{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRPS6KB1 (p70S6K1) is a key serine/threonine kinase that couples nutrient and growth‐factor signals to the protein synthesis machinery. It is activated downstream of the mTOR complex and, when active, phosphorylates multiple substrates involved in translation initiation. For example, inactive RPS6KB1 is tethered to the eukaryotic initiation factor 3 (eIF3) complex, and upon mTOR‐dependent phosphorylation it dissociates to phosphorylate targets such as PDCD4 and eIF4B, thereby relieving translational repression and enhancing protein production. Moreover, factors deposited on spliced mRNAs recruit activated S6K1 to boost the pioneer round of translation. (–."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to promoting translation, RPS6KB1 fulfills important feedback‐regulatory roles within the mTOR–Akt axis. Through its kinase activity, it contributes to the phosphorylation of mTOR itself as well as upstream regulators, thereby attenuating insulin receptor substrate function and fine‐tuning growth factor responses. By phosphorylating key serine residues on IRS‐1 and even components of mTOR complex 2 (such as Rictor), S6K1 establishes feedback loops that modulate insulin sensitivity and oncogenic signaling. (–."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "12"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNumerous studies have implicated dysregulated RPS6KB1 activity in cancer progression. Elevated or aberrantly spliced forms of RPS6KB1 promote cell cycle progression through up‐regulation of cyclins and modulation of the tumor suppressor machinery. In breast, ovarian, esophageal, and other cancers, overexpressed or constitutively active S6K1 phosphorylates substrates such as estrogen receptor α and Gli1 to enhance proliferation, invasion, and angiogenesis. Likewise, its activity is essential for proper cell cycle control and has been linked to drug resistance phenomena, underscoring its potential as a therapeutic target in oncology. 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"}, {"type": "b", "children": [{"type": "t", "text": "SKAR links pre-mRNA splicing to mTOR/S6K1-mediated enhanced translation efficiency of spliced mRNAs."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2008.02.031"}], "href": "https://doi.org/10.1016/j.cell.2008.02.031"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18423201"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18423201"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Oded Meyuhas, Avigail Dreazen "}, {"type": "b", "children": [{"type": "t", "text": "Ribosomal protein S6 kinase from TOP mRNAs to cell size."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Prog Mol Biol Transl Sci (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/S1877-1173(09)90003-5"}], "href": "https://doi.org/10.1016/S1877-1173(09"}, {"type": "t", "text": "90003-5) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20374740"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20374740"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Angel P Tabancay, Chia-Ling Gau, Iara M P Machado, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of dominant negative mutants of Rheb GTPase and their use to implicate the involvement of human Rheb in the activation of p70S6K."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M306553200"}], "href": "https://doi.org/10.1074/jbc.M306553200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12869548"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12869548"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Brendan D Manning "}, {"type": "b", "children": [{"type": "t", "text": "Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.200408161"}], "href": "https://doi.org/10.1083/jcb.200408161"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15533996"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15533996"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "O Jameel Shah, Tony Hunter "}, {"type": "b", "children": [{"type": "t", "text": "Turnover of the active fraction of IRS1 involves raptor-mTOR- and S6K1-dependent serine phosphorylation in cell culture models of tuberous sclerosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.01254-05"}], "href": "https://doi.org/10.1128/MCB.01254-05"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16914728"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16914728"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Hui H Zhang, Alex I Lipovsky, Christian C Dibble, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S6K1 regulates GSK3 under conditions of mTOR-dependent feedback inhibition of Akt."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2006.09.019"}], "href": "https://doi.org/10.1016/j.molcel.2006.09.019"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17052453"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17052453"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Bruno D Fonseca, Ewan M Smith, Vivian H-Y Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PRAS40 is a target for mammalian target of rapamycin complex 1 and is required for signaling downstream of this complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M704406200"}], "href": "https://doi.org/10.1074/jbc.M704406200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17604271"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17604271"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Jin Zhang, Zhanguo Gao, Jun Yin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-(alpha) signaling through IKK2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M806480200"}], "href": "https://doi.org/10.1074/jbc.M806480200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18952604"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18952604"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Louis-Andre Julien, Audrey Carriere, Julie Moreau, et al. "}, {"type": "b", "children": [{"type": "t", "text": "mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00601-09"}], "href": "https://doi.org/10.1128/MCB.00601-09"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19995915"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19995915"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Ning Gao, Daniel C Flynn, Zhuo Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Cell Physiol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpcell.00422.2003"}], "href": "https://doi.org/10.1152/ajpcell.00422.2003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15028555"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15028555"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Fikret Sahin, Rajesh Kannangai, Onikepe Adegbola, et al. "}, {"type": "b", "children": [{"type": "t", "text": "mTOR and P70 S6 kinase expression in primary liver