Affinage

PSENEN

Gamma-secretase subunit PEN-2 · UniProt Q9NZ42

Length
101 aa
Mass
12.0 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PSENEN/PEN-2 is the smallest subunit of the γ-secretase intramembrane protease complex (presenilin/nicastrin/APH-1/PEN-2), and its incorporation is required to convert nascent presenilin into the catalytically active enzyme that cleaves substrates including APP and Notch (PMID:12198112, PMID:12740439). PEN-2 is recruited into the complex by direct binding to transmembrane domain 4 of presenilin through a conserved Trp-Asn-Phe (NF) motif, and this engagement triggers presenilin endoproteolysis to generate the active PS1 N-terminal/C-terminal fragment heterodimer (PMID:16234244, PMID:16234243, PMID:12522139). Through its conserved C-terminal domain, PEN-2 then stabilizes the resulting PS NTF/CTF fragments, which otherwise undergo proteasomal degradation; PEN-2's transmembrane segment drives endoproteolysis while its C-terminus mediates fragment stabilization (PMID:15039426, PMID:15537629, PMID:15953349). Beyond a structural role, PEN-2 participates directly in the catalytic mechanism: its hydrophobic and loop domains lie within a water-containing cavity near the PS catalytic core, and PEN-2 modulates pore water accessibility to influence Aβ42 generation and cleavage specificity (PMID:21296884, PMID:17329245). Assembly is tightly quality-controlled, with unassembled PEN-2 retained in the ER through binding to Rer1 and degraded by the ERAD-proteasome pathway, while presenilin protects incorporated PEN-2 from turnover (PMID:17668005, PMID:14724271, PMID:15035625). PEN-2 also has γ-secretase-independent functions: it is a direct binding partner of metformin, coupling drug binding to ATP6AP1/v-ATPase inhibition and lysosomal AMPK activation, and it regulates the autophagy-lysosome system (PMID:35197629, PMID:34964690). In neural development, PEN-2-dependent Notch signaling maintains apical neural progenitors and suppresses p53-dependent apoptosis (PMID:30692224, PMID:16464238). Heterozygous truncating mutations in PSENEN cause Dowling-Degos disease with acne inversa through reduced Notch signaling and disrupted melanocyte migration (PMID:28287404, PMID:28922471).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2002 High

    Established that PEN-2 is a required, coordinately-expressed component of γ-secretase whose loss collapses complex formation, answering whether PEN-2 is integral to the protease.

    Evidence RNAi knockdown and co-immunoprecipitation in mammalian and Drosophila cells, with cross-species rescue in C. elegans

    PMID:12110170 PMID:12198112

    Open questions at the time
    • Did not define how PEN-2 physically engages the complex
    • Did not resolve PEN-2's specific catalytic versus assembly role
  2. 2003 High

    Showed that reconstituting the four components together generates active enzyme and that PEN-2 is specifically required for presenilin endoproteolysis, identifying PEN-2 as a limiting activating factor.

    Evidence Co-immunoprecipitation, overexpression, siRNA, and γ-secretase activity assays in mammalian cells

    PMID:12522139 PMID:12740439

    Open questions at the time
    • Did not map the binding interface on presenilin
    • Did not establish PEN-2 membrane topology
  3. 2004 High

    Defined PEN-2's domain-level division of labor — its transmembrane segment drives endoproteolysis while its C-terminus stabilizes the resulting PS fragments against proteasomal degradation.

    Evidence Stable RNAi knockdown with PEN-2 mutant rescue, chimeric/domain-swap mutagenesis, proteasome inhibitor studies

    PMID:15039426 PMID:15322109 PMID:15537629

    Open questions at the time
    • Did not resolve atomic interface contacts
    • Did not address how stabilization is coupled to catalysis
  4. 2004 High

    Resolved the assembly quality-control logic: unassembled PEN-2 is ER-retained, ubiquitylated and ERAD-degraded, while presenilin post-translationally protects incorporated PEN-2.

    Evidence Subcellular fractionation, ubiquitylation assays, pulse-chase, proteasome inhibition, and transgenic mouse validation in PS-deficient backgrounds

    PMID:14724271 PMID:15035625

    Open questions at the time
    • Did not identify the ER retention receptor at this stage
    • Did not define the degradation machinery components
  5. 2005 High

    Mapped the recruitment interface to presenilin TMD4 and its minimal NF motif, defining the molecular basis for PEN-2 incorporation and endoproteolysis triggering.

    Evidence TMD-swapping chimeras in Psen1/Psen2-null cells, deletion mutants, co-immunoprecipitation, and functional reconstitution

    PMID:16234243 PMID:16234244

    Open questions at the time
    • Did not resolve the reciprocal PEN-2 residues contacting PS1
    • Did not provide structural model of the interface
  6. 2007 Medium

    Identified Rer1 as the receptor that retains unassembled PEN-2 in the ER via PEN-2 TMD1, completing the assembly-checkpoint model.

    Evidence Co-immunoprecipitation, Rer1 knockdown and overexpression, surface localization assay

    PMID:17668005

    Open questions at the time
    • Single lab
    • Did not establish stoichiometry or competition with complex assembly
  7. 2007 High

    Demonstrated PEN-2 directly tunes catalytic output by altering water accessibility of the presenilin pore, linking PEN-2 to Aβ42 generation specificity rather than purely scaffolding.

    Evidence N-terminal elongation mutagenesis, in vitro γ-secretase assay, substituted cysteine accessibility method

    PMID:17329245

    Open questions at the time
    • Did not provide high-resolution structure of the pore
    • Did not quantify clinical relevance of altered specificity
  8. 2010 High

    Showed a trimeric PS1/PEN-2/APH-1a complex retains catalytic activity without nicastrin, refining the minimal active unit and PEN-2's place in it.

