Affinage

PLXNA2

Plexin-A2 · UniProt O75051

Length
1894 aa
Mass
211.1 kDa
Annotated
2026-06-10
100 papers in source corpus 3 papers cited in narrative 3 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PLXNA2 (Plexin A2) is a semaphorin co-receptor that transduces cell-guidance signals governing tissue morphogenesis, cell migration, and inflammatory cell states (PMID:24917502). During zebrafish eye morphogenesis, Plxna2 partners with the semaphorin Sema6a to mediate spatially restricted repulsion: sema6a is expressed throughout the eye vesicle while plxna2 is confined to the ventral vesicle, and genetic epistasis shows that simultaneous removal of both restores vesicle integrity, establishing that Sema6a/Plxna2 repulsion must be locally neutralized to permit cohesive cell-cell interactions within the tissue domain (PMID:24917502). In mammalian disease contexts, PLXNA2 is a direct transcriptional target of the TMPRSS2:ERG oncogenic fusion and acts dose-dependently downstream of it to drive prostate cancer cell migration and invasion, with elevated expression in metastatic relative to localized tumors (PMID:23708657). PLXNA2 also regulates microglial polarization after cerebral ischemia/reperfusion injury, where its loss shifts microglia from a pro-inflammatory M1 to an anti-inflammatory M2 state through mTOR/STAT3 signaling (PMID:34474008). The biochemical mechanism by which PLXNA2 couples semaphorin engagement to these downstream migratory and signaling outputs has not been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps
  1. 2013 Medium

    Established that PLXNA2 is a downstream effector of an oncogenic transcription factor fusion, linking semaphorin receptor expression to cancer cell invasiveness.

    Evidence Microarray, dose-titrated ectopic TMPRSS2:ERG expression, PLXNA2 knockdown/overexpression with migration/invasion assays, and IHC of clinical prostate cancer samples

    PMID:23708657

    Open questions at the time
    • No biochemical mechanism for how PLXNA2 drives migration/invasion
    • Ligand and signaling partners in prostate cancer not identified
    • Single lab; causality in metastasis not tested in vivo
  2. 2014 High

    Defined the core ligand-receptor pairing and showed that spatially restricted Sema6a/Plxna2 repulsion controls tissue cohesion during organ morphogenesis.

    Evidence Morpholino single and double knockdown with epistasis rescue, time-lapse live imaging, and explant experiments in zebrafish

    PMID:24917502

    Open questions at the time
    • Intracellular signaling downstream of Plxna2 not resolved
    • Established in zebrafish; mammalian morphogenetic role not tested
    • Structural basis of Sema6a-Plxna2 interaction not addressed
  3. 2021 Medium

    Extended PLXNA2 function to neuroinflammation, identifying mTOR/STAT3 as the pathway through which it controls microglial polarization after ischemic injury.

    Evidence PLXNA2 knockdown in MCAO/R rat model and OGD/R BV2 microglia with behavioral tests, immunofluorescence, qRT-PCR, and Western blot of M1/M2 and mTOR/STAT3 markers

    PMID:34474008

    Open questions at the time
    • Whether PLXNA2 acts cell-autonomously in microglia versus via an upstream semaphorin is unresolved
    • Direct molecular link between PLXNA2 and mTOR/STAT3 not established
    • Single lab; human relevance not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The biochemical signal-transduction mechanism connecting PLXNA2 semaphorin engagement to downstream migratory and inflammatory outputs remains undefined.
  • No structural or enzymatic mechanism for PLXNA2 signaling in the corpus
  • Co-receptors and cytoplasmic effectors across contexts not identified
  • Unifying model across morphogenesis, cancer, and inflammation absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Pathway
R-HSA-1266738 Developmental Biology 1 R-HSA-1643685 Disease 1
Partners
SEMA6A

