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The Mtor Substrate S6 Kinase 1 (S6K1) Is a Negative Regulator of Axon Regeneration and a Potential Drug Target for Central Nervous System Injury

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The Mtor Substrate S6 Kinase 1 (S6K1) Is a Negative Regulator of Axon Regeneration and a Potential Drug Target for Central Nervous System Injury This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Cellular/Molecular The mTOR substrate S6 Kinase 1 (S6K1) is a negative regulator of axon regeneration and a potential drug target for Central Nervous System injury Hassan Al-Ali1,2,3, Ying Ding5,6, Tatiana Slepak1, Wei Wu5, Yan Sun5,7, Yania Martinez1, Xiao-Ming Xu5, V.P. Lemmon1,3 and J.l. Bixby1,3,4 1The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA. 2Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. 3Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA. 4Department of Molecular & Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. 5Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA. 6Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. 7Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. DOI: 10.1523/JNEUROSCI.0931-17.2017 Received: 4 April 2017 Revised: 18 May 2017 Accepted: 27 May 2017 Published: 16 June 2017 Author contributions: H.A.-A., Y.D., T.S., W.W., Y.S., X.-M.X., V.P.L., and J.B. designed research; H.A.-A., Y.D., T.S., W.W., Y.S., and Y.M. performed research; H.A.-A., Y.D., and T.S. analyzed data; T.S., X.-M.X., V.P.L., and J.B. wrote the paper. Conflict of Interest: The authors declare no competing financial interests. We thank Yan Shi for her help with cell imaging and high content analysis. This work was supported by grants from the Department of Defense (W81XWH-13-1-077) and the National Institutes of Health (HD057632) to JLB and VPL, and NIH NS059622, DOD CDMRP W81XWH-12-1-0562, Merit Review Award I01 BX002356 from the U.S. Department of Veterans Affairs, and Craig H Neilsen Foundation 296749 to XMX. VPL holds the Walter G. Ross Distinguished Chair in Developmental Neuroscience. XMX holds the Mari Hulman George Chair in Neurological Surgery. Corresponding Authors: John L. Bixby, PhD, University of Miami Miller School of Medicine, 1400 NW 10th Ave., DT 1205, Miami, FL-33136, Phone: 305-243-7587, Email: [email protected]; Vance P. Lemmon, PhD, University of Miami Miller School of Medicine, 1095 NW 15th Ter., LPLC 1205, Miami, FL-33136, Phone: 305-243-7587, Email: [email protected] Cite as: J. Neurosci ; 10.1523/JNEUROSCI.0931-17.2017 Alerts: Sign up at www.jneurosci.org/cgi/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2017 the authors 1 Title: The mTOR substrate S6 Kinase 1 (S6K1) is a negative regulator of axon regeneration 2 and a potential drug target for Central Nervous System injury 3 4 Abbreviated title: Inhibiting S6 Kinase 1 promotes axon regeneration 5 6 Authors and affiliations: Hassan Al-Ali1,2,3,&, Ying Ding5,6.&, Tatiana Slepak1,&, Wei Wu5, Yan 7 Sun5,7, Yania Martinez1, Xiao-Ming Xu5, V.P. Lemmon1,3, *, J.L. Bixby1,3,4,* 8 9 1The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, 10 USA. 2Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of 11 Medicine, Miami, FL, 33136, USA. 3Department of Neurological Surgery, University of Miami Miller School 12 of Medicine, Miami, FL 33136, USA. 4Department of Molecular & Cellular Pharmacology, University of 13 Miami Miller School of Medicine, Miami, FL 33136, USA. 5Spinal Cord and Brain Injury Research Group, 14 Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School 15 of Medicine, Indianapolis, IN 46202, USA. 6Department of Histology and Embryology, Zhongshan School 16 of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. 7Department of Anatomy, 17 Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, 18 China. &Co-first author. *Co-corresponding author. 19 *Corresponding Authors: John L. Bixby, PhD Vance P. Lemmon, PhD University of Miami Miller School of Medicine University of Miami Miller School of Medicine 1400 NW 10th Ave., DT 1205 1095 NW 15th Ter., LPLC 1205 Miami, FL-33136 Miami, FL-33136 Phone: 305-243-7587 Phone: 305-243-7587 Email: [email protected] Email: [email protected] 20 21 Pages: 39, Figures: 11, Abstract: 204 words, Introduction: 495 words, Discussion: 1440 22 words 23 24 Conflict of Interest 25 The authors declare no competing financial interests. 26 27 Acknowledgements 28 We thank Yan Shi for her help with cell imaging and high content analysis. This work was 29 supported by grants from the Department of Defense (W81XWH-13-1-077) and the National 30 Institutes of Health (HD057632) to JLB and VPL, and NIH NS059622, DOD CDMRP W81XWH- 31 12-1-0562, Merit Review Award I01 BX002356 from the U.S. Department of Veterans Affairs, 32 and Craig H Neilsen Foundation 296749 to XMX. VPL holds the Walter G. Ross Distinguished 33 Chair in Developmental Neuroscience. XMX holds the Mari Hulman George Chair in 34 Neurological Surgery. 