Gene Symbol: PSENEN
Description: presenilin enhancer, gamma-secretase subunit
Alias: ACNINV2, MDS033, MSTP064, PEN-2, PEN2, gamma-secretase subunit PEN-2, hematopoietic stem/progenitor cells protein MDS033, presenilin enhancer 2 homolog
Species: human
Products:     PSENEN

Top Publications

  1. Marlow L, Canet R, Haugabook S, Hardy J, Lahiri D, Sambamurti K. APH1, PEN2, and Nicastrin increase Abeta levels and gamma-secretase activity. Biochem Biophys Res Commun. 2003;305:502-9 pubmed
    ..Recent genetic studies have identified a number of additional genes encoding APH1a, APH1b, PEN2, and Nicastrin proteins, which are part of the gamma-secretase complex with PS1...
  2. Fraering P, Ye W, Strub J, Dolios G, LaVoie M, Ostaszewski B, et al. Purification and characterization of the human gamma-secretase complex. Biochemistry. 2004;43:9774-89 pubmed
  3. He G, Luo W, Li P, Remmers C, Netzer W, Hendrick J, et al. Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease. Nature. 2010;467:95-8 pubmed publisher
    ..Thus, GSAP can serve as an amyloid-beta-lowering therapeutic target without affecting other key functions of gamma-secretase. ..
  4. Chen F, Hasegawa H, Schmitt Ulms G, Kawarai T, Bohm C, Katayama T, et al. TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity. Nature. 2006;440:1208-12 pubmed
    ..Here we report that TMP21, a member of the p24 cargo protein family, is a component of presenilin complexes and differentially regulates gamma-secretase cleavage without affecting epsilon-secretase activity. ..
  5. Placanica L, Tarassishin L, Yang G, Peethumnongsin E, Kim S, Zheng H, et al. Pen2 and presenilin-1 modulate the dynamic equilibrium of presenilin-1 and presenilin-2 gamma-secretase complexes. J Biol Chem. 2009;284:2967-77 pubmed publisher
    ..reveal that the equilibrium of PS1- and PS2-containing active complexes is dynamic and altered by overexpression of Pen2 or PS1 mutants and that formation of PS2 complexes is positively correlated with increased Abeta42:Abeta40 ratios...
  6. Ahn K, Shelton C, Tian Y, Zhang X, Gilchrist M, Sisodia S, et al. Activation and intrinsic gamma-secretase activity of presenilin 1. Proc Natl Acad Sci U S A. 2010;107:21435-40 pubmed publisher
    ..Thus, γ-secretase cleavage specificity is an inherent property of the polypeptide. Finally, we demonstrate that PEN2 is sufficient to promote the endoproteolysis of PS1 to generate the active form of γ-secretase...
  7. Lu Q, Ding K, Frosch M, Jones S, Wolfe M, Xia W, et al. Alzheimer's disease-linked presenilin mutation (PS1M146L) induces filamin expression and ?-secretase independent redistribution. J Alzheimers Dis. 2010;22:235-45 pubmed publisher
    ..These studies support a ?-secretase-independent role of PS1 in modulation of filamin-mediated actin cytoskeleton. ..
  8. Barthet G, Shioi J, Shao Z, Ren Y, Georgakopoulos A, Robakis N. Inhibitors of γ-secretase stabilize the complex and differentially affect processing of amyloid precursor protein and other substrates. FASEB J. 2011;25:2937-46 pubmed publisher
    ..Furthermore, our observations have implications for GSIs as therapeutics because processing of functionally important substrates may be inhibited at lower concentrations than Aβ. ..
  9. Dettmer U, Kuhn P, Abou Ajram C, Lichtenthaler S, Kruger M, Kremmer E, et al. Transmembrane protein 147 (TMEM147) is a novel component of the Nicalin-NOMO protein complex. J Biol Chem. 2010;285:26174-81 pubmed publisher
    ..We conclude that TMEM147 is a novel core component of the Nicalin-NOMO complex, further emphasizing its similarity with gamma-secretase. ..

More Information

Publications143 found, 100 shown here

  1. Matern A, Bottcher C, Eschen Lippold L, Westermann B, Smolka U, Döll S, et al. A substrate of the ABC transporter PEN3 stimulates bacterial flagellin (flg22)-induced callose deposition in Arabidopsis thaliana. J Biol Chem. 2019;294:6857-6870 pubmed publisher
    ..i>Arabidopsis thaliana controls pathogen entry through the penetration-resistance genes PEN2 and PEN3, encoding an atypical myrosinase and an ABC transporter, respectively, required for synthesis ..
  2. Ohwaki H, Yoshinari N, Konno T. Crystal-to-crystal interconversion of open and closed dicopper(ii) paddle wheels in a heterotrimetallic coordination polymer. Chem Commun (Camb). 2019;: pubmed publisher
  3. Cheng S, Liu T, Hu Y, Xia Y, Hou J, Huang C, et al. Conditional Inactivation of Pen-2 in the Developing Neocortex Leads to Rapid Switch of Apical Progenitors to Basal Progenitors. J Neurosci. 2019;39:2195-2207 pubmed publisher
    ..Presenilin enhancer 2 (Pen-2, also named as Psenen) is a key subunit of γ-secretase and has been implicated in neurodevelopmental disease...