Evidence

Reading pass · 3 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 TMPRSS2:ERG fusion directly and positively regulates PLXNA2 expression in prostate cancer cells (PC3c), and PLXNA2 upregulation contributes to TMPRSS2:ERG-mediated enhancement of cell migration and invasion in a dose-dependent manner. PLXNA2 expression is also elevated in metastatic PCa tumors compared with localized primary PCa tumors. Microarray analysis, ectopic expression of TMPRSS2:ERG at multiple doses, migration/invasion assays with PLXNA2 manipulation, immunohistochemistry of clinical samples Oncogene Medium 23708657
2021 PLXNA2 knockdown in rats with middle cerebral artery occlusion/reperfusion injury promotes microglial polarization from M1 (pro-inflammatory) to M2 (anti-inflammatory) phenotype, reduces neuroinflammation, and accelerates recovery of motor and cognitive function. The mTOR/STAT3 signaling pathway is mechanistically involved in PLXNA2-regulated microglia polarization. PLXNA2 knockdown in MCAO/R rat model and BV2 microglia with OGD/R; behavioral tests, immunofluorescence, qRT-PCR, Western blot for M1/M2 markers and mTOR/STAT3 pathway components Experimental Neurology Medium 34474008
2014 In zebrafish, Plxna2 acts together with Sema6a (semaphorin 6a) to maintain eye vesicle cohesion during morphogenesis. sema6a is expressed throughout the eye vesicle while plxna2 is restricted to the ventral vesicle; knockdown of either causes loss of vesicle integrity with eye progenitors failing to enter evaginating vesicles or delaminating from the eye epithelium. Simultaneous knockdown of both sema6a and plxna2 rescues eye vesicle integrity, indicating that neutralization of Sema6a/Plxna2-mediated repulsion promotes cell-cell interactions within the tissue domain. Morpholino knockdown of plxna2 and/or sema6a in zebrafish; time-lapse microscopy; explant experiments; epistasis rescue by double knockdown Development High 24917502