    Evidence NCT-deficient mouse fibroblasts, siRNA epistasis, γ-secretase inhibitor controls, endogenous Notch cleavage assay

    PMID:20130175

    Open questions at the time
    • Did not reconcile with models requiring nicastrin for substrate recognition
    • Did not measure efficiency relative to the full complex
  9. 2011 High

    Localized PEN-2 hydrophobic domain 1 and loop to a water-containing cavity near the PS C-terminal fragment, supporting a direct mechanistic contribution to catalysis.

    Evidence SCAM structural probing and point mutagenesis in PEN-2 null fibroblasts with functional rescue

    PMID:21296884 PMID:21914807

    Open questions at the time
    • Did not yield atomic structure
    • Did not separate catalytic contribution from complex stability
  10. 2014 High

    Comprehensive per-domain mutagenesis dissected which PEN-2 regions raise versus lower activity and showed minor PS1 endoproteolysis can occur without PEN-2, sharpening its role as enhancer rather than absolute requirement.

    Evidence Systematic mutagenesis across all PEN-2 domains with activity, endoproteolysis, trafficking, and stability readouts

    PMID:24941111

    Open questions at the time
    • Did not provide structural rationale for opposing-effect residues
    • Did not test these variants in vivo
  11. 2015 Medium

    Revised PEN-2 topology, showing HP1 forms a reentrant loop with a cytoplasmic N-terminus, correcting the earlier dual-pass hairpin model.

    Evidence Epitope accessibility in stably expressing cells, chimeric domain swaps, functional rescue in PEN-2-deficient fibroblasts

    PMID:26296997

    Open questions at the time
    • Contradicts earlier topology work and single lab
    • Did not crystallographically confirm the reentrant loop
  12. 2019 High

    Established PEN-2's physiological role in maintaining apical neural progenitors via Notch, placing PEN-2 upstream of Notch in neocortical neurogenesis.

    Evidence Conditional Nes-Cre knockout mouse with marker analysis and NICD genetic rescue

    PMID:30692224

    Open questions at the time
    • Did not separate γ-secretase-dependent from independent contributions in this setting
    • Did not address adult neurogenesis
  13. 2021 Medium

    Revealed a γ-secretase-independent function of PEN-2 in the autophagy-lysosome system, expanding its biology beyond the protease complex.

    Evidence Isogenic CRISPR knockout in HeLa, lysosomal/autophagosome marker imaging, TFEB quantification, tandem affinity purification identifying CLN3, with γ-secretase inhibitor controls

    PMID:34964690

    Open questions at the time
    • Single lab
    • Mechanism linking PEN-2-CLN3 to lysosomal output undefined
  14. 2022 High

    Identified PEN-2 as the direct molecular target of metformin, coupling drug binding to v-ATPase inhibition and lysosomal AMPK activation, defining a major drug-mechanism role independent of γ-secretase.

    Evidence Photoactive metformin probe crosslinking, SPR/ITC affinity measurement, PEN2-ATP6AP1 co-IP, tissue-specific conditional KO mice, and C. elegans lifespan assays

    PMID:35197629

    Open questions at the time
    • Did not provide structure of the metformin-PEN2-ATP6AP1 complex
    • Did not establish how PEN-2 partitions between γ-secretase and ATP6AP1 pools
  15. 2017 Medium

    Linked PSENEN loss-of-function mutations to Dowling-Degos disease with acne inversa via reduced Notch signaling and disrupted melanocyte behavior, establishing a human Mendelian disease connection.

    Evidence Mutation screening, Notch reporter assays in patient keratinocytes, and zebrafish knockdown with in vivo melanocyte imaging

    PMID:28287404 PMID:28922471

    Open questions at the time
    • Did not define why pigmentary skin tissue is selectively vulnerable
    • Did not establish genotype-phenotype dosage relationships

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PEN-2 is allocated between its γ-secretase role and its γ-secretase-independent ATP6AP1/autophagy-lysosome functions, and the structural basis for these distinct interactions, remains unresolved.
  • No structure of PEN-2 bound to ATP6AP1 or CLN3
  • Unknown regulation partitioning PEN-2 between complexes
  • Physiological balance between catalytic and non-catalytic roles undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0005198 structural molecule activity 3
Localization
GO:0005764 lysosome 2 GO:0005783 endoplasmic reticulum 2 GO:0005886 plasma membrane 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1643685 Disease 2 R-HSA-9612973 Autophagy 1
Partners
APH1AATP6AP1CLN3FTLNCSTNPSEN1RER1
Complex memberships
γ-secretase complex

