Affinage

PNN

Pinin · UniProt Q9H307

Length
717 aa
Mass
81.6 kDa
Annotated
2026-06-10
41 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PNN (pinin/DRS/memA) is a nuclear speckle-associated phosphoprotein that operates at the interface of transcription, mRNA processing, and epithelial cell adhesion (PMID:14517304, PMID:15735603). In the nucleus it associates preferentially with spliced mRNAs at positions immediately upstream of exon-exon junctions through direct interaction with the splicing/EJC factor RNPS1, and its suppression causes nuclear accumulation of poly(A)+ RNA, linking PNN to mRNA export (PMID:14517304). PNN assembles into multiprotein splicing complexes via its C-terminal RS-rich motif, interacting with SR-rich proteins (SRp75, SRm300, SRrp130) and with ESRP1 to regulate epithelial-type alternative splicing of defined gene subsets, including PAX6(5a), FOXJ3, and a class of long non-coding RNAs (PMID:14578391, PMID:23299472, PMID:25489234). PNN acts upstream of SRSF1 to control apoptotic splicing decisions: its depletion shifts Bcl-x toward the pro-apoptotic Bcl-xS isoform and alters ICAD splicing, driving apoptosis that is rescued by SRSF1 (PMID:22454513). Through interaction with the corepressor CtBP1, PNN relieves CtBP1-mediated repression of the E-cadherin promoter and is recruited to CtBP-associated chromatin, coupling transcriptional regulation to E-cadherin mRNA splicing via RNA polymerase II (PMID:15542832, PMID:18086895). At the cell periphery, PNN localizes to desmosomes where it promotes stable cell-cell adhesion and epithelial quiescence; its loss downregulates E-cadherin and desmosomal proteins and causes adhesion failure, while overexpression hyperstabilizes adhesion and suppresses migration (PMID:15735603, PMID:10798648). PNN is required for corneal epithelial identity and for pluripotency, and its homozygous knockout is embryonic lethal in mice (PMID:22454513, PMID:19892877, PMID:28595116).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2003 High

    Established PNN as an mRNA-binding factor coupling splicing to export, answering whether it has a direct role in RNA metabolism rather than being merely speckle-resident.

    Evidence Co-IP, RNase H mapping, heterokaryon assay, overexpression and RNAi in human cells

    PMID:14517304

    Open questions at the time
    • Does not define the RNA sequence/structure determinant of binding
    • Mechanism of export coupling beyond RNPS1 interaction not resolved
  2. 2003 Medium

    Showed PNN is a stable component of SR-rich splicing complexes in speckles, establishing the structural basis for its splicing role via its RS-rich motif.

    Evidence Yeast two-hybrid, co-IP, immunofluorescence co-localization

    PMID:14578391

    Open questions at the time
    • SRrp130 identity not molecularly defined
    • Functional consequence of each interaction on specific transcripts not tested
  3. 2004 High

    Linked PNN to transcriptional control by showing it antagonizes CtBP1 corepression at the E-cadherin promoter, connecting it to epithelial gene regulation.

    Evidence In vitro pull-down, co-IP, promoter reporter assays with gain/loss of function

    PMID:15542832

    Open questions at the time
    • Structural basis of PNN-CtBP1 interaction unknown
    • Whether de-repression generalizes beyond E-cadherin untested here
  4. 2005 High

    Defined PNN as required for epithelial cell-cell adhesion, demonstrating that its nuclear/splicing functions translate to a junctional phenotype.

    Evidence shRNA knockdown with rescue control, immunofluorescence, Western blot in corneal epithelial cells

    PMID:15735603

    Open questions at the time
    • Does not separate direct desmosomal role from indirect transcriptional/splicing effects
    • Causal ordering of E-cadherin loss vs adhesion failure unresolved
  5. 2007 High

    Resolved how PNN bridges transcription and splicing, showing CtBP recruits it to chromatin and that PNN and CtBP modulate E-cadherin splicing through RNA Pol II.

    Evidence ChIP, co-IP, reporter and splicing assays

    PMID:18086895

    Open questions at the time
    • Direct chromatin-remodeling activity of PNN not biochemically defined
    • Generality of Pol II coupling to other genes untested
  6. 2012 High

    Placed PNN upstream of SRSF1 in apoptotic splicing control and established its essentiality in development via embryonic lethality of knockout mice.

    Evidence RNAi, RT-PCR splicing analysis, SRSF1 overexpression rescue, flow cytometry, mouse knockout

    PMID:22454513

    Open questions at the time
    • Mechanism by which PNN sustains SRSF1 levels not defined
    • Cause of embryonic lethality not mapped to a specific splicing target
  7. 2009 Medium

    Showed PNN is required in vivo for corneal/lens epithelial identity, linking its loss to Wnt/β-catenin activation and keratin switching.