neoplasms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-04-0941"}], "href": "https://doi.org/10.1158/1078-0432.CCR-04-0941"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15623621"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15623621"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Hong Y Zhou, Alice S T Wong "}, {"type": "b", "children": [{"type": "t", "text": "Activation of p70S6K induces expression of matrix metalloproteinase 9 associated with hepatocyte growth factor-mediated invasion in human ovarian cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocrinology (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/en.2005-1404"}], "href": "https://doi.org/10.1210/en.2005-1404"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16469801"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16469801"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Qiao Meng, Chang Xia, Jing Fang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of PI3K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation through the p70S6K1 pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2006.05.019"}], "href": "https://doi.org/10.1016/j.cellsig.2006.05.019"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16839745"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16839745"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "So-Yon Woo, Dong-Hwan Kim, Chang-Bong Jun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M704343200"}], "href": "https://doi.org/10.1074/jbc.M704343200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17599906"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17599906"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Ling-Zhi Liu, Xiang-Dong Zhou, Guisheng Qian, et al. "}, {"type": "b", "children": [{"type": "t", "text": "AKT1 amplification regulates cisplatin resistance in human lung cancer cells through the mammalian target of rapamycin/p70S6K1 pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-06-4261"}], "href": "https://doi.org/10.1158/0008-5472.CAN-06-4261"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17616691"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17616691"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Wei Li, Dongfeng Tan, Zhaoping Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Activation of Akt-mTOR-p70S6K pathway in angiogenesis in hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2008)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18813808"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18813808"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Rachel L Yamnik, Alla Digilova, Daphne C Davis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S6 kinase 1 regulates estrogen receptor alpha in control of breast cancer cell proliferation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M807532200"}], "href": "https://doi.org/10.1074/jbc.M807532200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19112174"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19112174"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Tim R Fenton, Ivan T Gout "}, {"type": "b", "children": [{"type": "t", "text": "Functions and regulation of the 70kDa ribosomal S6 kinases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Biochem Cell Biol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biocel.2010.09.018"}], "href": "https://doi.org/10.1016/j.biocel.2010.09.018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20932932"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20932932"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "C K M Ip, A N Y Cheung, H Y S Ngan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "p70 S6 kinase in the control of actin cytoskeleton dynamics and directed migration of ovarian cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2010.615"}], "href": "https://doi.org/10.1038/onc.2010.615"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21258406"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21258406"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Marc A Becker, Yasir H Ibrahim, Xiaojiang Cui, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The IGF pathway regulates ERα through a S6K1-dependent mechanism in breast cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Endocrinol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/me.2010-0373"}], "href": "https://doi.org/10.1210/me.2010-0373"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21292829"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21292829"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Yan Wang, Qingqing Ding, Chia-Jui Yen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The crosstalk of mTOR/S6K1 and Hedgehog pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ccr.2011.12.028"}], "href": "https://doi.org/10.1016/j.ccr.2011.12.028"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22439934"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22439934"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Zhu-mei Shi, Jing Wang, Zhiping Yan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MiR-128 inhibits tumor growth and angiogenesis by targeting p70S6K1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0032709"}], "href": "https://doi.org/10.1371/journal.pone.0032709"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22442669"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22442669"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Vered Ben-Hur, Polina Denichenko, Zahava Siegfried, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S6K1 alternative splicing modulates its oncogenic activity and regulates mTORC1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2012.11.020"}], "href": "https://doi.org/10.1016/j.celrep.2012.11.020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23273915"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23273915"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Xiaomin Ma, Pengbo Guo, Yumin Qiu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of AIM2 expression promotes hepatocarcinoma progression through activation of mTOR-S6K1 pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.9154"}], "href": "https://doi.org/10.18632/oncotarget.9154"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27167192"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27167192"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Christelle Guillet, Magali Prod'homme, Michèle Balage, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Impaired anabolic response of muscle protein synthesis is associated with S6K1 dysregulation in elderly humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.03-1341fje"}], "href": "https://doi.org/10.1096/fj.03-1341fje"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15319361"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15319361"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "M Ueno, J B C Carvalheira, R C Tambascia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of insulin signalling by hyperinsulinaemia: role of IRS-1/2 serine phosphorylation and the mTOR/p70 S6K pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetologia (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00125-004-1662-6"}], "href": "https://doi.org/10.1007/s00125-004-1662-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15692808"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15692808"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Mickaël Ohanna, Andrew K Sobering, Thomas Lapointe, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Atrophy of S6K1(-/-) skeletal muscle cells reveals distinct mTOR effectors for cell cycle and size control."