  4. Jacobs B, Pando M, Jennings E, Jamshidi R, Zamora J, Chavera T, et al. Signaling characteristics and functional regulation of delta opioid-kappa opioid receptor (DOP-KOP) heteromers in peripheral sensory neurons. Neuropharmacology. 2019;: pubmed publisher
    ..the properties of the DOP-KOP heteromer agonist, 6'-guanidinonaltrindole (6'-GNTI), with agonists for DOP ([D-Pen2,5]-enkephalin [DPDPE]) and KOP (U50488) in peripheral sensory neurons in culture and in vivo...
  5. Nakandakari S, Muñoz V, Kuga G, Gaspar R, Sant Ana M, Pavan I, et al. Short-term high-fat diet modulates several inflammatory, ER stress, and apoptosis markers in the hippocampus of young mice. Brain Behav Immun. 2019;: pubmed publisher
    ..pTau, TNFα, IL1β, pJNK, PTP1B, peIF2α, CHOP, Caspase3, Cleaved-Caspase3 and Alzheimer-related genes (Bax, PS1, PEN2, Aph1b)...
  6. Moniruzzaman M, Ishihara S, Nobuhara M, Higashide H, Funamoto S. Glycosylation status of nicastrin influences catalytic activity and substrate preference of γ-secretase. Biochem Biophys Res Commun. 2018;502:98-103 pubmed publisher
    ..Our data suggests that thorough glycosylation of NCT is critical for enzymatic activity and substrate preference of γ-secretase. ..
  7. Yusof H, Lee H, Seth E, Wu X, Hewitt C, Scott H, et al. Expression Profiling of Notch Signalling Pathway and Gamma-Secretase Activity in the Brain of Ts1Cje Mouse Model of Down Syndrome. J Mol Neurosci. 2019;67:632-642 pubmed publisher
    ..In summary, the association and the role of Notch and gamma-secretase gene expression throughout development with neurogenic-to-gliogenic shift in Ts1Cje remain undefined and warrant further validation. ..
  8. Kuo L, Hu M, Hsu W, Tung Y, Wang B, Tsai W, et al. Tumor necrosis factor-alpha-elicited stimulation of gamma-secretase is mediated by c-Jun N-terminal kinase-dependent phosphorylation of presenilin and nicastrin. Mol Biol Cell. 2008;19:4201-12 pubmed publisher
    ..Together, our findings strongly suggest that JNK is a critical intracellular mediator of TNF-alpha-elicited regulation of gamma-secretase and governs the pivotal step in the assembly of functional gamma-secretase. ..
  9. Meng M, Ning J, Yu J, Chen D, Meng X, Xu J, et al. Antitumor activity of recombinant antimicrobial peptide penaeidin-2 against kidney cancer cells. J Huazhong Univ Sci Technolog Med Sci. 2014;34:529-534 pubmed publisher
    ..These results suggest that rPen-2 is a novel potential therapeutic agent that may be useful in treating kidney cancers. ..
  10. Inoue M, Hur J, Kihara T, Teranishi Y, Yamamoto N, Ishikawa T, et al. Human brain proteins showing neuron-specific interactions with γ-secretase. FEBS J. 2015;282:2587-99 pubmed publisher
  11. Meckler X, Checler F. Presenilin 1 and Presenilin 2 Target ?-Secretase Complexes to Distinct Cellular Compartments. J Biol Chem. 2016;291:12821-37 pubmed publisher
    ..They are composed of two constant subunits, nicastrin and PEN2, and two variable ones, presenilin (PS1 or PS2) and APH1 (APH1aL, APH1aS, or APH1b)...
  12. Xu G, Yang L, Guan P, Wang Z, Wang P. Prostaglandin A1 Inhibits the Cognitive Decline of APP/PS1 Transgenic Mice via PPARγ/ABCA1-dependent Cholesterol Efflux Mechanisms. Neurotherapeutics. 2019;: pubmed publisher
    ..The actions of PGA1 on the production and deposition of Aβ ultimately improved the cognitive decline of the amyloid precursor protein/presenilin1 (APP/PS1) transgenic mice. ..
  13. Wolfe M. Toward the structure of presenilin/γ-secretase and presenilin homologs. Biochim Biophys Acta. 2013;1828:2886-97 pubmed publisher
    ..This article is part of a Special Issue entitled: Intramembrane Proteases. ..
  14. Ali M, Heyob K, Velten M, Tipple T, Rogers L. DHA suppresses chronic apoptosis in the lung caused by perinatal inflammation. Am J Physiol Lung Cell Mol Physiol. 2015;309:L441-8 pubmed publisher
    ..Modest but inconsistent differences were observed in Notch-pathway proteins Jagged 1, DLL 1, PEN2, and presenilin-2...
  15. Jiang F, Sun F, Xu S. [Effect of βsheet blocking peptide H102 on APP metabolic enzymes in hippocampal brain of double transgenic AD mice]. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2017;33:299-303 pubmed publisher
    ..were used to detect the content of α-secretase (ADAM10, ADAM17), β-secretase (BACE1), γ-secretase (PS1, APH1a, PEN2) in the hippocampus brain regions...