    Evidence Pax6-Cre conditional knockout, histology, immunohistochemistry

    PMID:19892877

    Open questions at the time
    • Whether β-catenin/Tcf4 activation is direct or downstream of adhesion loss unresolved
    • p68 helicase misregulation mechanism unknown
  8. 2013 Medium

    Identified ESRP1 as a PNN partner and defined overlapping epithelial alternative-splicing programs, broadening the targets of PNN-dependent splicing.

    Evidence Reciprocal co-IP, deconvolution microscopy, transcriptome array with RT-PCR validation, shRNA

    PMID:23299472

    Open questions at the time
    • Direct versus indirect splicing regulation for each target not distinguished
    • Single cell-type context
  9. 2014 Medium

    Extended PNN's splicing role to long non-coding RNAs, showing it shapes lncRNA exon usage in corneal epithelium.

    Evidence RNAi knockdown, RT-PCR, in situ hybridization, conditional knockout mouse

    PMID:25489234

    Open questions at the time
    • Functional consequences of altered lncRNA isoforms unknown
    • Mechanism of lncRNA target selection unresolved
  10. 2017 Medium

    Demonstrated PNN is required for pluripotency and influences spliceosome assembly, via interaction with core spliceosomal proteins.

    Evidence Co-IP with SNRPA1/SNRPD1, RNAi, immunofluorescence, expression profiling in hiPSCs

    PMID:28595116

    Open questions at the time
    • How PNN promotes spliceosome assembly mechanistically not defined
    • Direct vs indirect effect on pluripotency factors untested
  11. 2020 Medium

    Revealed cell-type-specific PNN redistribution under ischemic stress, with nuclear-to-cytoplasmic translocation in neurons but not astrocytes.

    Evidence OGD and MCAO models, immunofluorescence, Western blot in primary cells

    PMID:33027948

    Open questions at the time
    • Functional role of cytoplasmic PNN under stress not established
    • Trigger for translocation unknown
  12. 2022 Medium

    Established a neuroprotective role for PNN against ischemia-reperfusion injury mediated through SRSF1/SRSF2 splicing balance and oxidative stress control.

    Evidence Inducible neuron-specific knockout, MCAO stroke model, Western blot, ROS measurement

    PMID:35326115

    Open questions at the time
    • Specific splicing targets driving neuroprotection not identified
    • Causal link between SRSF imbalance and oxidative damage not directly tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PNN's distinct activities—mRNP export, alternative splicing, CtBP-coupled transcription, and desmosomal adhesion—are mechanistically coordinated and what governs its context-dependent localization remains unresolved.
  • No structural model of PNN domains in complex with partners
  • No unifying mechanism linking nuclear and junctional pools
  • Direct RNA-binding specificity not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 2 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 2 GO:0005886 plasma membrane 2 GO:0005654 nucleoplasm 1 GO:0005829 cytosol 1
Pathway
R-HSA-8953854 Metabolism of RNA 4 R-HSA-1266738 Developmental Biology 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
CTBP1ESRP1RNPS1SNRPA1SNRPD1SRM300SRSF1SRSF11
Complex memberships
CtBP-associated chromatin complexexon-exon junction complexnuclear specklespliceosome