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 2800 10742100
1990 Differential transcriptional activation by Oct-1 and Oct-2: interdependent activation domains induce Oct-2 phosphorylation. Cell 652 2302733
2001 Oct-4: gatekeeper in the beginnings of mammalian development. Stem cells (Dayton, Ohio) 619 11463946
2004 Oct-3/4 and Sox2 regulate Oct-3/4 gene in embryonic stem cells. The Journal of biological chemistry 295 15557334
2000 Expression pattern of Oct-4 in preimplantation embryos of different species. Biology of reproduction 291 11090438
1996 The POU factor Oct-6 and Schwann cell differentiation. Science (New York, N.Y.) 242 8662541
1991 Mitotic phosphorylation of the Oct-1 homeodomain and regulation of Oct-1 DNA binding activity. Science (New York, N.Y.) 228 1684878
2007 OCT-4, an embryonic stem cell marker, is highly expressed in bladder cancer. International journal of cancer 223 17205510
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
1992 Oct-1 and Oct-2 potentiate functional interactions of a transcription factor with the proximal sequence element of small nuclear RNA genes. Molecular and cellular biology 168 1535687
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
2019 Measurement Floors and Dynamic Ranges of OCT and OCT Angiography in Glaucoma. Ophthalmology 139 30858023
2000 Oct-4 expression in inner cell mass and trophectoderm of human blastocysts. Molecular human reproduction 139 11044462
2011 Optical coherence tomography (OCT): imaging the visual pathway as a model for neurodegeneration. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 137 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
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 99 29037595
2013 Oct transcription factors in development and stem cells: insights and mechanisms. Development (Cambridge, England) 98 23821033
2010 Oct-4 controls cell-cycle progression of embryonic stem cells. The Biochemical journal 93 19968627
1991 Structure, expression and chromosomal location of the Oct-4 gene. Mechanisms of development 92 1768618
1992 The Oct-1 POU domain mediates interactions between Oct-1 and other POU proteins. Molecular and cellular biology 80 1346336
2014 OCT: New perspectives in neuro-ophthalmology. Saudi journal of ophthalmology : official journal of the Saudi Ophthalmological Society 79 25859135
2015 Intraoperative OCT-Assisted DMEK: 14 Consecutive Cases. Cornea 78 26002152
2022 Detecting glaucoma with only OCT: Implications for the clinic, research, screening, and AI development. Progress in retinal and eye research 77 35216894
2006 Oct-4 expression in human endometrium. Molecular human reproduction 76 16421218
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
2006 The orphan nuclear receptor GCNF recruits DNA methyltransferase for Oct-3/4 silencing. Biochemical and biophysical research communications 70 16631596
1993 Hybrid cell extinction and re-expression of Oct-3 function correlates with differentiation potential. The EMBO journal 70 8223459
2003 Oct-4 expression in pluripotent cells of the rhesus monkey. Biology of reproduction 68 12890723
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 67 24934219
1992 Mini-Oct and Oct-2c: two novel, functionally diverse murine Oct-2 gene products are differentially expressed in the CNS. Neuron 67 1550677
2014 Recent advances in OCT imaging of the lamina cribrosa. The British journal of ophthalmology 66 24934221
2020 Optical coherence tomography (OCT) in neuro-ophthalmology. Eye (London, England) 64 33239763
2013 Identification of novel TMPRSS2:ERG mechanisms in prostate cancer metastasis: involvement of MMP9 and PLXNA2. Oncogene 63 23708657
1997 Using altered specificity Oct-1 and Oct-2 mutants to analyze the regulation of immunoglobulin gene transcription. The EMBO journal 58 9384588
2019 CKIP-1 limits foam cell formation and inhibits atherosclerosis by promoting degradation of Oct-1 by REGγ. Nature communications 57 30683852
2019 Quantitative Assessment of the Retina Using OCT and Associations with Cognitive Function. Ophthalmology 56 31307828
2004 Analysis of transcription factor OCT.1, OCT.2 and BOB.1 expression using tissue arrays in classical Hodgkin's lymphoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 56 15257313
2013 Precise comparison of protein localization among OCT, OAT, and MATE in human kidney. Journal of pharmaceutical sciences 55 23630107
2007 Anxiety and comorbid measures associated with PLXNA2. Archives of general psychiatry 52 17339520
1993 Mouse Oct-1 contains a composite homeodomain of human Oct-1 and Oct-2. Nucleic acids research 52 8441632
1991 Oct-3 is a maternal factor required for the first mouse embryonic division. Cell 49 2004418
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
1993 Cloning, chromosomal localization and expression pattern of the POU domain gene Oct-11. Nucleic acids research 46 8441607
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
2021 PLXNA2 knockdown promotes M2 microglia polarization through mTOR/STAT3 signaling to improve functional recovery in rats after cerebral ischemia/reperfusion injury. Experimental neurology 44 34474008
2011 Expression of oct-4 and c-kit antigens in endometriosis. Fertility and sterility 43 21075367
2007 DNA-PK phosphorylation sites on Oct-1 promote cell survival following DNA damage. Oncogene 40 17213819
2018 Peripapillary Retinoschisis in Glaucoma: Association With Progression and OCT Signs of Müller Cell Involvement. Investigative ophthalmology & visual science 37 29860466
1998 Oct-4: more than just a POUerful marker of the mammalian germline? APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 37 9524569
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
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
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
2021 OBF1 and Oct factors control the germinal center transcriptional program. Blood 30 33512466
1996 Oct-1 [corrected] and Oct-2 DNA-binding site specificity is regulated in vitro by different kinases. The Biochemical journal 29 8645173
2014 Sema6a and Plxna2 mediate spatially regulated repulsion within the developing eye to promote eye vesicle cohesion. Development (Cambridge, England) 28 24917502
2006 GABPalpha regulates Oct-3/4 expression in mouse embryonic stem cells. Biochemical and biophysical research communications 28 17194449
1993 Chromosomal structure and expression of the human OTF1 locus encoding the Oct-1 protein. Genomics 28 8314572
2004 Effect of ploidy and parental genome composition on expression of Oct-4 protein in mouse embryos. Gene expression patterns : GEP 26 15183310
1991 Both Oct-1 and Oct-2A contain domains which can activate the ubiquitously expressed U2 snRNA genes. The EMBO journal 25 1829677
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
2020 Cellular Functions of OCT-3/4 Regulated by Ubiquitination in Proliferating Cells. Cancers 23 32178477
2005 Effect of nicotine on Oct-4 and Rex-1 expression of mouse embryonic stem cells. Reproductive toxicology (Elmsford, N.Y.) 23 15749260
2022 Association of macular OCT and OCTA parameters with visual acuity in glaucoma. The British journal of ophthalmology 22 36126109
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
2023 Optical coherence tomography (OCT) measurements and disability in multiple sclerosis (MS): A systematic review and meta-analysis. Journal of the neurological sciences 21 37924591
2022 Optical coherence tomography (OCT) measurements and cognitive performance in multiple sclerosis: a systematic review and meta-analysis. Journal of neurology 21 36396812
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
2025 En face OCT: Breakthroughs in understanding the pathoanatomy of retinal disease and clinical applications. Progress in retinal and eye research 20 40054600
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
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
2022 Ability of Swept-source OCT and OCT-angiography to detect neuroretinal and vasculature changes in patients with Parkinson disease and essential tremor. Eye (London, England) 18 35650321
2016 Role of OCT-1 and partner proteins in T cell differentiation. Biochimica et biophysica acta 18 27126747
2012 Spatial and temporal distribution of Oct-4 and acetylated H4K5 in rabbit embryos. Reproductive biomedicine online 18 22381206
2007 The EWS-Oct-4 fusion gene encodes a transforming gene. The Biochemical journal 18 17564582
2002 Expression of Oct-6, a POU III domain transcription factor, in schizophrenia. The American journal of psychiatry 18 12091196
2023 OCT and OCT-A biomarkers in multiple sclerosis - review. Romanian journal of ophthalmology 17 37522023

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