Affinage

PLXNA2

Plexin-A2 · UniProt O75051

Length
1894 aa
Mass
211.1 kDa
Annotated
2026-04-28
100 papers in source corpus 5 papers cited in narrative 5 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PLXNA2 encodes plexin A2, a transmembrane semaphorin receptor that mediates repulsive cell signaling during development. In zebrafish, Plxna2 acts with Sema6a through a repulsion-neutralization mechanism to maintain eye vesicle epithelial cohesion; loss of either gene disrupts eye progenitor integration, and simultaneous knockdown rescues tissue integrity (PMID:24917502). In human prostate cancer cells, PLXNA2 is transcriptionally induced by the TMPRSS2:ERG fusion oncoprotein and functionally promotes cell migration and invasion downstream of ERG signaling (PMID:23708657).

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps
  1. 2006 Low

    Genetic association studies linked PLXNA2 polymorphisms to schizophrenia susceptibility and bone metabolism traits, establishing PLXNA2 as a candidate gene with pleiotropic effects but without direct mechanistic insight into protein function.

    Evidence Genome-wide and targeted SNP association studies in human cohorts

    PMID:16402134 PMID:16932874

    Open questions at the time
    • No functional experiments on the PLXNA2 protein were performed
    • Association signals have not been linked to specific molecular mechanisms
    • Not independently replicated with functional validation
  2. 2013 Medium

    Establishing a functional role in cancer biology, PLXNA2 was shown to be a direct transcriptional target of TMPRSS2:ERG that promotes prostate cancer cell migration and invasion, linking semaphorin receptor signaling to oncogenic phenotypes.

    Evidence Ectopic TMPRSS2:ERG expression, microarray, siRNA knockdown of PLXNA2, migration/invasion assays in PC3c cells

    PMID:23708657

    Open questions at the time
    • Downstream signaling pathway from PLXNA2 to migration/invasion not delineated
    • Semaphorin ligand dependence of the pro-migratory function not tested
    • Single cell line; generalizability to other cancer contexts unknown
  3. 2014 Medium

    A repulsion-neutralization mechanism was established whereby Plxna2 and Sema6a counterbalance each other to maintain epithelial cohesion during zebrafish eye morphogenesis, providing the first in vivo epistatic dissection of PLXNA2 function in tissue organization.

    Evidence Morpholino knockdown in zebrafish with time-lapse imaging; double-knockdown epistasis rescue

    PMID:24917502

    Open questions at the time
    • Mechanism by which Plxna2–Sema6a interaction regulates cell adhesion at the molecular level is unresolved
    • Whether mammalian PLXNA2 performs an analogous tissue-cohesion role has not been tested
    • Morpholino-based evidence; genetic mutant confirmation not reported

Open questions

Synthesis pass · forward-looking unresolved questions
  • The intracellular signaling cascades downstream of PLXNA2 activation — including GAP activity regulation, cytoskeletal effectors, and co-receptor partnerships — remain largely uncharacterized by direct experimental evidence in mammalian systems.
  • No structural model of PLXNA2 in complex with semaphorin ligands
  • Intrinsic GAP activity and GTPase substrates not experimentally defined
  • Specific co-receptors (neuropilins) required for PLXNA2 signaling not functionally dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 1
Localization
GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1266738 Developmental Biology 1
Partners
SEMA6A

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 PLXNA2 was identified as a candidate schizophrenia susceptibility gene on chromosome 1q32; it encodes a transmembrane semaphorin receptor involved in axonal guidance during development, and genetic association spanning ~60 kb of the PLXNA2 gene was confirmed across multiple independent cohorts. Genome-wide association study with >25,000 SNPs; high-density SNP mapping; replication in independent case-control and family-based samples Molecular psychiatry Low 16402134
2013 PLXNA2 expression is directly and positively regulated by the TMPRSS2:ERG transcription factor fusion in prostate cancer cells, and PLXNA2 upregulation contributes to TMPRSS2:ERG-mediated enhancement of PC3c cell migration and invasion; PLXNA2 expression is also elevated in metastatic versus localized primary prostate cancer tumors. Ectopic TMPRSS2:ERG expression in PC3c cells; high-throughput microarray; siRNA knockdown of PLXNA2; migration and invasion assays; correlation analysis in PCa cohort Oncogene Medium 23708657
2014 Plxna2 (plexin A2) acts alongside Sema6a to maintain zebrafish eye vesicle cohesion during morphogenesis; Plxna2 is restricted to the ventral eye vesicle while sema6a is expressed throughout, and knockdown of either causes eye progenitors to fail to enter evaginating vesicles or delaminate from the eye epithelium; simultaneous knockdown of both rescues integrity, indicating a repulsion-neutralization mechanism. Morpholino knockdown in zebrafish; time-lapse microscopy; explant experiments; epistasis by double knockdown rescue Development (Cambridge, England) Medium 24917502
2006 Genetic polymorphisms in PLXNA2 (a semaphorin 3A receptor) are associated with vertebral fracture risk and bone mineral density in postmenopausal women, implicating PLXNA2 in neural regulation of bone metabolism via semaphorin 3A signaling. Resequencing of PLXNA2; SNP genotyping in postmenopausal cohort (n=560); association analysis Osteoporosis international Low 16932874
2007 A PLXNA2 intronic SNP (rs2478813) shows allelic association with anxiety, depression, neuroticism, and psychological distress, and the mouse ortholog maps to a significant linkage region for anxiety, suggesting PLXNA2 influences psychiatric traits through its role in nervous system development and adult neurogenesis. Genetic association study in extreme discordant/concordant sibling pairs; Composite International Diagnostic Interview; Bonferroni-corrected association testing Archives of general psychiatry Low 17339520