  16. Hiruma K, Gerlach N, Sacristan S, Nakano R, Hacquard S, Kracher B, et al. Root Endophyte Colletotrichum tofieldiae Confers Plant Fitness Benefits that Are Phosphate Status Dependent. Cell. 2016;165:464-74 pubmed publisher
    ..PGP also requires PEN2-dependent indole glucosinolate metabolism, a component of innate immune responses, indicating a functional link ..
  17. Carcolé M, Castany S, Leánez S, Pol O. Treatment with a heme oxygenase 1 inducer enhances the antinociceptive effects of µ-opioid, δ-opioid, and cannabinoid 2 receptors during inflammatory pain. J Pharmacol Exp Ther. 2014;351:224-32 pubmed publisher
    ..Therefore, the coadministration of CoPP with local morphine, DPDPE, or JWH-015 may be a good strategy for the management of chronic inflammatory pain. ..
  18. Bird M, Vardanyan R, Hruby V, Calo G, Guerrini R, Salvadori S, et al. Development and characterisation of novel fentanyl-delta opioid receptor antagonist based bivalent ligands. Br J Anaesth. 2015;114:646-56 pubmed publisher
    ..This highlights the difficulty in multifunctional opioid development. ..
  19. Jo E, Ahn J, Mo J, Yoon J, Ann E, Baek H, et al. Akt1 phosphorylates Nicastrin to regulate its protein stability and activity. J Neurochem. 2015;134:799-810 pubmed publisher
    ..As a result, Akt1 plays role in reducing gamma-secretase activity through phosphorylation-dependent regulation of NCT protein degradation. ..
  20. Mamada N, Tanokashira D, Ishii K, Tamaoka A, Araki W. Mitochondria are devoid of amyloid ?-protein (A?)-producing secretases: Evidence for unlikely occurrence within mitochondria of A? generation from amyloid precursor protein. Biochem Biophys Res Commun. 2017;486:321-328 pubmed publisher
    ..In view of the particularly low expression levels of BACE1, ?-secretase complex proteins, and ?-CTF in mitochondria, we propose that it is unlikely that A? generation from APP occurs locally within this organelle. ..
  21. Cai Z, Liu Z, Xiao M, Wang C, Tian F. Chronic Cerebral Hypoperfusion Promotes Amyloid-Beta Pathogenesis via Activating ?/?-Secretases. Neurochem Res. 2017;42:3446-3455 pubmed publisher
    ..The non-amyloidogenic pathway can't overcome the damage role of the amyloidogenic pathway in the process of chronic cerebral hypoperfusion which promotes amyloid-beta pathogenesis. ..
  22. Chu Y, Peng X, Long Z, Wang K, Luo S, Sharma A, et al. Distribution and expression of Pen-2 in the central nervous system of APP/PS1 double transgenic mice. Acta Biochim Biophys Sin (Shanghai). 2015;47:258-66 pubmed publisher
    ..The present study provides an anatomical basis for Pen-2 as a key component of γ-secretase complex in the brain of developing and adult mice, and Pen-2 might be closely related to Aβ burden in aging nervous system. ..
  23. Schafer M, Alldred M, Lee S, Calhoun M, Petkova E, Mathews P, et al. Reduction of β-amyloid and γ-secretase by calorie restriction in female Tg2576 mice. Neurobiol Aging. 2015;36:1293-302 pubmed publisher
    ..Sustained CR also significantly reduced expression of presenilin enhancer 2 (Psenen) and presenilin 1, components of the γ-secretase complex, in Tg2576 females...
  24. Du Z, Jin Y. Molecular Characterization and Antibacterial Activity Analysis of Two Novel Penaeidin Isoforms from Pacific White Shrimp, Litopenaeus vannamei. Appl Biochem Biotechnol. 2015;177:1607-20 pubmed publisher
    ..Here, we reported two penaeidin isoforms from Litopenaeus vannamei, which were named as Lva-PEN 2 and Lva-PEN 3 according to the respective structure features...
  25. Fukumori A, Steiner H. Substrate recruitment of ?-secretase and mechanism of clinical presenilin mutations revealed by photoaffinity mapping. EMBO J. 2016;35:1628-43 pubmed publisher
    ..We propose that sequential binding steps might be common for intramembrane proteases to sample and select cognate substrates for catalysis. ..
  26. Cargnel M, Demkura P, Ballaré C. Linking phytochrome to plant immunity: low red : far-red ratios increase Arabidopsis susceptibility to Botrytis cinerea by reducing the biosynthesis of indolic glucosinolates and camalexin. New Phytol. 2014;204:342-54 pubmed publisher
    ..cinerea was not present in mutants deficient in the biosynthesis of camalexin (pad3) or metabolism of iGS (pen2)...
  27. Sanjo N, Katayama T, Hasegawa H, Jin H, Duthie M, Mount H, et al. Localization and trafficking of endogenous anterior pharynx-defective 1, a component of Alzheimer's disease related gamma-secretase. Neurosci Lett. 2010;483:53-6 pubmed publisher
    ..Endogenous Aph-1a and its proteolytic fragment have unique properties for cleavage control that may have implications for gamma-secretase regulation and intracellular distribution. ..