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 PEN-2 (PSENEN) is an integral component of γ-secretase complexes containing PS1 and PS2. RNAi-mediated knockdown of PEN-2 reduces presenilin levels, impairs nicastrin maturation, and blocks γ-secretase complex formation, demonstrating coordinated expression of complex components. RNA interference knockdown, co-immunoprecipitation, Western blotting in mammalian cells The Journal of biological chemistry High 12198112
2002 aph-1 and pen-2 are required for Notch pathway signaling and γ-secretase cleavage of βAPP. RNAi-mediated inactivation in Drosophila cells reduces γ-secretase cleavage of βAPP and Notch substrates and reduces processed presenilin levels. Human PEN-2 and APH-1 must be provided together to rescue C. elegans mutant phenotypes. C. elegans genetic screen, RNAi in Drosophila cells, cross-species complementation assay Developmental cell High 12110170
2003 Aph-1 and Pen-2 associate directly with presenilin and nicastrin in the active γ-secretase protease complex. Coexpression of all four proteins (PS, NCT, Aph-1, Pen-2) leads to marked increases in presenilin heterodimers, full glycosylation of nicastrin, and enhanced γ-secretase activity, indicating they comprise the limiting components of γ-secretase. Co-immunoprecipitation, overexpression, γ-secretase activity assay in mammalian cells Proceedings of the National Academy of Sciences of the United States of America High 12740439
2003 PEN-2 preferentially interacts with PS1 holoprotein. Downregulation of PEN-2 by siRNA abolishes endoproteolysis of PS1, whereas overexpression of PEN-2 promotes PS1 fragment production, establishing a critical role for PEN-2 in PS1 endoproteolysis. APH-1 coordinately regulates this process. siRNA knockdown, overexpression, Western blotting, co-immunoprecipitation The Journal of biological chemistry High 12522139
2003 PEN-2 membrane topology: PEN-2 spans the membrane twice in a hairpin configuration with both N- and C-termini facing the lumen of the endoplasmic reticulum, and the loop domain is cytosolic. Glycosylation of the N-terminal domain prevented association with presenilin 1, indicating the N-terminal domain is important for PS1 interaction. N-linked glycosylation site mutagenesis, selective plasma membrane permeabilization, immunofluorescence microscopy, protease protection assay The Journal of biological chemistry High 12639958
2004 PEN-2 is required for stabilization of the presenilin N-/C-terminal fragment heterodimer within the γ-secretase complex following PS endoproteolysis. The PEN-2 C-terminus is critical for this stabilization function; C-terminally truncated PEN-2 fails to incorporate stably into the complex, and the PS1 NTF/CTF heterodimer undergoes proteasomal degradation without functional PEN-2. Stable RNAi knockdown cells, PEN-2 mutant rescue experiments, Western blotting, proteasome inhibitor studies The Journal of biological chemistry High 15039426
2004 Detergent (DDM)-dependent dissociation of active γ-secretase reveals that Pen-2 directly interacts with PS1-NTF within the active complex, generating a Pen-2–PS1-NTF inactive sub-complex upon dissociation. Pen-2 can also associate with PS1 holoprotein in complexes devoid of NCT and Aph-1. Detergent dissociation of purified active γ-secretase, co-immunoprecipitation of dissociation products Biochemistry Medium 14717586
2004 In the absence of presenilin, Pen-2 is sequestered in the endoplasmic reticulum, ubiquitylated, and degraded via the ER-associated degradation (ERAD)–proteasome pathway. PS1 regulates Pen-2 subcellular localization, preventing its ER retention. Subcellular fractionation, immunofluorescence, ubiquitylation assay, proteasome inhibitor studies in PS-deficient cells The Journal of biological chemistry High 14724271
2004 PS1 selectively protects Pen-2 from proteasomal degradation post-translationally. In the absence of PS1, Pen-2 is rapidly degraded by the proteasome; increasing PS1 levels increases Pen-2 half-life and steady-state levels in a correlated manner confirmed both in cell culture and transgenic mice. Pulse-chase analysis, proteasome inhibitor studies, PS1 overexpression and knockout systems, transgenic mouse models Biochemistry High 15035625
2004 NCT, APH-1, PEN-2, and PS1 form a high-molecular-weight γ-secretase complex localized in mitochondria. γ-Secretase activity in isolated mitochondria was demonstrated using APP C-terminal fragment substrates, and activity was inhibited by γ-secretase inhibitors. Immunoelectron microscopy, subcellular fractionation, co-immunoprecipitation, in vitro γ-secretase activity assay with inhibitors The Journal of biological chemistry Medium 15456764
2003 Functional γ-secretase complex assembles and generates amyloid β-protein and APP intracellular domain in the Golgi/trans-Golgi network compartment. Interactions among PS1, NCT, Aph1, and Pen-2 occur specifically in Golgi/TGN fractions. Subcellular fractionation of membrane vesicles, co-immunoprecipitation, in vitro γ-secretase activity assay, immunofluorescence Neurobiology of disease Medium 14572442
2005 Pen-2 is incorporated into the γ-secretase complex through direct binding to transmembrane domain 4 (TMD4) of presenilin 1. The proximal two-thirds of PS1 TMD4, including the conserved Trp-Asn-Phe sequence, is required for interaction with Pen-2, demonstrated by TMD-swapping experiments. TMD swapping with CD4/CLAC-P chimeras in Psen1/Psen2-deficient cells, co-immunoprecipitation, functional reconstitution The Journal of biological chemistry High 16234244
2005 The 'NF' motif within TMD4 of PS1 is the minimal sequence required for binding to PEN-2, promoting PS1 endoproteolysis and γ-secretase activity. PS1 TMDs 1 and 2 are dispensable for PEN-2 binding; the proximal two-thirds of PEN-2 TMD1 is required for PS1 binding. PS1 deletion and chimeric mutants, co-immunoprecipitation with endogenous PEN-2, γ-secretase activity assay The Journal of biological chemistry High 16234243