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nature genetics 2792 10742100
1996 Germline regulatory element of Oct-4 specific for the totipotent cycle of embryonal cells. Development (Cambridge, England) 716 8631266
2000 Expression pattern of Oct-4 in preimplantation embryos of different species. Biology of reproduction 291 11090438
2017 Optical coherence elastography - OCT at work in tissue biomechanics [Invited]. Biomedical optics express 253 28271011
1996 The POU factor Oct-6 and Schwann cell differentiation. Science (New York, N.Y.) 241 8662541
1990 Oct-6: a POU transcription factor expressed in embryonal stem cells and in the developing brain. The EMBO journal 229 1976514
2007 OCT-4, an embryonic stem cell marker, is highly expressed in bladder cancer. International journal of cancer 222 17205510
2016 Improving our understanding, and detection, of glaucomatous damage: An approach based upon optical coherence tomography (OCT). Progress in retinal and eye research 220 28012881
1998 In line with our ancestors: Oct-4 and the mammalian germ. BioEssays : news and reviews in molecular, cellular and developmental biology 191 9819561
2000 Oct-4: control of totipotency and germline determination. Molecular reproduction and development 190 10694754
2007 Pyruvate kinase isozyme type M2 (PKM2) interacts and cooperates with Oct-4 in regulating transcription. The international journal of biochemistry & cell biology 188 18191611
1991 A nexus between Oct-4 and E1A: implications for gene regulation in embryonic stem cells. Cell 175 1830243
2004 Developmental expression of POU5F1 (OCT-3/4) in normal and dysgenetic human gonads. Human reproduction (Oxford, England) 168 15105401
1998 The molecular biology of Oct-4 in the early mouse embryo. Molecular human reproduction 149 9835353
2009 Expression of an exogenous human Oct-4 promoter identifies tumor-initiating cells in osteosarcoma. Cancer research 140 19584295
2011 Optical coherence tomography (OCT): imaging the visual pathway as a model for neurodegeneration. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 136 21274691
1989 The Oct-2 protein binds cooperatively to adjacent octamer sites. Genes & development 134 2612908
2006 Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia. Molecular psychiatry 114 16402134
2002 BRCA1 regulates GADD45 through its interactions with the OCT-1 and CAAT motifs. The Journal of biological chemistry 114 11777930
2001 Oct-2 and Bob-1 deficiency in Hodgkin and Reed Sternberg cells. Cancer research 109 11280769
2017 Cellular Characterization of OCT and Outer Retinal Bands Using Specific Immunohistochemistry Markers and Clinical Implications. Ophthalmology 96 29037595
2013 Oct transcription factors in development and stem cells: insights and mechanisms. Development (Cambridge, England) 96 23821033
2010 Oct-4 controls cell-cycle progression of embryonic stem cells. The Biochemical journal 92 19968627
1997 Linker length and composition influence the flexibility of Oct-1 DNA binding. The EMBO journal 83 9155030
1998 Interaction of Oct-1 and automodification domain of poly(ADP-ribose) synthetase. FEBS letters 81 9537509
1992 The Oct-1 POU domain mediates interactions between Oct-1 and other POU proteins. Molecular and cellular biology 80 1346336
2020 Imaging of Macrophage-Like Cells in Living Human Retina Using Clinical OCT. Investigative ophthalmology & visual science 78 32574351
2003 STAT5 and Oct-1 form a stable complex that modulates cyclin D1 expression. Molecular and cellular biology 76 14645506
1994 Regulation of the Oct-4 gene by nuclear receptors. Nucleic acids research 76 8152920
2022 Detecting glaucoma with only OCT: Implications for the clinic, research, screening, and AI development. Progress in retinal and eye research 75 35216894
2006 The orphan nuclear receptor GCNF recruits DNA methyltransferase for Oct-3/4 silencing. Biochemical and biophysical research communications 70 16631596
2000 Synergy of SF1 and RAR in activation of Oct-3/4 promoter. The Journal of biological chemistry 68 10692469
2014 On improving the use of OCT imaging for detecting glaucomatous damage. The British journal of ophthalmology 66 24934219
2014 Recent advances in OCT imaging of the lamina cribrosa. The British journal of ophthalmology 66 24934221
2013 Identification of novel TMPRSS2:ERG mechanisms in prostate cancer metastasis: involvement of MMP9 and PLXNA2. Oncogene 63 23708657