  28. Jang C, Choi J, Na Y, Jang B, Wasco W, Buxbaum J, et al. Calsenilin regulates presenilin 1/?-secretase-mediated N-cadherin ?-cleavage and ?-catenin signaling. FASEB J. 2011;25:4174-83 pubmed publisher
    ..Taken together, our findings suggest that calsenilin is a novel negative regulator of N-cadherin processing that plays an important role in ?-catenin signaling. ..
  29. Suzuki Y, Ohta K, Itoh M, Sakoh Sumitomo Y, Mitsuda T, Ueda M, et al. An alternative spliced mouse presenilin-2 mRNA encodes a novel gamma-secretase inhibitor. FEBS Lett. 2009;583:1403-8 pubmed publisher
    ..PS2beta disturbed the interaction between NCT and APH-1, resulting in the inhibition of amyloid-beta production. We concluded that PS2beta may inhibit gamma-secretase activity by affecting the gamma-secretase complex assembly. ..
  30. Geissler K, Eschen Lippold L, Naumann K, Schneeberger K, Weigel D, Scheel D, et al. Mutations in the EDR1 Gene Alter the Response of Arabidopsis thaliana to Phytophthora infestans and the Bacterial PAMPs flg22 and elf18. Mol Plant Microbe Interact. 2015;28:122-33 pubmed publisher
    ..Besides PEN2 and PEN3, which contribute to penetration resistance, no further components have been identified so far...
  31. Marinangeli C, Tasiaux B, Opsomer R, Hage S, Sodero A, Dewachter I, et al. Presenilin transmembrane domain 8 conserved AXXXAXXXG motifs are required for the activity of the γ-secretase complex. J Biol Chem. 2015;290:7169-84 pubmed publisher
  32. Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, et al. The role of presenilin cofactors in the gamma-secretase complex. Nature. 2003;422:438-41 pubmed
    ..Thus, APH-1 stabilizes the presenilin holoprotein in the complex, whereas PEN-2 is required for endoproteolytic processing of presenilin and conferring gamma-secretase activity to the complex. ..
  33. Pardossi Piquard R, Chen F, Silva Gagliardi N, Szego M, McInnes R, McGlade C, et al. Overexpression of human CRB1 or related isoforms, CRB2 and CRB3, does not regulate the human presenilin complex in culture cells. Biochemistry. 2007;46:13704-10 pubmed
    The presenilin proteins (PS1 and PS2) with their partners (NCT, Aph1, and Pen2) are the major components of the high molecular weight gamma-secretase complex which facilitates the intramembraneous cleavage of various type 1 transmembrane ..
  34. St George Hyslop P, Fraser P. Assembly of the presenilin γ-/ε-secretase complex. J Neurochem. 2012;120 Suppl 1:84-8 pubmed publisher
    The presenilin complex is composed of four core proteins (presenilin 1 or presenilin 2, APH1, nicastrin, and PEN2)...
  35. Li Y, Bohm C, Dodd R, Chen F, Qamar S, Schmitt Ulms G, et al. Structural biology of presenilin 1 complexes. Mol Neurodegener. 2014;9:59 pubmed publisher
    ..An increasingly detailed understanding of the structural biology of the presenilin complex is an essential step towards rational design of substrate- and/or cleavage site-specific modulators of presenilin complex function. ..
  36. Zhang X, Sullivan E, Scimeca M, Wu X, Li Y, Sisodia S. Evidence That the "Lid" Domain of Nicastrin Is Not Essential for Regulating γ-Secretase Activity. J Biol Chem. 2016;291:6748-53 pubmed publisher
  37. Thompson A, Feeney C, Kristal M. Amniotic-fluid ingestion enhances central ?-opioid-induced hypoalgesia in rats in the cold-water tail-flick assay in a repeated-measures design. Brain Res. 2018;1697:53-58 pubmed publisher
    ..the CWTF assay; (b) there are no repeated-exposure effects associated with repeated central injections of DPDPE ([D-Pen2,D-Pen5]-Enkephalin, a selective ?-opioid agonist) as measured by the CWTF assay; and (c) ingestion of AF in ..
  38. Tomita T. Probing the Structure and Function Relationships of Presenilin by Substituted-Cysteine Accessibility Method. Methods Enzymol. 2017;584:185-205 pubmed publisher
    ..The SCAM provides new insights into the relationship between the structure and activity of presenilin, and is useful for probing the protein dynamics of the membrane-embedded enzymes. ..
  39. Pardossi Piquard R, Yang S, Kanemoto S, Gu Y, Chen F, Böhm C, et al. APH1 polar transmembrane residues regulate the assembly and activity of presenilin complexes. J Biol Chem. 2009;284:16298-307 pubmed publisher
    ..protein are composed primarily of presenilin (PS1 or PS2), nicastrin, anterior pharynx defective-1 (APH1), and PEN2. The presenilin aspartyl residues form the catalytic site, and similar potentially functional polar transmembrane ..