2004 A sequence within the proximal two-thirds of PEN-2 transmembrane domain 1 (TMD1) is functionally critical for endoproteolysis of PS1 holoproteins and generation of PS1 fragments. The C-terminal hydrophilic domain of PEN-2 is dispensable for endoproteolysis but critical for stabilizing PS1 derivatives. Chimeric PEN-2 molecules with heterologous TMDs, deletion mutagenesis, co-expression with APH-1/NCT/PS1 in mammalian cells The Journal of biological chemistry High 15537629
2004 Both the conserved DYLSF domain (residues 90-94) at the PEN-2 C-terminus and the overall length of the C-terminus are critical for PEN-2 binding to other presenilin complex components and for functional γ-secretase activity. C-terminal deletion and mutagenesis of conserved residues, co-immunoprecipitation, γ-secretase activity assay The Journal of biological chemistry Medium 15322109
2005 The PS-fragment stabilizing function of PEN-2 depends on the length and overall sequence of its C-terminal domain; progressive C-terminal truncation causes increasing loss of this stabilizing function. Loss-of-function PEN-2 C-terminal mutants permit PS1 endoproteolysis but fail to stably associate with the resulting PS1 fragments, which undergo proteasomal degradation. PEN-2 C-terminal deletion and point mutagenesis, stable RNAi knockdown rescue, co-immunoprecipitation, proteasome inhibitor studies Journal of neurochemistry Medium 15953349
2007 Unassembled Pen-2 is retained/retrieved to the endoplasmic reticulum through direct binding to Rer1 (Retention in ER 1). This binding is mediated by the first transmembrane domain of Pen-2, with a conserved asparagine in this domain required. Knockdown of Rer1 increases surface localization of Pen-2; overexpression stabilizes unassembled Pen-2. Co-immunoprecipitation, RNAi knockdown of Rer1, overexpression studies, surface localization assay EMBO reports Medium 17668005
2007 N-terminal elongation of Pen-2 specifically increases generation of Aβ42 by affecting the water accessibility of the luminal side of the PS1 catalytic pore, as shown by substituted cysteine accessibility method (SCAM). Pen-2 directly affects the Aβ42-generating activity of γ-secretase in vitro. N-terminal elongation mutagenesis, in vitro γ-secretase assay, substituted cysteine accessibility method (SCAM) The Journal of biological chemistry High 17329245
2004 PEN-2 enhances γ-cleavage after presenilin heterodimer formation without affecting the heterodimer formation itself. Overexpression of PEN-2 in PS-null cells expressing PS1 NTF/CTF increases Aβ generation and reduces IC50 of a transition state analogue γ-secretase inhibitor, suggesting PEN-2 enhances substrate accessibility to the catalytic site. PS1 NTF/CTF co-expression in PS-null cells, Aβ generation assay, γ-secretase inhibitor IC50 determination Journal of neurochemistry Medium 15341524
2006 Knockdown of Pen-2 in zebrafish leads to reduction of islet-1 positive neurons, reduced Notch signaling, and massive p53-dependent apoptosis. Neuronal loss can be suppressed by simultaneous p53 knockdown, establishing that Pen-2 promotes neuronal survival through suppression of a p53-dependent apoptotic pathway. Antisense morpholino knockdown in zebrafish, in vivo imaging, double knockdown epistasis with p53 Journal of neurochemistry Medium 16464238
2006 PEN-2 transcription is regulated by CREB. A CREB binding site within 238 bp upstream of the PEN-2 translational start codon is essential for promoter activity; mutation of this site abolishes transcription. Forskolin (CREB activator) dramatically promotes PEN-2 mRNA and protein expression without affecting other γ-secretase components. Promoter deletion analysis, CREB site mutagenesis, EMSA, chromatin immunoprecipitation, forskolin stimulation Molecular and cellular biology Medium 16449647
2010 A trimeric PS1/Pen2/Aph1a complex is an active γ-secretase enzyme capable of cleaving Notch and APP substrates in the absence of nicastrin. NCT-independent activity requires PS1, Pen2, and Aph1a but tolerates knockdown of PS2 or Aph1b. NCT acts to stabilize γ-secretase but is not required for substrate recognition. NCT-deficient mouse embryonic fibroblasts, siRNA knockdown, γ-secretase inhibitor treatment, endogenous Notch cleavage assay The Journal of neuroscience High 20130175
2011 Glycine 22 and proline 27 in hydrophobic domain 1 of Pen-2 are essential for γ-secretase complex formation and stability. Hydrophobic domain 1 and the loop domain of Pen-2 reside in a water-containing cavity in proximity to the PS C-terminal fragment, supporting a role for Pen-2 in the catalytic mechanism beyond structural scaffolding. Pen-2 knockout fibroblasts, scanning cysteine accessibility method (SCAM), point mutagenesis, rescue assays The Journal of biological chemistry High 21296884
2011 Polar amino acids in TMD4 of PS1 mediate Pen2 binding through a single asparagine that interacts with an asparagine in Pen2. Additional polar residues in PS1 TMD4 form an interface important for ER retention/retrieval and complex stabilization. Alanine-scanning mutagenesis of PS1 TMD4 polar residues, co-immunoprecipitation with Pen2, ER retention assay The Journal of biological chemistry Medium 21914807
2013 PEN-2 directly interacts with ferritin light chain (FTL). Overexpression of FTL increases PEN-2 and PS1 NTF protein levels and promotes γ-secretase activity; downregulation of FTL decreases PEN-2 and PS1 NTF levels, establishing FTL as a regulator of PEN-2 stability and γ-secretase activity. Co-immunoprecipitation, overexpression and siRNA knockdown of FTL, γ-secretase activity assay (NICD and Aβ production) Neuroscience letters Medium 23685131
2014 Systematic mutagenesis reveals that mutations in the first half of PEN-2 TMD1 decrease PS1 endoproteolysis and γ-secretase activity; mutations in the second half of TMD1 increase activity; mutations in the cytosolic loop decrease activity; mutations within TMD2 decrease PS1 endoproteolysis and activity; and C-terminal residue mutations decrease activity. Minor PS1 endoproteolysis can occur in the complete absence of Pen-2. Systematic mutagenesis across all Pen-2 domains, γ-secretase activity assay, PS1 endoproteolysis assay, complex trafficking and stability assays Biochemistry High 24941111
