC/FAK and MET/SRC/STAT3/NANOG signaling Cell reports High 36857181 37768037
2009 The missense mutation R538H in the extracellular domain of PLXNB3 prevents binding of its ligand Sema5A, establishing that PLXNB3 functions as a receptor for Sema5A. Functional binding assay in cellular models using cancer-associated somatic mutations; ligand-receptor binding assay Human mutation Medium 19462467
2023 M2-type tumor-associated macrophage (TAM)-derived SEMA5A binds to tumor cell-expressed PLXNB3 to promote pancreatic adenocarcinoma (PDAC) tumor cell proliferation and outgrowth via enhancement of aerobic glycolysis (Warburg effect). In vivo intrasplenic injection mouse models, KPC mouse models, in vitro mechanistic studies of SEMA5A-PLXNB3 axis and glycolysis Journal of immunology research Medium 36741230
2022 PLXNB3 is a cell surface glycoprotein enriched in triple-negative breast cancer (TNBC) cells, and its knockdown by siRNA or CRISPR-Cas9 editing impairs TNBC cell line growth, invasion, and migration in vitro and in vivo. N-glycoproteomics, siRNA knockdown, CRISPR-Cas9 editing, in vitro invasion/migration assays, in vivo models Journal of proteome research High 35981243
2022 A pathogenic PLXNB3 mutation (p.E1440V) inhibits cell migration and proliferation in AC16 and HEK293T cells and affects activity of key factors in the Notch signaling pathway, myocardial contraction pathway, and neurodevelopmental pathways, linking PLXNB3 to congenital heart disease with neurodevelopmental disabilities. Scratch wound assay, Ki-67 flow cytometry, RT-qPCR of pathway genes, whole-exome sequencing, AlphaFold/PyRosetta structural modeling Translational pediatrics Medium 36506778
2015 A KIAA1199/PLXNB3/SEMA5A/CTGF axis was proposed to enhance cell proliferation and angiogenesis in fibroblast-like synoviocytes; PLXNB3 knockdown and overexpression experiments were used to dissect contributions of this pathway. KIAA1199 knockdown and overexpression, MTT proliferation assay, tube formation assay, western blotting, qPCR Arthritis research & therapy Low 26022278

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Plexin-B family members demonstrate non-redundant expression patterns in the developing mouse nervous system: an anatomical basis for morphogenetic effects of Sema4D during development. The European journal of neuroscience 69 15147296
2005 The expression of plexins during mouse embryogenesis. Gene expression patterns : GEP 65 15661641
2009 Molecular profiling of the "plexinome" in melanoma and pancreatic cancer. Human mutation 39 19462467
2020 Characterization of Class-3 Semaphorin Receptors, Neuropilins and Plexins, as Therapeutic Targets in a Pan-Cancer Study. Cancers 35 32640719
2006 Plexin B3 is genetically associated with verbal performance and white matter volume in human brain. Molecular psychiatry 32 17033634
2015 KIAA1199 as a potential diagnostic biomarker of rheumatoid arthritis related to angiogenesis. Arthritis research & therapy 31 26022278
2020 A Rare TP53 Mutation Predominant in Ashkenazi Jews Confers Risk of Multiple Cancers. Cancer research 26 32675277
2012 Contiguous ABCD1 DXS1357E deletion syndrome: report of an autopsy case. Neuropathology : official journal of the Japanese Society of Neuropathology 23 22994209
2023 Mechanisms of Breast Cancer Stem Cell Specification and Self-Renewal Mediated by Hypoxia-Inducible Factor 1. Stem cells translational medicine 19 37768037
2023 Plasma levels of neurology-related proteins are associated with cognitive performance in an older population with overweight/obesity and metabolic syndrome. GeroScience 15 36964401
2024 Identification of Immune-Related Biomarkers of Schizophrenia in the Central Nervous System Using Bioinformatic Methods and Machine Learning Algorithms. Molecular neurobiology 14 39243324
2023 Plexin-B3 expression stimulates MET signaling, breast cancer stem cell specification, and lung metastasis. Cell reports 13 36857181
2023 Cardiorespiratory fitness and targeted proteomics involved in brain and cardiovascular health in children with overweight/obesity. European journal of sport science 11 36622372
2022 Glycoproteomics Identifies Plexin-B3 as a Targetable Cell Surface Protein Required for the Growth and Invasion of Triple-Negative Breast Cancer Cells. Journal of proteome research 10 35981243
2023 SEMA5A-PLXNB3 Axis Promotes PDAC Liver Metastasis Outgrowth through Enhancing the Warburg Effect. Journal of immunology research 8 36741230
2019 Transcriptome profiling of mouse brain and lung under Dip2a regulation using RNA-sequencing. PloS one 8 31291246
2023 A novel immune-related gene signature for predicting immunotherapy outcomes and survival in clear cell renal cell carcinoma. Scientific reports 7 37919459
2023 Association of muscular strength and targeted proteomics involved in brain health in children with overweight/obesity. Scandinavian journal of medicine & science in sports 6 37190796
2022 An X-linked PLXNB3 mutation identified in patients with congenital heart disease with neurodevelopmental disabilities. Translational pediatrics 6 36506778
2024 Proteogenomic characterization of difficult-to-treat breast cancer with tumor cells enriched through laser microdissection. Breast cancer research : BCR 5 38745208
2021 Promising Therapeutic Targets in Kidney Renal Clear Cell Carcinoma: PLXNA1 and PLXNB3. Cancer biotherapy & radiopharmaceuticals 5 34851747
2023 Brain-wide transcriptome-based metabolic alterations in Parkinson's disease: human inter-region and human-experimental model correlations. Molecular omics 3 36928892
2022 Plasma exosomal IRAK1 can be a potential biomarker for predicting the treatment response to renin-angiotensin system inhibitors in patients with IgA nephropathy. Frontiers in immunology 3 36091017
2026 DNA methylation site loss for plasticity-led novel trait genetic fixation. Proceedings of the National Academy of Sciences of the United States of America 1 41880574
2025 Improved epigenetic age prediction models by combining sex chromosome and autosomal markers. Epigenetics & chromatin 1 40665390

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