  40. Poelman C, Hummers L, Wigley F, Anderson C, Boin F, Shah A. Intravenous immunoglobulin may be an effective therapy for refractory, active diffuse cutaneous systemic sclerosis. J Rheumatol. 2015;42:236-42 pubmed publisher
    ..005) groups, and was comparable to the group of primary MMF responders (-7.1 ± 9, p = 0.67). Our observational study suggests that IVIG may be an effective adjunctive therapy for active dcSSc in patients failing other therapies. ..
  41. Bekris L, Tsuang D, Peskind E, Yu C, Montine T, Zhang J, et al. Cerebrospinal fluid Aβ42 levels and APP processing pathway genes in Parkinson's disease. Mov Disord. 2015;30:936-44 pubmed publisher
    ..region tagging single-nucleotide polymorphisms (SNPs) within nine genes (APP, ADAM10, BACE1, BACE2, PSEN1, PSEN2, PEN2, NCSTN, and APH1B) involved in the cleavage of APP...
  42. Chen W, Hsieh Y, Huang Y, Lin C, Lin Y, Liu Y, et al. G206D Mutation of Presenilin-1 Reduces Pen2 Interaction, Increases Aβ42/Aβ40 Ratio and Elevates ER Ca(2+) Accumulation. Mol Neurobiol. 2015;52:1835-1849 pubmed publisher
    ..Presenilin enhancer 2 (Pen2) is critical for activating γ-secretase and exporting PS1 from endoplasmic reticulum (ER)...
  43. Pink A, Simpson M, Brice G, Smith C, Desai N, Mortimer P, et al. PSENEN and NCSTN mutations in familial hidradenitis suppurativa (Acne Inversa). J Invest Dermatol. 2011;131:1568-70 pubmed publisher
  44. Yonemura Y, Futai E, Yagishita S, Suo S, Tomita T, Iwatsubo T, et al. Comparison of presenilin 1 and presenilin 2 ?-secretase activities using a yeast reconstitution system. J Biol Chem. 2011;286:44569-75 pubmed publisher
    Secretase is composed of at least four proteins, presenilin (PS), nicastrin (NCT), Aph1, and Pen2. PS is the catalytic subunit of the ?-secretase complex, having aspartic protease activity. PS has two homologs, namely, PS1 and PS2...
  45. Zhang X, Hoey R, Koide A, Dolios G, Paduch M, Nguyen P, et al. A synthetic antibody fragment targeting nicastrin affects assembly and trafficking of γ-secretase. J Biol Chem. 2014;289:34851-61 pubmed publisher
    ..The reduced cell surface levels of mature γ-secretase complexes, in turn, compromise the intramembranous processing of Notch. ..
  46. Takagi Niidome S, Sasaki T, Osawa S, Sato T, Morishima K, Cai T, et al. Cooperative roles of hydrophilic loop 1 and the C-terminus of presenilin 1 in the substrate-gating mechanism of γ-secretase. J Neurosci. 2015;35:2646-56 pubmed publisher
    ..Moreover, we propose that substrate binding triggers conformational changes in PS1, rendering it suitable for catalysis. Our data provide new insights into the complicated catalytic mechanism of PS1. ..
  47. Wang Z, Liu J, Wei Y, Liu M, Wang Q, Liang L, et al. Huannao Yicong Formula () regulates ?-secretase activity through APH-1 and PEN-2 gene ragulation pathways in hippocampus of APP/PS1 double transgenic mice. Chin J Integr Med. 2017;23:270-278 pubmed publisher
    ..HYF can improve the learning and memory ability by inhibiting the activity of ?-secretase through the CREB/PEN-2 signaling pathway, and this may be one of the therapeutic mechanisms of HYF in Alzheimer's disease. ..
  48. Sun L, Zhao L, Yang G, Yan C, Zhou R, Zhou X, et al. Structural basis of human γ-secretase assembly. Proc Natl Acad Sci U S A. 2015;112:6003-8 pubmed publisher
    ..TM6 and TM7 in PS1, which harbor the catalytic aspartate residues, are located on the convex side of the TM horseshoe. This structure serves as an important framework for understanding the function and mechanism of γ-secretase. ..
  49. Sarajärvi T, Marttinen M, Natunen T, Kauppinen T, Mäkinen P, Helisalmi S, et al. Genetic Variation in δ-Opioid Receptor Associates with Increased β- and γ-Secretase Activity in the Late Stages of Alzheimer's Disease. J Alzheimers Dis. 2015;48:507-16 pubmed publisher
  50. Castany S, Carcolé M, Leánez S, Pol O. The antinociceptive effects of a δ-opioid receptor agonist in mice with painful diabetic neuropathy: Involvement of heme oxygenase 1. Neurosci Lett. 2016;614:49-54 pubmed publisher
    ..In conclusion, this study shows that the administration of CORM-2 or CoPP combined with a DOR agonist could be an interesting strategy for the treatment of painful diabetic neuropathy. ..
  51. Takahashi T, Shibuya H, Ishikawa A. SOBIR1 contributes to non-host resistance to Magnaporthe oryzae in Arabidopsis. Biosci Biotechnol Biochem. 2016;80:1577-9 pubmed publisher
    The rate of entry of Magnaporthe oryzae into Arabidopsis pen2 sobir1 plants was significantly higher than that into pen2 plants. The length of the infection hyphae in pen2 sobir1 plants was significantly longer than that in pen2 plants...