2015 The first hydrophobic domain (HP1) of Pen-2 forms a reentrant loop rather than a transmembrane domain, with the N-terminus exposed to the cytoplasm (not lumenal as previously reported) and the C-terminus lumenal. This revised topology applies to endogenous Pen-2 stably expressed in mammalian cells. The first 14 amino acids of HP1 are required for γ-secretase activity. Epitope accessibility in stably expressing cells, domain swapping with chimeras, functional rescue in Pen-2-deficient fibroblasts Molecular neurodegeneration Medium 26296997
2019 Conditional knockout of Pen-2 in neural progenitor cells causes rapid depletion of apical progenitors (APs) and accelerated switch to basal progenitors (BPs) in the developing neocortex. Mechanistically, Pen-2 loss decreases Hes1/Hes5 and increases Ngn2/NeuroD1 levels; reintroduction of Notch1 intracellular domain (NICD) restores the AP/BP balance, placing Pen-2 upstream of Notch signaling in maintaining neural stem cells. Conditional knockout mouse (Nes-Cre), molecular marker analysis, rescue with NICD expression, in vivo neurogenesis assay The Journal of neuroscience High 30692224
2021 PSENEN/PEN2 knockout causes γ-secretase-independent alterations in the autophagy-lysosome system, including reduced lysosomal enzyme activity, reduced lysosome number, increased autophagosome number, increased lysosome-autophagosome fusion, and elevated TFEB levels. PEN2 interacts with CLN3 (identified by screening). These autophagy-lysosomal effects are independent of γ-secretase catalytic activity. CRISPR knockout of PSENEN and CLN3 in HeLa cells, lysosomal enzyme activity assay, immunocytochemistry for lysosome/autophagosome markers, TFEB quantification, tandem affinity purification for interactor screen Autophagy Medium 34964690
2022 PEN2 is a direct binding partner of metformin at clinically relevant (micromolar) concentrations, identified by a photoactive metformin probe. Metformin-bound PEN2 forms a complex with ATP6AP1 (a v-ATPase subunit), leading to v-ATPase inhibition and AMPK activation without changes in cellular AMP levels. Knockout of PEN2, or re-introduction of a PEN2 mutant that cannot bind ATP6AP1, blunts AMPK activation. Liver-specific Pen2 KO abolishes metformin-mediated hepatic fat reduction; intestine-specific Pen2 KO impairs glucose-lowering; pen-2 knockdown in C. elegans abrogates metformin-induced lifespan extension. Photoactive metformin probe crosslinking and pull-down, SPR/ITC for dissociation constant, co-IP of PEN2-ATP6AP1 complex, tissue-specific conditional KO mice, v-ATPase activity assay, AMPK activation assay, C. elegans lifespan assay Nature High 35197629
2009 Pen2 overexpression or PS1 FAD mutations alter the dynamic equilibrium between PS1- and PS2-containing active γ-secretase complexes. Formation of PS2-containing complexes positively correlates with increased Aβ42:Aβ40 ratios, suggesting that Pen2 modulates γ-secretase cleavage specificity through effects on complex composition equilibrium. Small molecule affinity probes to characterize active complexes, in vitro γ-secretase assay, Pen2 overexpression The Journal of biological chemistry Medium 19036728
2009 Both presenilins regulate Pen2 promoter transactivation: presenilin depletion drastically reduces Pen2 mRNA and promoter activity; this regulation depends on γ-secretase activity and involves AICD (APP intracellular domain). p53 is required for Pen2 transcription; Pen2 expression is reduced in p53-knockout fibroblasts and mouse brain. Promoter transactivation assay, qRT-PCR, knockout fibroblasts (PS-null, p53-null, APP-null), AICD rescue, reporter assay Journal of cell science Medium 19889971
2007 Overexpression of Pen-2 (or Aph-1a/b) in neuronal TSM1 cells reduces staurosporine- and etoposide-induced apoptosis in a p53-dependent manner, lowering p53 expression and caspase-3 activity. This anti-apoptotic phenotype requires the molecular integrity of the γ-secretase complex (absent in PS-null or NCT-null cells) but is independent of γ-secretase catalytic activity (not blocked by γ-secretase inhibitors). TUNEL assay, DNA fragmentation, caspase-3 activity assay, p53 reporter, siRNA knockdown of Pen-2/Aph-1, γ-secretase inhibitor treatment, PS-null and NCT-null fibroblasts The Journal of biological chemistry Medium 17276981
2009 PSENEN (PSENEN/PEN2) is involved in adipocyte differentiation via Notch signaling. Ectopic expression of PSENEN in 3T3-L1 reduces adipogenesis; siRNA-mediated knockdown of PSENEN induces adipogenesis. Notch signaling genes (Notch-1, Hes-1, Pref-1) are regulated by PSENEN expression during adipocyte differentiation. PSENEN overexpression and siRNA knockdown in 3T3-L1 cells, adipogenesis assay, Notch signaling gene expression analysis Domestic animal endocrinology Low 19592191
2017 Heterozygous truncating mutations in PSENEN cause Dowling-Degos disease (DDD) associated with acne inversa. In vivo monitoring of pigment cells in psenen-knockdown zebrafish larvae demonstrated that disturbances in melanocyte migration and differentiation underlie the DDD pathogenesis associated with PSENEN mutations. PSENEN mutation screening, zebrafish morpholino knockdown with in vivo live imaging of melanocyte migration and differentiation The Journal of clinical investigation Medium 28287404
2017 PSENEN mutations causing combined Dowling-Degos disease and hidradenitis suppurativa/acne inversa lead to decreased Notch signaling activity, demonstrated by reporter assay in patient keratinocytes carrying the c.168T>G (p.Y56X) mutation. Notch signaling reporter assay in patient-derived keratinocytes, haplotype analysis confirming founder mutation The British journal of dermatology Medium 28922471