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 PNN/DRS protein associates preferentially with spliced mRNAs in vitro (by immunoprecipitation), binds to mRNAs at a position immediately upstream of the splice junction (shown by oligonucleotide-directed RNase H digestion), and interacts directly with RNPS1, a pre-mRNA splicing factor and exon-exon junction complex component. Overexpression of the amino-terminal fragment of PNN that directly interacts with RNPS1 blocks pre-mRNA splicing. Suppression of PNN leads to nuclear accumulation of bulk poly(A)+ RNA, implicating PNN in mRNA export via its interaction with RNPS1. Immunoprecipitation, RNase H digestion, heterokaryon assay, overexpression, RNA interference Molecular and cellular biology High 14517304
2003 PNN/DRS/memA interacts with SR-rich proteins SRp75, SRm300, and a novel 130-kDa protein SRrp130 via its C-terminal polyserine/RS motif, as determined by yeast two-hybrid analysis and co-immunoprecipitation. These proteins co-localize in nuclear speckles with pre-mRNA splicing machinery, suggesting PNN is part of a multiprotein complex involved in pre-mRNA processing. Yeast two-hybrid, co-immunoprecipitation, immunofluorescence co-localization Investigative ophthalmology & visual science Medium 14578391
2004 PNN interacts with the transcriptional corepressor CtBP1 via in vitro pull-down and in vivo co-immunoprecipitation, and this interaction enables PNN to relieve CtBP1-mediated repression of the E-cadherin promoter, as shown by reporter assays combined with overexpression and RNA interference experiments. In vitro pull-down, co-immunoprecipitation, reporter assay, overexpression, RNA interference, immunofluorescence Molecular and cellular biology High 15542832
2005 RNAi-mediated knockdown of PNN in human corneal epithelial cells leads to loss of cell-cell adhesion, altered cell shape, downregulation of E-cadherin and desmosomal proteins (desmoplakin, desmoglein), redistribution of keratin filaments away from desmosomes, and altered distribution of SR proteins and SRm300. A conservatively mutated rescue construct restores cell-cell adhesion, confirming specificity. shRNAi knockdown, rescue construct, immunofluorescence, Western blot Molecular vision High 15735603
2007 CtBP recruits PNN to CtBP-associated chromatin complexes at the E-cadherin promoter, leading to PNN-dependent chromatin remodeling. CtBP and PNN can differentially modulate E-cadherin mRNA splicing, with RNA polymerase II serving as an interface, establishing a novel mechanism linking CtBP-mediated transcriptional regulation to mRNA splicing of E-cadherin. Co-immunoprecipitation, chromatin immunoprecipitation, reporter assay, splicing assay Molecular and cellular biology High 18086895
2000 Overexpression of full-length PNN in cultured MDCK epithelial cells results in hyperstable cell adhesion and markedly reduced cell migration after wound scraping. During corneal wound healing in vivo, PNN dissociates from desmosomes in migrating epithelial cells and returns after wound closure, correlating PNN desmosomal localization with epithelial quiescence. Transfection/overexpression, wound scratch migration assay, immunofluorescence, immunoelectron microscopy Investigative ophthalmology & visual science Medium 10798648
2012 Pnn depletion by RNAi in MCF-7 cells induces cellular apoptosis, disrupts nuclear speckles, reduces SR protein levels, and alters alternative splicing of SRSF1, Bcl-x (shifting toward pro-apoptotic Bcl-xS), and ICAD. Apoptosis is rescued by overexpression of SRSF1, which restores Bcl-xL and functionless ICAD splicing, placing Pnn upstream of SRSF1 in the regulation of apoptotic alternative splicing. Pnn homozygous knockout in mice causes early embryonic lethality. RNA interference, RT-PCR for alternative splicing, overexpression rescue, flow cytometry (apoptosis), mouse knockout Journal of cell science High 22454513