  52. Lee J, Feng Z, Xie X, Bahar I. Allosteric Modulation of Intact γ-Secretase Structural Dynamics. Biophys J. 2017;113:2634-2649 pubmed publisher
  53. Edbauer D, Winkler E, Regula J, Pesold B, Steiner H, Haass C. Reconstitution of gamma-secretase activity. Nat Cell Biol. 2003;5:486-8 pubmed
    ..Thus, the biological activity of gamma-secretase is reconstituted by the co-expression of human PS, Nct, APH-1 and PEN-2 in yeast. ..
  54. Wang R, Zhang Y, Sun P, Liu R, Zhang X, Zhang X, et al. Transcriptional regulation of PEN-2, a key component of the gamma-secretase complex, by CREB. Mol Cell Biol. 2006;26:1347-54 pubmed
    ..These results demonstrate that expression of PEN-2 is regulated by CREB and suggest that the specific control of PEN-2 expression may imply additional physiological functions uniquely assigned to PEN-2. ..
  55. Lu P, Bai X, Ma D, Xie T, Yan C, Sun L, et al. Three-dimensional structure of human ?-secretase. Nature. 2014;512:166-170 pubmed publisher
    ..This structure serves as an important basis for understanding the functional mechanisms of the ?-secretase complex...
  56. Frerigmann H, Piślewska Bednarek M, Sánchez Vallet A, Molina A, Glawischnig E, Gigolashvili T, et al. Regulation of Pathogen-Triggered Tryptophan Metabolism in Arabidopsis thaliana by MYB Transcription Factors and Indole Glucosinolate Conversion Products. Mol Plant. 2016;9:682-695 pubmed publisher
    ..Strikingly, the PENETRATION 2 (PEN2)-dependent IG-metabolism products, which are absent in myb34/51/122 and pen2 mutants, were indispensable for full ..
  57. Stahl E, Bellwon P, Huber S, Schlaeppi K, Bernsdorff F, Vallat Michel A, et al. Regulatory and Functional Aspects of Indolic Metabolism in Plant Systemic Acquired Resistance. Mol Plant. 2016;9:662-681 pubmed publisher
    ..Local I3A production, by contrast, occurs via indole glucosinolate breakdown by PEN2- dependent and independent pathways...
  58. Shrivastava P, Cabrera M, Chastain L, Boyadjieva N, Jabbar S, Franklin T, et al. Mu-opioid receptor and delta-opioid receptor differentially regulate microglial inflammatory response to control proopiomelanocortin neuronal apoptosis in the hypothalamus: effects of neonatal alcohol. J Neuroinflammation. 2017;14:83 pubmed publisher
    ..However, a DOR agonist [D-Pen2,5]enkephalin (DPDPE) increased microglial secretion of anti-inflammatory cytokines and suppressed ethanol's ability ..
  59. McDonnell C, Leánez S, Pol O. The induction of the transcription factor Nrf2 enhances the antinociceptive effects of delta-opioid receptors in diabetic mice. PLoS ONE. 2017;12:e0180998 pubmed publisher
    ..These results propose SFN, alone and/or combined with DOR agonists, as interesting approaches for the treatment of painful diabetic neuropathy associated to type 2 diabetes in mice. ..
  60. Li X, Liu Y, Zheng Q, Yao G, Cheng P, Bu G, et al. Ferritin light chain interacts with PEN-2 and affects ?-secretase activity. Neurosci Lett. 2013;548:90-4 pubmed publisher
  61. Zeng L, Hu C, Zhang F, Xu D, Cui M, Xu X. Cellular FLICE-like Inhibitory Protein (c-FLIP) and PS1-associated Protein (PSAP) Mediate Presenilin 1-induced γ-Secretase-dependent and -independent Apoptosis, Respectively. J Biol Chem. 2015;290:18269-80 pubmed publisher
    ..In addition, our results suggest that PS2 induces apoptosis through a pathway that is different from that of PS1. ..
  62. Sogorb Esteve A, García Ayllón M, Llansola M, Felipo V, Blennow K, Saez Valero J. Inhibition of γ-Secretase Leads to an Increase in Presenilin-1. Mol Neurobiol. 2018;55:5047-5058 pubmed publisher
    ..Prolonged avagacestat treatment of rats produced a subtle impairment in anxiety-like behavior. The rebound increase in PS1 in response to GSIs must be taken into consideration for future drug development. ..
  63. Teranishi Y, Hur J, Gu G, Kihara T, Ishikawa T, Nishimura T, et al. Erlin-2 is associated with active ?-secretase in brain and affects amyloid ?-peptide production. Biochem Biophys Res Commun. 2012;424:476-81 pubmed publisher
    ..In summary, we have found a novel brain GSAP, erlin-2, that resides in DRMs and affects A? production. ..
  64. Ponnurangam S, Dandawate P, Dhar A, Tawfik O, Parab R, Mishra P, et al. Quinomycin A targets Notch signaling pathway in pancreatic cancer stem cells. Oncotarget. 2016;7:3217-32 pubmed publisher
    ..The γ-secretase complex proteins, Presenilin 1, Nicastrin, Pen2, and APH-1, required for Notch activation also exhibited decreased expression...