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron 808 12691659
2002 aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Developmental cell 691 12110170
2003 Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proceedings of the National Academy of Sciences of the United States of America 656 12740439
2022 Low-dose metformin targets the lysosomal AMPK pathway through PEN2. Nature 492 35197629
1991 Lack of antinociceptive cross-tolerance between [D-Pen2, D-Pen5]enkephalin and [D-Ala2]deltorphin II in mice: evidence for delta receptor subtypes. The Journal of pharmacology and experimental therapeutics 252 1650835
2002 PEN-2 is an integral component of the gamma-secretase complex required for coordinated expression of presenilin and nicastrin. The Journal of biological chemistry 244 12198112
2004 Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria. The Journal of biological chemistry 209 15456764
2003 PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1. The Journal of biological chemistry 200 12522139
1987 Role of mu and delta receptors in the supraspinal and spinal analgesic effects of [D-Pen2, D-Pen5]enkephalin in the mouse. The Journal of pharmacology and experimental therapeutics 192 3033214
1989 Modulation of mu-mediated antinociception by delta agonists in the mouse: selective potentiation of morphine and normorphine by [D-Pen2,D-Pen5]enkephalin. European journal of pharmacology 119 2548877
2004 Detergent-dependent dissociation of active gamma-secretase reveals an interaction between Pen-2 and PS1-NTF and offers a model for subunit organization within the complex. Biochemistry 113 14717586
2006 Zebrafish lacking Alzheimer presenilin enhancer 2 (Pen-2) demonstrate excessive p53-dependent apoptosis and neuronal loss. Journal of neurochemistry 105 16464238
1997 The mu-opioid receptor is necessary for [D-Pen2,D-Pen5]enkephalin-induced analgesia. European journal of pharmacology 105 9145787
2004 Requirement of PEN-2 for stabilization of the presenilin N-/C-terminal fragment heterodimer within the gamma-secretase complex. The Journal of biological chemistry 104 15039426
2005 Pen-2 is incorporated into the gamma-secretase complex through binding to transmembrane domain 4 of presenilin 1. The Journal of biological chemistry 103 16234244
2003 Presenilins mutated at Asp-257 or Asp-385 restore Pen-2 expression and Nicastrin glycosylation but remain catalytically inactive in the absence of wild type Presenilin. The Journal of biological chemistry 99 12885769
1988 Beta-endorphin-(1-27) antagonizes beta-endorphin- but not morphine-, D-Pen2-D-Pen5-enkephalin- and U50, 488H-induced analgesia in mice. Neuropharmacology 93 2972939
2003 Functional gamma-secretase complex assembly in Golgi/trans-Golgi network: interactions among presenilin, nicastrin, Aph1, Pen-2, and gamma-secretase substrates. Neurobiology of disease 91 14572442
1992 Systemic analgesic activity and delta-opioid selectivity in [2,6-dimethyl-Tyr1,D-Pen2,D-Pen5]enkephalin. Journal of medicinal chemistry 89 1311764
1989 A high affinity, highly selective ligand for the delta opioid receptor: [3H]-[D-Pen2, pCl-Phe4, d-Pen5]enkephalin. Life sciences 84 2552241
2010 Gamma-secretase composed of PS1/Pen2/Aph1a can cleave notch and amyloid precursor protein in the absence of nicastrin. The Journal of neuroscience : the official journal of the Society for Neuroscience 78 20130175
2003 Membrane topology of gamma-secretase component PEN-2. The Journal of biological chemistry 78 12639958
1990 [D-Pen2,D-Pen5]enkephalin analogues with increased affinity and selectivity for delta opioid receptors. Journal of medicinal chemistry 77 2153205
2017 Mutations in γ-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa. The Journal of clinical investigation 76 28287404
1993 Evidence for delta opioid receptor subtypes in rat spinal cord: studies with intrathecal naltriben, cyclic[D-Pen2, D-Pen5] enkephalin and [D-Ala2, Glu4]deltorphin. The Journal of pharmacology and experimental therapeutics 75 8394918
2007 Endoplasmic reticulum retention of the gamma-secretase complex component Pen2 by Rer1. EMBO reports 72 17668005
1992 Whole body and brain distribution of [3H]cyclic [D-Pen2,D-Pen5] enkephalin after intraperitoneal, intravenous, oral and subcutaneous administration. The Journal of pharmacology and experimental therapeutics 70 1469637
2005 Evidence that the "NF" motif in transmembrane domain 4 of presenilin 1 is critical for binding with PEN-2. The Journal of biological chemistry 69 16234243
2004 Pen-2 is sequestered in the endoplasmic reticulum and subjected to ubiquitylation and proteasome-mediated degradation in the absence of presenilin. The Journal of biological chemistry 67 14724271
2007 Abeta42 overproduction associated with structural changes in the catalytic pore of gamma-secretase: common effects of Pen-2 N-terminal elongation and fenofibrate. The Journal of biological chemistry 62 17329245
2005 Ubiquilin regulates presenilin endoproteolysis and modulates gamma-secretase components, Pen-2 and nicastrin. The Biochemical journal 61 15975090
2004 A sequence within the first transmembrane domain of PEN-2 is critical for PEN-2-mediated endoproteolysis of presenilin 1. The Journal of biological chemistry 58 15537629
2017 A phenotype combining hidradenitis suppurativa with Dowling-Degos disease caused by a founder mutation in PSENEN. The British journal of dermatology 55 28922471
2004 Functional reconstitution of gamma-secretase through coordinated expression of presenilin, nicastrin, Aph-1, and Pen-2. Journal of neuroscience research 54 15248287
2004 Immature nicastrin stabilizes APH-1 independent of PEN-2 and presenilin: identification of nicastrin mutants that selectively interact with APH-1. Journal of neurochemistry 53 15189355
