{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T18:59:01Z","timestamp":1774637941881,"version":"3.50.1"},"reference-count":38,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2004,12,10]],"date-time":"2004-12-10T00:00:00Z","timestamp":1102636800000},"content-version":"vor","delay-in-days":70,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Dev Growth Differ"],"published-print":{"date-parts":[[2004,10]]},"abstract":"<jats:p>It still remains intriguing how signal specificity is achieved when different signals are relayed by the common intracellular signal transduction pathways. A well documented example for signal specificity determination is found in rat phaeochromocytoma PC12 cells where epidermal growth factor (EGF) stimulation produces a transient mitogen\u2010activated protein kinase (MAPK) activation and leads to cell proliferation while nerve growth factor (NGF) initiates a sustained MAPK activation and induces cell differentiation. In this simulation, we demonstrated that NGF\u2010induced sustained MAPK activation may mainly depend on continual regeneration of NGF receptors and that the presence of a small pool of surface receptors is enough to maintain a sustained MAPK activation. On the other hand, MAPK activation is not significantly sensitive to the half\u2010life of internalized receptors and the levels of NGF\u2010specific MAPK phosphatase MAP kinase phosphatase\u20103 (MKP\u20103), though cytoplasmic persistence of internalized NGF\u2010bound receptors and the MKP\u20103 dependent feedback control also contribute to the sustaining of MAPK activation. These results are consistent with the recent experimental evidence that persistent tyrosine receptor kinase A (TrkA) activity is necessary to maintain transcription in the differentiating PC12 cells (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"#b1\">Chang <jats:italic>et\u00a0al<\/jats:italic>. 2003<\/jats:ext-link>) and a sustained Src kinase activity is detected in response to NGF stimulation (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"#b2\">Gatti 2003<\/jats:ext-link>). It is suggested that sustained or transient MAPK activation induced by different growth factor and neurotrophins, which is crucial to their signaling specificity, could be satisfactorily accounted for by their specific receptor turnover kinetics rather than by the activation of specific downstream signaling cascades.<\/jats:p>","DOI":"10.1111\/j.1440-169x.2004.00756.x","type":"journal-article","created":{"date-parts":[[2004,12,10]],"date-time":"2004-12-10T17:20:32Z","timestamp":1102699232000},"page":"393-403","source":"Crossref","is-referenced-by-count":16,"title":["Sustained MAPK activation is dependent on continual NGF receptor regeneration"],"prefix":"10.1111","volume":"46","author":[{"given":"Dongru","family":"Qiu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Likai","family":"Mao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinichi","family":"Kikuchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaru","family":"Tomita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2004,12,10]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/bp010009k"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.283.5400.381"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(00)02037-8"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.12.6.1897"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(98)00250-6"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M308155200"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.21.8.2695-2705.2001"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(97)82217-7"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.280.5365.895"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.8.1901"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0898-6568(03)00075-5"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1070127"},{"key":"e_1_2_6_14_1","first-page":"7950","article-title":"Endocytosis of activated TrkA: evidence that nerve growth factor induces formation of signaling endosomes","volume":"16","author":"Grimes M. 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