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncb1231"}], "href": "https://doi.org/10.1038/ncb1231"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15723049"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15723049"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Claire Lafay-Chebassier, Marc Paccalin, Guylène Page, et al. "}, {"type": "b", "children": [{"type": "t", "text": "mTOR/p70S6k signalling alteration by Abeta exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurochem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1471-4159.2005.03187.x"}], "href": "https://doi.org/10.1111/j.1471-4159.2005.03187.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15953364"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15953364"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Maya P Byfield, James T Murray, Jonathan M Backer "}, {"type": "b", "children": [{"type": "t", "text": "hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M507201200"}], "href": "https://doi.org/10.1074/jbc.M507201200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16049009"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16049009"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "René Koopman, Antoine H G Zorenc, Rudy J J Gransier, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Increase in S6K1 phosphorylation in human skeletal muscle following resistance exercise occurs mainly in type II muscle fibers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Endocrinol Metab (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpendo.00530.2005"}], "href": "https://doi.org/10.1152/ajpendo.00530.2005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16434552"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16434552"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Christopher E Pelloski, E Lin, Li Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prognostic associations of activated mitogen-activated protein kinase and Akt pathways in glioblastoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-05-2202"}], "href": "https://doi.org/10.1158/1078-0432.CCR-05-2202"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16818690"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16818690"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Satoshi Fujita, Takashi Abe, Micah J Drummond, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Blood flow restriction during low-intensity resistance exercise increases S6K1 phosphorylation and muscle protein synthesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Appl Physiol (1985) (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/japplphysiol.00195.2007"}], "href": "https://doi.org/10.1152/japplphysiol.00195.2007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17569770"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17569770"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Sean M Armour, Joseph A Baur, Sherry N Hsieh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibition of mammalian S6 kinase by resveratrol suppresses autophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Aging (Albany NY) (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/aging.100056"}], "href": "https://doi.org/10.18632/aging.100056"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20157535"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20157535"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Nissim Hay "}, {"type": "b", "children": [{"type": "t", "text": "Interplay between FOXO, TOR, and Akt."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbamcr.2011.03.013"}], "href": "https://doi.org/10.1016/j.bbamcr.2011.03.013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21440577"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21440577"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "Antonella Caccamo, Caterina Branca, Joshua S Talboom, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reducing Ribosomal Protein S6 Kinase 1 Expression Improves Spatial Memory and Synaptic Plasticity in a Mouse Model of Alzheimer's Disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.2781-15.2015"}], "href": "https://doi.org/10.1523/JNEUROSCI.2781-15.2015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26468204"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26468204"}]}, {"type": "r", "ref": 39, "children": [{"type": "t", "text": "L Liu, F Li, J A Cardelli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1209691"}], "href": "https://doi.org/10.1038/sj.onc.1209691"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16715128"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16715128"}]}, {"type": "r", "ref": 40, "children": [{"type": "t", "text": "Ling-Zhi Liu, Xiao-Wen Hu, Chang Xia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reactive oxygen species regulate epidermal growth factor-induced vascular endothelial growth factor and hypoxia-inducible factor-1alpha expression through activation of AKT and P70S6K1 in human ovarian cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Free Radic Biol Med (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.freeradbiomed.2006.08.003"}], "href": "https://doi.org/10.1016/j.freeradbiomed.2006.08.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17045920"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17045920"}]}, {"type": "r", "ref": 41, "children": [{"type": "t", "text": "Angelika Riedl, Michaela Schlederer, Karoline Pudelko, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Comparison of cancer cells in 2D vs 3D culture reveals differences in AKT-mTOR-S6K signaling and drug responses."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.188102"}], "href": "https://doi.org/10.1242/jcs.188102"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27663511"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27663511"}]}, {"type": "r", "ref": 42, "children": [{"type": "t", "text": "Keng Po Lai, Wai Fook Leong, Jenny Fung Ling Chau, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S6K1 is a multifaceted regulator of Mdm2 that connects nutrient status and DNA damage response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2010.166"}], "href": "https://doi.org/10.1038/emboj.2010.166"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20657550"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20657550"}]}]}]}