2020 Optical coherence tomography (OCT) in neuro-ophthalmology. Eye (London, England) 61 33239763
2019 CKIP-1 limits foam cell formation and inhibits atherosclerosis by promoting degradation of Oct-1 by REGγ. Nature communications 56 30683852
2019 Quantitative Assessment of the Retina Using OCT and Associations with Cognitive Function. Ophthalmology 55 31307828
2013 Precise comparison of protein localization among OCT, OAT, and MATE in human kidney. Journal of pharmaceutical sciences 54 23630107
2007 Anxiety and comorbid measures associated with PLXNA2. Archives of general psychiatry 52 17339520
1998 The Oct-1 POU domain activates snRNA gene transcription by contacting a region in the SNAPc largest subunit that bears sequence similarities to the Oct-1 coactivator OBF-1. Genes & development 50 9832505
1996 Identification of putative downstream genes of Oct-3, a pluripotent cell-specific transcription factor. Genes to cells : devoted to molecular & cellular mechanisms 50 9140067
1992 Regulation of expression of the neuronal POU protein Oct-2 by nerve growth factor. The Journal of biological chemistry 49 1381354
2005 Stimulation of Oct-4 activity by Ewing's sarcoma protein. Stem cells (Dayton, Ohio) 47 15917470
2001 Analysis of Oct-4 expression and ploidy in individual human blastomeres. Molecular human reproduction 46 11160841
1996 The Oct-2 transcription factor. The international journal of biochemistry & cell biology 46 8930131
2020 Combination of optical coherence tomography (OCT) and OCT angiography increases diagnostic efficacy of Parkinson's disease. Quantitative imaging in medicine and surgery 45 33014726
2012 STAT3 is involved in esophageal carcinogenesis through regulation of Oct-1. Carcinogenesis 45 23172665
1997 Interdigitated residues within a small region of VP16 interact with Oct-1, HCF, and DNA. Molecular and cellular biology 44 9199328
2011 Expression of oct-4 and c-kit antigens in endometriosis. Fertility and sterility 43 21075367
2011 Implications of transcriptional factor, OCT-4, in human bladder malignancy and tumor recurrence. Medical oncology (Northwood, London, England) 41 21533858
2004 Relative contribution of OAT and OCT transporters to organic electrolyte transport in rabbit proximal tubule. American journal of physiology. Renal physiology 40 15251863
2001 Identification of putative downstream genes of Oct-4 by suppression-subtractive hybridization. Biochemical and biophysical research communications 38 11401518
2012 Oct-3/4 promotes migration and invasion of glioblastoma cells. Journal of cellular biochemistry 37 21938739
2000 Oct-1 preferentially interacts with androgen receptor in a DNA-dependent manner that facilitates recruitment of SRC-1. The Journal of biological chemistry 36 11096094
1999 Functional interaction between Oct-1 and retinoid X receptor. The Journal of biological chemistry 36 10383413
2018 Peripapillary Retinoschisis in Glaucoma: Association With Progression and OCT Signs of Müller Cell Involvement. Investigative ophthalmology & visual science 35 29860466
2002 Oct-1 is involved in the transcriptional repression of the gonadotropin-releasing hormone receptor gene. Endocrinology 34 12446597
2004 B cell development and immunoglobulin transcription in Oct-1-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 33 14762167
2000 Reconstitution of T cell-specific transcription directed by composite NFAT/Oct elements. Journal of immunology (Baltimore, Md. : 1950) 33 11067921
2016 Comparison of the Abilities of SD-OCT and SS-OCT in Evaluating the Thickness of the Macular Inner Retinal Layer for Glaucoma Diagnosis. PloS one 31 26812064
2011 Co-expression of Oct-4 and Nestin in human breast cancers. Molecular biology reports 31 22207173
2010 Skn-1a/Oct-11 and ΔNp63α exert antagonizing effects on human keratin expression. Biochemical and biophysical research communications 31 20888799
2009 POU homeodomain protein Oct-1 functions as a sensor for cyclic AMP. The Journal of biological chemistry 31 19617623
2021 OBF1 and Oct factors control the germinal center transcriptional program. Blood 28 33512466
2019 OCT angiography in optic disc drusen: comparison with structural and functional parameters. The British journal of ophthalmology 28 31744797
2018 Sequential phases of RGC axonal and somatic injury in EAE mice examined using DTI and OCT. Multiple sclerosis and related disorders 28 30469023