  65. Fuchs R, Kopischke M, Klapprodt C, Hause G, Meyer A, Schwarzländer M, et al. Immobilized Subpopulations of Leaf Epidermal Mitochondria Mediate PENETRATION2-Dependent Pathogen Entry Control in Arabidopsis. Plant Cell. 2016;28:130-45 pubmed publisher
    The atypical myrosinase PENETRATION2 (PEN2) is required for broad-spectrum invasion resistance to filamentous plant pathogens. Previous localization studies suggested PEN2-GFP association with peroxisomes...
  66. Fukunaga S, Sogame M, Hata M, Singkaravanit Ogawa S, Pislewska Bednarek M, Onozawa Komori M, et al. Dysfunction of Arabidopsis MACPF domain protein activates programmed cell death via tryptophan metabolism in MAMP-triggered immunity. Plant J. 2017;89:381-393 pubmed publisher
    ..Surprisingly, loss-of-function mutations in PEN2, involved in the metabolism of tryptophan (Trp)-derived indole glucosinolates, suppressed the flg22-induced and ..
  67. Herrero Fresno A, Zachariasen C, Hansen M, Nielsen A, Hendriksen R, Nielsen S, et al. Apramycin treatment affects selection and spread of a multidrug-resistant Escherichia coli strain able to colonize the human gut in the intestinal microbiota of pigs. Vet Res. 2016;47:12 pubmed publisher
    ..Nineteen pigs were randomly allocated into two inoculation groups, one treated with apramycin (pen 2) and one non-treated (pen 3), along with a non-inoculated control group (pen 1)...
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    ..Further genetic analyses revealed that SYT1 also regulates the atypical peroxisomal myrosinase PEN2-associated secretory pathway.
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    ..NRF1 target genes-APLP1, APP, GRIN1, GRIN2B, MAPT, PSEN2, PEN2, and IDE-are also regulated by E2...
  70. Hsu E, Kulp S, Huang H, Tu H, Salunke S, Sullivan N, et al. Function of Integrin-Linked Kinase in Modulating the Stemness of IL-6-Abundant Breast Cancer Cells by Regulating γ-Secretase-Mediated Notch1 Activation in Caveolae. Neoplasia. 2015;17:497-508 pubmed publisher
    ..Based on these findings, we propose a novel function of ILK in regulating γ-secretase-mediated Notch1 activation, which suggests the targeting of ILK as a therapeutic approach to suppress IL-6-induced breast CSCs. ..
  71. Takahashi T, Shibuya H, Ishikawa A. ERECTA contributes to non-host resistance to Magnaporthe oryzae in Arabidopsis. Biosci Biotechnol Biochem. 2016;80:1390-2 pubmed publisher
    ..We investigated the function of ERECTA in non-host resistance to Magnaporthe oryzae in Arabidopsis. In the pen2 er mutant, penetration resistance and post-penetration resistance to M. oryzae were compromised...
  72. Baulac S, LaVoie M, Kimberly W, Strahle J, Wolfe M, Selkoe D, et al. Functional gamma-secretase complex assembly in Golgi/trans-Golgi network: interactions among presenilin, nicastrin, Aph1, Pen-2, and gamma-secretase substrates. Neurobiol Dis. 2003;14:194-204 pubmed
  73. Zhao F, Qiao P, Yan N, Gao D, Liu M, Yan Y. Hydrogen Sulfide Selectively Inhibits γ-Secretase Activity and Decreases Mitochondrial Aβ Production in Neurons from APP/PS1 Transgenic Mice. Neurochem Res. 2016;41:1145-59 pubmed publisher
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    ..Under the action of PENETRATION2 (PEN2), an atypical myrosinase, and PEN3, an ATP binding cassette transporter, 4MI3G is converted to extracellular ..
  75. Gerber H, Wu F, Dimitrov M, Garcia Osuna G, Fraering P. Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by γ-Secretase and Amyloid-β Peptide Production. J Biol Chem. 2017;292:3751-3767 pubmed publisher
    ..They further suggest that dimerization of APP-C99 or the specific targeting of individual residues regulating the production of the long, toxic Aβ species, may offer two therapeutic strategies for preventing AD. ..
  76. Hu C, Xu J, Zeng L, Li T, Cui M, Xu X. Pen-2 and Presenilin are Sufficient to Catalyze Notch Processing. J Alzheimers Dis. 2017;56:1263-1269 pubmed publisher
    ..Our data also suggested that there may be different requirements for components to process A?PP and Notch. This information would be important for therapeutic strategy aimed at inhibition or modulation of ?-secretase activity. ..
  77. Massey L, Mah A, Monteiro M. Ubiquilin regulates presenilin endoproteolysis and modulates gamma-secretase components, Pen-2 and nicastrin. Biochem J. 2005;391:513-25 pubmed
    ..These studies implicate ubiquilin as an important factor in regulating PS biogenesis and metabolism. ..