35 36 37 38 1 39 Abstract 40 The mammalian target of Rapamycin (mTOR) positively regulates axon growth in the 41 mammalian central nervous system (CNS). Though axon regeneration and functional recovery 42 from CNS injuries are typically limited, knockdown or deletion of PTEN, a negative regulator of 43 mTOR, increases mTOR activity and induces robust axon growth and regeneration. It has been 44 suggested that inhibition of S6 Kinase 1 (S6K1, gene symbol: RPS6KB1), a prominent mTOR 45 target, would blunt mTOR’s positive effect on axon growth. In contrast to this expectation, we 46 demonstrate that inhibition of S6K1 in CNS neurons promotes neurite outgrowth in vitro by 2-3 47 fold. Biochemical analysis revealed that an mTOR-dependent induction of PI3K signaling is 48 involved in mediating this effect of S6K1 inhibition. Importantly, treating female mice in vivo with 49 PF-4708671, a selective S6K1 inhibitor, stimulated corticospinal tract (CST) regeneration across 50 a dorsal spinal hemisection between the cervical 5 and 6 cord segments (C5/C6), increasing 51 axon counts for at least 3 mm beyond the injury site at 8 weeks after injury. Concomitantly, 52 treatment with PF-4708671 produced significant locomotor recovery. Pharmacological targeting 53 of S6K1 may therefore constitute an attractive strategy for promoting axon regeneration 54 following CNS injury, especially given that S6K1 inhibitors are being assessed in clinical trials 55 for non-oncological indications. 56 Significance statement 57 Despite mTOR’s well-established function in promoting axon regeneration, the role of its 58 downstream target, S6K1, has been unclear. We used cellular assays with primary neurons to 59 demonstrate that S6K1 is a negative regulator of neurite outgrowth, and a spinal cord injury 60 model to show that it is a viable pharmacological target for inducing axon regeneration. We 61 provide mechanistic evidence that S6K1’s negative feedback to PI3K signaling is involved in 2 62 axon growth inhibition, and show that phosphorylation of S6K1 is a more appropriate 63 regeneration indicator than is S6 phosphorylation. 64 Introduction 65 The PI3K/mTOR pathway is a key regulator of axon growth and regeneration in the CNS (Park 66 et al., 2008). Typically, axons in the adult mammalian CNS have limited capacity for 67 regeneration following injury. Activating the PI3K/mTOR pathway by knockdown or genetic 68 deletion of its negative regulator, PTEN, results in a marked increase in regenerative capacity 69 (Zerhouni, 2004; Park et al., 2008, 2010; Zukor et al., 2013), and mTOR activity is critical for the 70 regeneration induced by loss of PTEN (Park et al., 2010). The mechanisms through which 71 mTOR promotes axon growth/regeneration are less clear; in particular, the role(s) of S6K1, a 72 downstream effector of mTOR, are incompletely understood (Hubert et al., 2014; Yang et al., 73 2014). 74 We previously screened a large number of kinase inhibitors in a neurite outgrowth assay 75 utilizing primary hippocampal neurons, and identified “hit” compounds that promote neurite 76 outgrowth (Al-Ali et al., 2013b). This phenotypic assay is reliable (Z’-factor > 0.7), and has 77 identified both chemical and genetic perturbagens that promote axon growth from a variety of 78 CNS neurons (Al-Ali et al., 2013a, 2017). In a followup study, we used machine learning to 79 relate data from the phenotypic screen of kinase inhibitors to kinase profiling data, which 80 allowed us to identify (and verify) “target” kinases whose inhibition induces neurite outgrowth 81 (Al-Ali et al., 2015). These target kinases included representatives of the family of ribosomal S6 82 protein kinases (RPS6Ks). 83 Two types of S6 kinases have been described based on their domain topology: the p70 84 ribosomal S6 kinases (S6K1 and S6K2, which phosphorylate S6 at S235/236/240/244/247) and the 85 p90 ribosomal S6 kinases (RSK1, RSK2, RSK3, and RSK4, which phosphorylate S6 at S235/236) 3 86 (Meyuhas, 2015). Two additional p90 kinases, MSK1 and MSK2, are included in the family by 87 virtue of sequence similarity (Pearce et al., 2010b), but don’t appear to have substantial activity 88 towards S6. Previous studies have shown that RSKs and MSKs negatively regulate neurite 89 outgrowth (Loh et al., 2008; Fischer et al., 2009; Buchser et al., 2010; Hubert et al., 2014).
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