2009 Conditional inactivation of Pnn in developing mouse eye ectoderm (via Pax6-Cre) causes severe malformation of cornea and lens, loss of corneal epithelial identity (loss of K12, gain of K10/K14), squamous metaplasia correlated with elevated β-catenin activity and Tcf4 level, and misregulated p68 RNA helicase in mutant corneal epithelium. Conditional knockout (Cre-lox), histology, immunohistochemistry, mouse genetics Investigative ophthalmology & visual science Medium 19892877
2013 ESRP1 and PNN physically associate in protein complexes within nuclear speckles (by co-immunoprecipitation and deconvolution microscopy) in corneal epithelial cells. Whole transcriptome array analysis of PNN or ESRP1 knockdown cells reveals distinct but overlapping subsets of alternatively spliced genes, including PAX6(5a), FOXJ3, ARHGEF11, and SLC37A2, supporting a role for PNN in epithelial-type alternative splicing regulation. Co-immunoprecipitation, deconvolution microscopy, transcriptome array, RT-PCR validation, shRNA knockdown Investigative ophthalmology & visual science Medium 23299472
2017 PNN physically interacts with SNRPA1 and SNRPD1 (spliceosomal components) in human pluripotent stem cells, as shown by co-immunoprecipitation. PNN depletion leads to loss of pluripotency and blocks hiPS generation. PNN co-localizes with hPS spliceosomes and positively influences hPS spliceosome assembly. Co-immunoprecipitation, RNAi knockdown, immunofluorescence, gene expression profiling Stem cell research Medium 28595116
2014 PNN knockdown in human corneal epithelial cells (HCET) causes altered alternative splicing of a specific subset of long non-coding RNAs (lncRNAs) including Has2as, RP11-322M19.1, and RP11-18I14.1, affecting cassette exon inclusion and alternative splice site usage. Pnn-deficient mouse corneas show differential splicing patterns in lncRNA orthologues, establishing PNN's role in lncRNA splicing regulation in corneal epithelium. RNAi knockdown, RT-PCR, in situ hybridization, Pnn conditional knockout mouse Molecular vision Medium 25489234
2022 Inducible neuron-specific Pnn deficiency in mice increases SRSF2 expression and decreases SRSF1 expression in brain tissue, elevates ROS generators (NOX-1, NOX-2) and antioxidant proteins (GR, HO-1, NQO-1), and increases oxidized proteins in cortical and hippocampal neurons. Upon MCAO-induced stroke, neuronal Pnn-deficient mice show increased cerebral infarct area and elevated pro-apoptotic protein expression, establishing Pnn's neuroprotective role against ischemia-reperfusion injury through SRSF1/SRSF2 splicing regulation. Inducible conditional knockout, MCAO stroke model, Western blot, immunofluorescence, ROS measurement Antioxidants (Basel, Switzerland) Medium 35326115
1999 Sequence analysis identified that MEMA/PNN protein contains three coiled-coil domains and one glycine loop domain, and is identical to a 160 kDa nuclear 'domain rich in serines' (DRS) protein that occurs free in the nucleoplasm and in U2-ribonucleoprotein structures, establishing its presence in RNA-associated nuclear complexes. Subtractive hybridization, sequence analysis, expression analysis Biochimica et biophysica acta Low 10095061
2020 In primary cultured neurons and astrocytes subjected to oxygen-glucose deprivation (OGD), Pnn expression increases during OGD and decreases during reoxygenation in neurons, while in astrocytes Pnn expression decreases with OGD and increases during reoxygenation. Cytoplasmic translocation of Pnn (normally nuclear speckle-localized) is observed in neurons under OGD/reoxygenation but not in astrocytes, demonstrating cell-type-specific redistribution under ischemic stress. OGD model, MCAO mouse model, immunofluorescence, Western blot, primary cell culture Brain sciences Medium 33027948