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  79. Wang J, Lu R, Yang J, Li H, He Z, Jing N, et al. TRPC6 specifically interacts with APP to inhibit its cleavage by γ-secretase and reduce Aβ production. Nat Commun. 2015;6:8876 pubmed publisher
    ..Thus, TRPC6 specifically modulates γ-secretase cleavage of APP and preventing APP (C99) interaction with PS1 via TRPC6 could be a novel strategy to reduce Aβ formation. ..
  80. Crystal A, Morais V, Pierson T, Pijak D, Carlin D, Lee V, et al. Membrane topology of gamma-secretase component PEN-2. J Biol Chem. 2003;278:20117-23 pubmed
    ..A protease protection assay also demonstrated that the loop domain of PEN-2 is cytosolic. Thus, PEN-2 spans the membrane twice, with the N and C termini facing the lumen of the endoplasmic reticulum. ..
  81. Vetrivel K, Cheng H, Lin W, Sakurai T, Li T, Nukina N, et al. Association of gamma-secretase with lipid rafts in post-Golgi and endosome membranes. J Biol Chem. 2004;279:44945-54 pubmed
    ..These findings are consistent with the localization of gamma-secretase in lipid raft microdomains of post-Golgi and endosomes, organelles previously implicated in amyloidogenic processing of APP. ..
  82. Luo W, Wang H, Li H, Kim B, Shah S, Lee H, et al. PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1. J Biol Chem. 2003;278:7850-4 pubmed
    ..Our data reveal a direct role of PEN-2 in proteolytic cleavage of PS1 and a regulatory function of APH-1, in coordination with PEN-2, in the biogenesis of the PS1 complex. ..
  83. Hébert S, Serneels L, Dejaegere T, Horré K, Dabrowski M, Baert V, et al. Coordinated and widespread expression of gamma-secretase in vivo: evidence for size and molecular heterogeneity. Neurobiol Dis. 2004;17:260-72 pubmed
    ..In conclusion, our results suggest that gamma-secretase is a heterogeneous family of protein complexes widely expressed in the adult organism. ..
  84. Kim S, Sisodia S. Evidence that the "NF" motif in transmembrane domain 4 of presenilin 1 is critical for binding with PEN-2. J Biol Chem. 2005;280:41953-66 pubmed
    ..Further mutational analyses revealed that the "NF" sequence within the TMD4 of PS1 is the minimal motif that is required for binding with PEN-2, promoting PS1 endoproteolysis and gamma-secretase activity. ..
  85. Takeo K, Watanabe N, Tomita T, Iwatsubo T. Contribution of the ?-secretase subunits to the formation of catalytic pore of presenilin 1 protein. J Biol Chem. 2012;287:25834-43 pubmed publisher
    ..We propose a model in which the ?-secretase subunits restrict the arrangement of the transmembrane domains of PS during the formation of the functional structure of the catalytic pore. ..
  86. Yonemura Y, Futai E, Yagishita S, Kaether C, Ishiura S. Specific combinations of presenilins and Aph1s affect the substrate specificity and activity of ?-secretase. Biochem Biophys Res Commun. 2016;478:1751-7 pubmed publisher
    ..complex comprises presenilin (PS), nicastrin (NCT), anterior pharynx-defective 1 (Aph1), and presenilin enhancer 2 (Pen2). PS has two homologues, PS1 and PS2...
  87. Dunys J, Sevalle J, Giaime E, Pardossi Piquard R, Vitek M, Renbaum P, et al. p53-dependent control of transactivation of the Pen2 promoter by presenilins. J Cell Sci. 2009;122:4003-8 pubmed publisher
    ..The depletion of both presenilins drastically reduces Pen2 mRNA levels and its promoter transactivation...
  88. Wang B, Yang W, Wen W, Sun J, Su B, Liu B, et al. Gamma-secretase gene mutations in familial acne inversa. Science. 2010;330:1065 pubmed publisher
    ..well as additional skin lesions on back, face, nape, and waist and found independent loss-of-function mutations in PSENEN, PSEN1, or NCSTN, the genes encoding essential components of the ?-secretase multiprotein complex...
  89. Bolduc D, Montagna D, Seghers M, Wolfe M, Selkoe D. The amyloid-beta forming tripeptide cleavage mechanism of ?-secretase. elife. 2016;5: pubmed publisher
    ..We uncover and exploit substrate cleavage preferences dictated by these three pockets to investigate the mechanism by which familial Alzheimer's disease mutations within APP increase the production of pathogenic A? species. ..
  90. Pink A, Simpson M, Desai N, Trembath R, Barker J. ?-Secretase mutations in hidradenitis suppurativa: new insights into disease pathogenesis. J Invest Dermatol. 2013;133:601-607 pubmed publisher
    ..It may segregate as an autosomal dominant trait, and heterozygous mutations in the ?-secretase genes NCSTN, PSENEN, and PSEN1 have recently been reported in a small number of multiplex kindreds and sporadic cases...
  91. Laurent S, Hoffmann F, Kuhn P, Cheng Q, Chu Y, Schmidt Supprian M, et al. γ-Secretase directly sheds the survival receptor BCMA from plasma cells. Nat Commun. 2015;6:7333 pubmed publisher
    ..Together, shedding of BCMA by γ-secretase controls plasma cells in the bone marrow and yields a potential biomarker for B-cell involvement in human autoimmune diseases. ..