2004 Both the sequence and length of the C terminus of PEN-2 are critical for intermolecular interactions and function of presenilin complexes. The Journal of biological chemistry 53 15322109
1992 Ring substituted and other conformationally constrained tyrosine analogues of [D-Pen2,D-Pen5]enkephalin with delta opioid receptor selectivity. Journal of medicinal chemistry 50 1320122
1989 Differential modulation by [D-Pen2, D-Pen5]enkephalin and dynorphin A-(1-17) of the inhibitory bladder motility effects of selected mu agonists in vivo. The Journal of pharmacology and experimental therapeutics 50 2566676
2008 Pen2 and presenilin-1 modulate the dynamic equilibrium of presenilin-1 and presenilin-2 gamma-secretase complexes. The Journal of biological chemistry 48 19036728
1994 Interaction of [D-Pen2,D-Pen5]enkephalin and [D-Ala2,Glu4]deltorphin with delta-opioid receptor subtypes in vivo. European journal of pharmacology 48 8157053
1995 Contrasting actions of intrathecal U50,488H, morphine, or [D-Pen2, D-Pen5] enkephalin or intravenous U50,488H on the visceromotor response to colorectal distension in the rat. Anesthesiology 42 7631956
2011 Functional and topological analysis of Pen-2, the fourth subunit of the gamma-secretase complex. The Journal of biological chemistry 38 21296884
2004 Presenilin modulates Pen-2 levels posttranslationally by protecting it from proteasomal degradation. Biochemistry 36 15035625
2013 Ferritin light chain interacts with PEN-2 and affects γ-secretase activity. Neuroscience letters 35 23685131
2006 Transcriptional regulation of PEN-2, a key component of the gamma-secretase complex, by CREB. Molecular and cellular biology 34 16449647
2001 Pharmacodynamic and pharmacokinetic characterization of poly(ethylene glycol) conjugation to met-enkephalin analog [D-Pen2, D-Pen5]-enkephalin (DPDPE). The Journal of pharmacology and experimental therapeutics 34 11454951
2016 Novel Mutations in PSENEN Gene in Two Chinese Acne Inversa Families Manifested as Familial Multiple Comedones and Dowling-Degos Disease. Chinese medical journal 32 27900998
2004 Hepatobiliary disposition of the metabolically stable opioid peptide [D-Pen2, D-Pen5]-enkephalin (DPDPE): pharmacokinetic consequences of the interplay between multiple transport systems. The Journal of pharmacology and experimental therapeutics 32 15302892
1989 The antinociception produced by intrathecal morphine, calcium, A23187, U50,488H, [D-Ala2, N-Me-Phe4, Gly-ol]enkephalin and [D-Pen2, D-Pen5]enkephalin after intrathecal administration of calcitonin gene-related peptide in mice. The Journal of pharmacology and experimental therapeutics 32 2552070
1985 Studies in vitro with ICI 174,864, [D-Pen2, D-Pen5]-enkephalin (DPDPE) and [D-Ala2, NMePhe4, Gly-ol]-enkephalin (DAGO). Neuropeptides 32 2987739
1997 Effect of 7-nitroindazole on tolerance to morphine, U-50,488H and [D-Pen2, D-Pen5] enkephalin in mice. Peptides 29 9285927
1996 Effect of nitric oxide synthase inhibition on tolerance to the analgesic action of D-Pen2, D-Pen5 enkephalin and morphine in the mouse. Neuropeptides 29 8819145
1996 Effect of antagonism of the NMDA receptor on tolerance to [D-Pen2,D-Pen5]enkephalin, a delta 1-opioid receptor agonist. Peptides 27 8801526
2005 Length and overall sequence of the PEN-2 C-terminal domain determines its function in the stabilization of presenilin fragments. Journal of neurochemistry 26 15953349
2003 Spinal nitric oxide contributes to the analgesic effect of intrathecal [d-pen2,d-pen5]-enkephalin in normal and diabetic rats. Anesthesiology 26 12503000
1997 Binding of [3H][D-Ala2, MePhe4, Gly-ol5] enkephalin, [3H][D-Pen2, D-Pen5]enkephalin, and [3H]U-69,593 to airway and pulmonary tissues of normal and sensitized rats. Peptides 26 9437722
2007 p53-Dependent Aph-1 and Pen-2 anti-apoptotic phenotype requires the integrity of the gamma-secretase complex but is independent of its activity. The Journal of biological chemistry 25 17276981
1993 Cocaine-like discriminative stimulus properties of the delta-selective opioid receptor agonist, [D-Pen2,L-Pen5]enkephalin, in the rat. European journal of pharmacology 25 8383062
2014 Pen-2 is essential for γ-secretase complex stability and trafficking but partially dispensable for endoproteolysis. Biochemistry 24 24941111
2005 Effects of RNAi-mediated silencing of PEN-2, APH-1a, and nicastrin on wild-type vs FAD mutant forms of presenilin 1. Journal of molecular neuroscience : MN 23 15781968
1985 Comparative binding properties of linear and cyclic delta-selective enkephalin analogues: [3H]-[D-Thr2, Leu5] enkephalyl-Thr6 and [3H]-[D-Pen2, D-Pen5] enkephalin. FEBS letters 23 2985440
2004 PEN-2 enhances gamma-cleavage after presenilin heterodimer formation. Journal of neurochemistry 22 15341524
1992 Lack of antinociceptive efficacy of intracerebroventricular [D-Ala2,Glu4]deltorphin, but not [D-Pen2,D-Pen5]enkephalin, in the mu-opioid receptor deficient CXBK mouse. European journal of pharmacology 22 1330585
1991 [D-Pen2,4'-125I-Phe4,D-Pen5]enkephalin: a selective high affinity radioligand for delta opioid receptors with exceptional specific activity. The Journal of pharmacology and experimental therapeutics 22 1653834
1991 Chronic effect of [D-Pen2,D-Pen5]enkephalin on rat brain opioid receptors. European journal of pharmacology 22 1665782
2005 Characterization of the reconstituted gamma-secretase complex from Sf9 cells co-expressing presenilin 1, nicastrin [correction of nacastrin], aph-1a, and pen-2. Biochemistry 21 15766275
1989 Multi-dimensional analysis of behavior in mice treated with the delta opioid agonists DADL (D-Ala2-D-Leu5-enkephalin) and DPLPE (D-Pen2-L-Pen5-enkephalin). Neuropharmacology 21 2554179