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 RNA-Seq Profiling of Serum Exosomal Circular RNAs Reveals Circ-PNN as a Potential Biomarker for Human Colorectal Cancer. Frontiers in oncology 87 32626660
2014 Catalytic mechanisms of direct pyrrole synthesis via dehydrogenative coupling mediated by PNP-Ir or PNN-Ru pincer complexes: crucial role of proton-transfer shuttles in the PNP-Ir system. Journal of the American Chemical Society 71 24611673
2004 Nuclear speckle-associated protein Pnn/DRS binds to the transcriptional corepressor CtBP and relieves CtBP-mediated repression of the E-cadherin gene. Molecular and cellular biology 64 15542832
2003 Nuclear Pnn/DRS protein binds to spliced mRNPs and participates in mRNA processing and export via interaction with RNPS1. Molecular and cellular biology 61 14517304
2003 Pinin/DRS/memA interacts with SRp75, SRm300 and SRrp130 in corneal epithelial cells. Investigative ophthalmology & visual science 54 14578391
2000 Characterization of the gene encoding pinin/DRS/memA and evidence for its potential tumor suppressor function. Oncogene 41 10645008
2009 Tumor classification by combining PNN classifier ensemble with neighborhood rough set based gene reduction. Computers in biology and medicine 39 20044083
2005 Reduction of Pnn by RNAi induces loss of cell-cell adhesion between human corneal epithelial cells. Molecular vision 36 15735603
2000 Role of cell adhesion-associated protein, pinin (DRS/memA), in corneal epithelial migration. Investigative ophthalmology & visual science 36 10798648
2011 Insights into dehydrogenative coupling of alcohols and amines catalyzed by a (PNN)-Ru(II) hydride complex: unusual metal-ligand cooperation. Inorganic chemistry 33 21942421
2019 RNA sequencing reveals PNN and KCNQ1OT1 as predictive biomarkers of clinical outcome in stage III colorectal cancer patients treated with adjuvant chemotherapy. International journal of cancer 32 30973654
2012 Loss of Pnn expression results in mouse early embryonic lethality and cellular apoptosis through SRSF1-mediated alternative expression of Bcl-xS and ICAD. Journal of cell science 32 22454513
2009 Disruption of mouse corneal epithelial differentiation by conditional inactivation of pnn. Investigative ophthalmology & visual science 27 19892877
2019 Neuronal Pentraxin 2 Binds PNNs and Enhances PNN Formation. Neural plasticity 26 31772567
2017 The unique spliceosome signature of human pluripotent stem cells is mediated by SNRPA1, SNRPD1, and PNN. Stem cell research 26 28595116
2006 PNN-curve: a new 2D graphical representation of DNA sequences and its application. Journal of theoretical biology 26 16945387
2014 Role of Pnn in alternative splicing of a specific subset of lncRNAs of the corneal epithelium. Molecular vision 19 25489234
2013 Transcriptomic analysis of PNN- and ESRP1-regulated alternative pre-mRNA splicing in human corneal epithelial cells. Investigative ophthalmology & visual science 17 23299472
2007 Corepressor CtBP and nuclear speckle protein Pnn/DRS differentially modulate transcription and splicing of the E-cadherin gene. Molecular and cellular biology 17 18086895
2010 Mechanism for the light-induced O(2) evolution from H(2)O promoted by Ru(II) PNN complex: A DFT study. The journal of physical chemistry. A 15 20804156
2021 Hsa_circ_0032463 acts as the tumor promoter in osteosarcoma by regulating the miR‑330‑3p/PNN axis. International journal of molecular medicine 14 33786605
1999 memA/DRS, a putative mediator of multiprotein complexes, is overexpressed in the metastasizing human melanoma cell lines BLM and MV3. Biochimica et biophysica acta 14 10095061
2022 Neuronal Pnn Deficiency Increases Oxidative Stress and Exacerbates Cerebral Ischemia/Reperfusion Injury in Mice. Antioxidants (Basel, Switzerland) 13 35326115
2020 Novel nickel(II), palladium(II), and platinum(II) complexes having a pyrrolyl-iminophosphine (PNN) pincer: Synthesis, crystal structures, and cytotoxic activity. Journal of inorganic biochemistry 12 32032825
2022 DNN-PNN: A parallel deep neural network model to improve anticancer drug sensitivity. Methods (San Diego, Calif.) 11 36410694
2020 PNN and KCNQ1OT1 Can Predict the Efficacy of Adjuvant Fluoropyrimidine-Based Chemotherapy in Colorectal Cancer Patients. Oncology research 10 33208224
2021 The role and regulation of Pnn in proliferative and non-dividing cells: Form embryogenesis to pathogenesis. Biochemical pharmacology 9 34237338
2021 Ascendancy of Nitrogen Heterocycles in the Computationally Designed Mn(I)PNN Pincer Catalysts on the Hydrogenation of Carbon Dioxide to Methanol. Inorganic chemistry 9 34714058
2022 The Signature of Moderate Perinatal Hypoxia on Cortical Organization and Behavior: Altered PNN-Parvalbumin Interneuron Connectivity of the Cingulate Circuitries. Frontiers in cell and developmental biology 8 35295859
2011 Pnn and SR family proteins are differentially expressed in mouse central nervous system. Histochemistry and cell biology 8 21437620
2024 Identification of a Novel miR-195-5p/PNN Axis in Colorectal Cancer. International journal of molecular sciences 7 38892168
2023 The Mechanism of Markovnikov-Selective Epoxide Hydrogenolysis Catalyzed by Ruthenium PNN and PNP Pincer Complexes. Organometallics 7 36937786
2024 Decreased extrasynaptic δ-GABAA receptors in PNN-associated parvalbumin interneurons correlates with anxiety in APP and tau mouse models of Alzheimer's disease. British journal of pharmacology 6 38886118
2024 ZC3H13 may participate in the ferroptosis process of sepsis-induced cardiomyopathy by regulating the expression of Pnn and Rbm25. Gene 5 39284557
2014 Classification of ovary abnormality using the probabilistic neural network (PNN). Technology and health care : official journal of the European Society for Engineering and Medicine 5 25335972
2023 Zinc-a2-Glycoprotein Acts as a Component of PNN to Protect Hippocampal Neurons from Apoptosis. Molecular neurobiology 4 38001359
2020 Expression and Distribution Pattern of Pnn in Ischemic Cerebral Cortex and Cultured Neural Cells Exposed to Oxygen-Glucose Deprivation. Brain sciences 4 33027948
2016 In silico investigation of agonist activity of a structurally diverse set of drugs to hPXR using HM-BSM and HM-PNN. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 3 27376821
2022 High-Throughput Microenvironment Microarray (MEMA) High-Resolution Imaging. Methods in molecular biology (Clifton, N.J.) 1 35094321
2026 Band Gap Tuneability in Antiperovskite-Based Nitrides AE3PnN and Imides AE5Pn2(NH)2 (AE = Ca, Sr; Pn = As, Sb, Bi). Angewandte Chemie (International ed. in English) 0 41919461
2021 A 0.3 V PNN Based 10T SRAM with Pulse Control Based Read-Assist and Write Data-Aware Schemes for Low Power Applications. Sensors (Basel, Switzerland) 0 34640911

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