2006 GABPalpha regulates Oct-3/4 expression in mouse embryonic stem cells. Biochemical and biophysical research communications 28 17194449
2014 Sema6a and Plxna2 mediate spatially regulated repulsion within the developing eye to promote eye vesicle cohesion. Development (Cambridge, England) 27 24917502
2001 Tissue-specific isoforms of the ubiquitous transcription factor Oct-1. Molecular genetics and genomics : MGG 27 11683265
1999 Binding of Sp1 and Sp3 transcription factors to the Oct-4 gene promoter. Cellular and molecular biology (Noisy-le-Grand, France) 27 10512200
2012 Correlating RNFL thickness by OCT with perimetric sensitivity in glaucoma patients. Journal of glaucoma 26 21336150
1991 Both Oct-1 and Oct-2A contain domains which can activate the ubiquitously expressed U2 snRNA genes. The EMBO journal 25 1829677
2017 A method for quantifying limbal stem cell niches using OCT imaging. The British journal of ophthalmology 24 28228408
2009 Abnormal DNA methylation of the Oct-4 enhancer region in cloned mouse embryos. Molecular reproduction and development 24 18932201
2007 Aberrant expression and distribution of the OCT-4 transcription factor in seminomas. Journal of biomedical science 24 17682839
2006 Association of PLXNA2 polymorphisms with vertebral fracture risk and bone mineral density in postmenopausal Korean population. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 24 16932874
2021 Biological importance of OCT transcription factors in reprogramming and development. Experimental & molecular medicine 23 34117345
2005 Effect of nicotine on Oct-4 and Rex-1 expression of mouse embryonic stem cells. Reproductive toxicology (Elmsford, N.Y.) 23 15749260
2004 NFI and Oct-1 bend the Ad5 origin in the same direction leading to optimal DNA replication. Nucleic acids research 23 15576348
2017 Retinal Findings on OCT in Systemic Conditions. Seminars in ophthalmology 22 28640657
2007 Failure to confirm an association between the PLXNA2 gene and schizophrenia in a Japanese population. Progress in neuro-psychopharmacology & biological psychiatry 22 17346868
2005 The POU protein Oct-6 is a nucleocytoplasmic shuttling protein. Nucleic acids research 22 16260476
1998 Oct-1 promoter region contains octamer sites and TAAT motifs recognized by Oct proteins. FEBS letters 22 9598983
1997 Characterization of a trimeric complex containing Oct-1, SNAPc, and DNA. The Journal of biological chemistry 22 9188510
2020 Cellular Functions of OCT-3/4 Regulated by Ubiquitination in Proliferating Cells. Cancers 21 32178477
2016 Oct-1, to go or not to go? That is the PolII question. Biochimica et biophysica acta 21 27063953
2014 Clinical significance of the stem cell gene Oct-4 in cervical cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 21 24532469
2010 OCT-4 expression in follicular and luteal phase endometrium: a pilot study. Reproductive biology and endocrinology : RB&E 21 20412569
2007 Oct-1 is involved in the transcriptional repression of the p15(INK4b) gene. FEBS letters 21 17316622
2022 Association of macular OCT and OCTA parameters with visual acuity in glaucoma. The British journal of ophthalmology 20 36126109
2022 Optical coherence tomography (OCT) measurements and cognitive performance in multiple sclerosis: a systematic review and meta-analysis. Journal of neurology 20 36396812
2021 Virtual Reality Oculokinetic Perimetry Test Reproducibility and Relationship to Conventional Perimetry and OCT. Ophthalmology science 20 36276927
2019 Imaging Amblyopia: Insights from Optical Coherence Tomography (OCT). Seminars in ophthalmology 20 31158044
2003 Human Oct-1L isoform has tissue-specific expression pattern similar to Oct-2. Immunology letters 20 12663137
1998 Comparison of sequence and function of the Oct-6 genes in zebrafish, chicken and mouse. Mechanisms of development 20 9651490
2023 Optical coherence tomography (OCT) measurements and disability in multiple sclerosis (MS): A systematic review and meta-analysis. Journal of the neurological sciences 19 37924591
2020 Comparison of Rates of Progression of Macular OCT Measures in Glaucoma. Translational vision science & technology 19 32832255
2006 Btk expression is controlled by Oct and BOB.1/OBF.1. Nucleic acids research 19 16582106
2016 Role of OCT-1 and partner proteins in T cell differentiation. Biochimica et biophysica acta 18 27126747