2021 Converging roles of PSENEN/PEN2 and CLN3 in the autophagy-lysosome system. Autophagy 19 34964690
2009 p53-dependent control of transactivation of the Pen2 promoter by presenilins. Journal of cell science 19 19889971
2005 PEN-2 gene mutation in a familial Alzheimer's disease case. Journal of neurology 19 16170650
1992 Central opioid modulation of breathing dynamics in the fetal lamb: effects of [D-Pen2,D-Pen5]-enkephalin and partial antagonism by naltrindole. The Journal of pharmacology and experimental therapeutics 18 1326619
1992 Morphine, D-Pen2, D-Pen5 enkephalin and U50,488H differentially affect the locomotor activity and behaviours induced by quinpirole in guinea-pigs. Psychopharmacology 18 1603903
2006 Catabolism of endogenous and overexpressed APH1a and PEN2: evidence for artifactual involvement of the proteasome in the degradation of overexpressed proteins. The Biochemical journal 16 16302845
1997 Effects of multiple intracerebroventricular injections of [D-Pen2,D-Pen5]enkephalin and [D-Ala2,Glu4]deltorphin II on tolerance to their analgesic action and on brain delta-opioid receptors. Brain research 16 9037415
1995 Differential modulation by muscimol and baclofen on antinociception induced by morphine, beta-endorphin, D-Pen2,5-enkephalin and U50,488H administered intracerebroventricularly in the mouse. Naunyn-Schmiedeberg's archives of pharmacology 16 9053732
1994 [D-Pen2-D-Pen5]enkephalin, a delta opioid agonist, given intracerebroventricularly in the mouse produces antinociception through medication of spinal GABA receptors. Pharmacology, biochemistry, and behavior 16 7862723
1991 Probing the opioid receptor complex with (+)-trans-superfit. I. Evidence that [D-Pen2,D-Pen5]enkephalin interacts with high affinity at the delta cx binding site. Peptides 16 1648715
1987 [D-Pen2,L-Pen5]enkephalin induced analgesia in the jimpy mouse: in vivo evidence for delta-receptor mediated analgesia. European journal of pharmacology 16 3038573
2020 Angiopoietin-1 accelerates Alzheimer's disease via FOXA2/PEN2/APP pathway in APP/PS1 mice. Life sciences 15 32061671
2019 Conditional Inactivation of Pen-2 in the Developing Neocortex Leads to Rapid Switch of Apical Progenitors to Basal Progenitors. The Journal of neuroscience : the official journal of the Society for Neuroscience 15 30692224
2015 The topology of pen-2, a γ-secretase subunit, revisited: evidence for a reentrant loop and a single pass transmembrane domain. Molecular neurodegeneration 15 26296997
1992 Delta-opioid-receptor activation by [D-Pen2,D-Pen5]enkephalin and morphine inhibits substance P release from trigeminal nucleus slices. European journal of pharmacology 15 1282103
1990 [D-Pen2, D-Pen5]enkephalin, the standard delta opioid agonist, induces morphine-like behaviors in mice. Psychopharmacology 15 2251341
2015 A Frameshift Mutation in PEN-2 Causes Familial Comedones Syndrome. Dermatology (Basel, Switzerland) 14 26044244
2015 Propylthiouracil Attenuates Experimental Pulmonary Hypertension via Suppression of Pen-2, a Key Component of Gamma-Secretase. PloS one 14 26367462
2012 Pen-2 is dispensable for endoproteolysis of presenilin 1, and nicastrin-Aph subcomplex is important for both γ-secretase assembly and substrate recruitment. Journal of neurochemistry 14 22973949
1997 Effect of chronic administration of morphine, U-50, 488H and [D-Pen2, D-Pen5]enkephalin on the concentration of cGMP in brain regions and spinal cord of the mouse. Peptides 14 9437726
1996 Conformational analysis of beta-methyl-para-nitrophenylalanine stereoisomers of cyclo[D-Pen2, D-Pen5]enkephalin by NMR spectroscopy and conformational energy calculations. Biopolymers 14 8589249
1991 Comparative conformational analysis of [D-Pen2,D-Pen5]enkephalin (DPDPE): a molecular mechanics study. Journal of computer-aided molecular design 14 1795179
1990 Single residue modifications of the delta opioid receptor selective peptide, [D-Pen2,D-Pen5]-enkephalin (DPDPE). Correlation of pharmacological effects with structural and conformational features. International journal of peptide and protein research 14 2177042
2002 Role of spinal nitric oxide in the inhibitory effect of [D-Pen2, D-Pen5]-enkephalin on ascending dorsal horn neurons in normal and diabetic rats. The Journal of pharmacology and experimental therapeutics 13 12438523
2004 PEN2 is not a genetic risk factor for Alzheimer's disease in a large family sample. Neurology 12 14745076
2011 Polar transmembrane-based amino acids in presenilin 1 are involved in endoplasmic reticulum localization, Pen2 protein binding, and γ-secretase complex stabilization. The Journal of biological chemistry 11 21914807
1996 Discriminative stimulus effects of a centrally administered, delta-opioid peptide (D-Pen2-D-Pen5-enkephalin) in pigeons. Psychopharmacology 11 8912400
1991 Delta opioid receptor-selective ligands: [D-Pen2,D-Pen5]enkephalin-dermenkephalin chimeric peptides. Life sciences 11 1650414
2023 Berberine stimulates lysosomal AMPK independent of PEN2 and maintains cellular AMPK activity through inhibiting the dephosphorylation regulator UHRF1. Frontiers in pharmacology 10 37144221
2012 Human PSENEN and U2AF1L4 genes are concertedly regulated by a genuine bidirectional promoter. Gene 10 23246698
2009 Presenilin enhancer-2 (PSENEN), a component of the gamma-secretase complex, is involved in adipocyte differentiation. Domestic animal endocrinology 10 19592191
2007 Genetic association between polymorphisms of Pen2 gene and late onset Alzheimer's disease in the North Chinese population. Brain research 10 17280645
1988 Role of steric interactions in the delta opioid receptor selectivity of [D-Pen2, D-Pen5]enkephalin. International journal of peptide and protein research 10 2851561

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