{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T08:20:54Z","timestamp":1740126054641,"version":"3.37.3"},"reference-count":34,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2015,7,16]],"date-time":"2015-07-16T00:00:00Z","timestamp":1437004800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Korea Healthcare technology R&D Project"},{"name":"Ministry of Health & Welfare, Republic of Korea","award":["A121274"],"award-info":[{"award-number":["A121274"]}]},{"name":"Basic Science Research Program"},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Ministry of Science, ICT and future Planning","award":["NRF-2014R1A4A1003642"],"award-info":[{"award-number":["NRF-2014R1A4A1003642"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2015,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>The gamma\u2010secretase is a multiprotein complex that cleaves many type\u2010I membrane proteins<jats:bold>,<\/jats:bold> such as the Notch receptor and the amyloid precursor protein. Nicastrin (NCT) is an essential component of the multimeric gamma\u2010secretase complex and functions as a receptor for gamma\u2010secretase substrates. In this study, we found that Akt1 markedly regulated the protein stability of NCT. Importantly, the kinase activity of Akt1 was essential for the inhibition of gamma\u2010secretase activity through degradation of NCT. Notably, the protein level of endogenous NCT was higher in shAkt1\u2010expressing cells than in shCon\u2010expressing cells. Akt1 physically interacted with NCT and mediated its degradation through proteasomal and lysosomal pathways. We also found that Akt1 phosphorylates NCT at Ser437, resulting in a significant reduction in NCT protein stability. Importantly, a phospho\u2010deficient mutation in NCT at Ser437 stabilized its protein levels. Collectively, our results reveal that Akt1 functions as a negative regulator of the gamma\u2010secretase activity through phosphorylation and degradation of NCT.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc13173-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\nGeneration of the amyloid peptide (A\u2010beta) and the amyloid precursor protein (APP) intracellular domain (AICD) can happen by sequential proteolysis of APP by beta and gamma\u2010secretase. The gamma\u2010secretase complex consists of four essential proteins: presenilin (PS1 or PS2), presenilin enhancer 2 (PEN\u20102), anterior pharynx\u2010defective 1 (APH\u20101), and the Nicastrin (NCT). NCT can interact and be phosphorylated by Akt1, and phosphorylated NCT promotes its proteasomal and lysosomal degradation. As a result, Akt1 plays role in reducing gamma\u2010secretase activity through phosphorylation\u2010dependent regulation of NCT protein degradation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.13173","type":"journal-article","created":{"date-parts":[[2015,5,21]],"date-time":"2015-05-21T14:05:17Z","timestamp":1432217117000},"page":"799-810","source":"Crossref","is-referenced-by-count":5,"title":["Akt1 phosphorylates Nicastrin to regulate its protein stability and activity"],"prefix":"10.1111","volume":"134","author":[{"given":"Eun\u2010Hye","family":"Jo","sequence":"first","affiliation":[{"name":"Hormone Research Center School of Biological Sciences and Technology Chonnam National University Gwangju Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji\u2010Seon","family":"Ahn","sequence":"additional","affiliation":[{"name":"Hormone Research Center School of Biological Sciences and Technology Chonnam National University Gwangju Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jung\u2010Soon","family":"Mo","sequence":"additional","affiliation":[{"name":"Hormone Research Center School of Biological Sciences and Technology Chonnam National University Gwangju Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji\u2010Hye","family":"Yoon","sequence":"additional","affiliation":[{"name":"Hormone Research Center School of Biological Sciences and Technology Chonnam National University Gwangju Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eun\u2010Jung","family":"Ann","sequence":"additional","affiliation":[{"name":"Hormone Research Center School of Biological Sciences and Technology Chonnam National University Gwangju Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyeong\u2010Jin","family":"Baek","sequence":"additional","affiliation":[{"name":"Hormone Research Center School of Biological Sciences and Technology Chonnam National University Gwangju Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hye\u2010Jin","family":"Lee","sequence":"additional","affiliation":[{"name":"Hormone Research Center School of Biological Sciences and Technology Chonnam National University Gwangju Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seol\u2010Hee","family":"Kim","sequence":"additional","affiliation":[{"name":"Hormone Research Center School of Biological Sciences and Technology Chonnam National University Gwangju Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mi\u2010Yeon","family":"Kim","sequence":"additional","affiliation":[{"name":"Hormone Research Center School of Biological Sciences and Technology Chonnam National University Gwangju Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hee\u2010Sae","family":"Park","sequence":"additional","affiliation":[{"name":"Hormone Research Center School of Biological Sciences and Technology Chonnam National University Gwangju Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,7,16]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2009.12.051"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(02)02865-6"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.8.4240"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M806380200"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3350001"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(03)00205-8"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.07.021"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.12.22.3499"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(98)80149-X"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E05-11-1094"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0901933106"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.889901"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2007.04449.x"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C100649200"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C400396200"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.05-4055fje"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3440189"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(02)00585-8"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E07-09-0987"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(02)00749-2"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.114.16.2903"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2009.07264.x"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0037111"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0898-6568(01)00271-6"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M304009200"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01640"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.05.022"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M800013200"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2003.01616.x"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.2003.02731.x"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(03)00287-9"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110871200"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1110"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/35024009"}],"container-title":["Journal of Neurochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjnc.13173","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjnc.13173","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.13173","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T09:02:42Z","timestamp":1696150962000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jnc.13173"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,7,16]]},"references-count":34,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2015,9]]}},"alternative-id":["10.1111\/jnc.13173"],"URL":"https:\/\/doi.org\/10.1111\/jnc.13173","archive":["Portico"],"relation":{},"ISSN":["0022-3042","1471-4159"],"issn-type":[{"type":"print","value":"0022-3042"},{"type":"electronic","value":"1471-4159"}],"subject":[],"published":{"date-parts":[[2015,7,16]]}}}