@article{c395fb83b8034fe4b74ea84cddf6a76a,
title = "Small molecule H89 renders the phosphorylation of S6K1 and AKT resistant to mTOR inhibitors",
abstract = "The mammalian target of rapamycin (mTOR) is an evolutionarily conserved Ser/Thr kinase that comprises two complexes, termed mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 phosphorylates S6K1 at Thr 389, whereas mTORC2 phosphorylates AKT at Ser 473 to promote cell growth. As the mTOR name implies it is the target of natural product called rapamycin, a clinically approved drug used to treat human disease. Short-term rapamycin treatment inhibits the kinase activity of mTORC1 but not mTORC2. However, the ATP-competitive catalytic mTOR inhibitor Torin1 was identified to inhibit the kinase activity of both mTORC1 and mTORC2. Here, we report that H89 (N-(2-(4-bromocinnamylamino) ethyl)-5-isoquinolinesulfonamide), a well-characterized ATP-mimetic kinase inhibitor, renders the phosphorylation of S6K1 and AKT resistant to mTOR inhibitors across multiple cell lines. Moreover, H89 prevented the dephosphorylation of AKT and S6K1 under nutrient depleted conditions. PKA and other known H89-targeted kinases do not alter the phosphorylation status of S6K1 and AKT. Pharmacological inhibition of some phosphatases also enhanced S6K1 and AKT phosphorylation. These findings suggest a new target for H89 by which it sustains the phosphorylation status of S6K1 and AKT, resulting in mTOR signaling.",
author = "Melick, {Chase H.} and Jewell, {Jenna L.}",
note = "Funding Information: We are grateful to all members of the Jewell laboratory for insightful discussions. We thank Thu Nguyen and Greg Urquhart for technical help. This work was supported by grants from Cancer Prevention Research Institute of Texas (CPRIT) Scholar Recruitment of First-Time, Tenure-Track Faculty Member (RR150032), Cancer Prevention Research Institute of Texas (CPRIT) High-Impact/High-Risk Research Award (RP160713), The Welch Foundation (I-1927-20170325), 2017 UT Southwestern President's Research Council Distinguished Researcher Award, American Cancer Society Institutional Research Grant (ACS-IRG-17-174-13), and National Institutes of Health (R01GM129097-01) to J.L.J and NIH T32 (5 T32 GM 8203-30) to C.H.M. Funding Information: Foundation (I-1927-20170325), 2017 UT Southwestern President{\textquoteright}s Research Council Distinguished Researcher Award, American Cancer Society Institutional Research Grant (ACS-IRG-17-174-13), and National Institutes of Health (R01GM129097-01) to J.L.J and NIH T32 (5 T32 GM 8203-30) to C.H.M. Funding Information: We are grateful to all members of the Jewell laboratory for insightful discussions. We thank Thu Nguyen and Greg Urquhart for technical help. This work was supported by grants from Cancer Prevention Research Institute of Texas (CPRIT) Scholar Recruitment of First-Time, Tenure-Track Faculty Member (RR150032), Cancer Prevention Research Institute of Texas (CPRIT) High-Impact/High-Risk Research Award (RP160713), The Welch Publisher Copyright: {\textcopyright} 2020 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND).",
year = "2020",
month = may,
doi = "10.1042/BCJ20190958",
language = "English (US)",
volume = "447",
pages = "1847--1863",
journal = "Biochemical Journal",
issn = "0264-6021",
publisher = "Portland Press Ltd.",
number = "10",
}