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-Ali, Ying Ding, Tatiana Slepak, Wei Wu, Yan Sun, Yania Martinez, Xiao Ming Xu, Vance Lemmon, John Bixby

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Themammaliantarget of rapamycin(mTOR)positively regulatesaxongrowth in themammaliancentral nervous system (CNS). Althoughaxon regeneration and functional recovery from CNS injuries are typically limited, knockdown or deletion of PTEN, a negative regulator of mTOR, increases mTOR activity and induces robust axon growth and regeneration. It has been suggested that inhibition of S6 kinase 1 (S6K1, gene symbol: RPS6KB1), a prominent mTOR target, would blunt mTOR’s positive effect on axon growth. In contrast to this expectation, we demonstrate that inhibition of S6K1 inCNSneurons promotes neurite outgrowth in vitro by twofold to threefold. Biochemical analysis revealed that an mTOR-dependent induction of PI3K signaling is involved in mediating this effect of S6K1 inhibition. Importantly, treating female mice in vivo with PF-4708671, a selective S6K1 inhibitor, stimulated corticospinal tract regeneration across a dorsal spinal hemisection between the cervical 5 and 6 cord segments (C5/C6), increasing axon counts for at least 3mmbeyond the injury site at 8 weeks after injury. Concomitantly, treatment withPF-4708671producedsignificantlocomotorrecovery. Pharmacological targeting ofS6K1maytherefore constituteanattractive strategy for promoting axon regeneration following CNS injury, especially given that S6K1 inhibitors are being assessed in clinical trials for nononcological indications.

Original languageEnglish (US)
Pages (from-to)7079-7095
Number of pages17
JournalJournal of Neuroscience
Volume37
Issue number30
DOIs
StatePublished - Jul 26 2017

Fingerprint

Ribosomal Protein S6 Kinases
Nervous System Trauma
Axons
Regeneration
Pharmaceutical Preparations
Wounds and Injuries
Pyramidal Tracts
Sirolimus
Growth
Phosphatidylinositol 3-Kinases
Nervous System
Clinical Trials
Pharmacology
Genes

Keywords

  • Axon regeneration
  • Drug discovery
  • Drug target
  • Kinase
  • S6K
  • Spinal cord injury

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

The mTOR substrate S6 kinase 1 (S6K1) is a negative regulator of axon regeneration and a potential drug target for central nervous system injury. / Al-Ali, Hassan; Ding, Ying; Slepak, Tatiana; Wu, Wei; Sun, Yan; Martinez, Yania; Xu, Xiao Ming; Lemmon, Vance; Bixby, John.

In: Journal of Neuroscience, Vol. 37, No. 30, 26.07.2017, p. 7079-7095.

Research output: Contribution to journalArticle

@article{409ccc2f6afc471d8c477b72b49fa8f9,
title = "The mTOR substrate S6 kinase 1 (S6K1) is a negative regulator of axon regeneration and a potential drug target for central nervous system injury",
abstract = "Themammaliantarget of rapamycin(mTOR)positively regulatesaxongrowth in themammaliancentral nervous system (CNS). Althoughaxon regeneration and functional recovery from CNS injuries are typically limited, knockdown or deletion of PTEN, a negative regulator of mTOR, increases mTOR activity and induces robust axon growth and regeneration. It has been suggested that inhibition of S6 kinase 1 (S6K1, gene symbol: RPS6KB1), a prominent mTOR target, would blunt mTOR’s positive effect on axon growth. In contrast to this expectation, we demonstrate that inhibition of S6K1 inCNSneurons promotes neurite outgrowth in vitro by twofold to threefold. Biochemical analysis revealed that an mTOR-dependent induction of PI3K signaling is involved in mediating this effect of S6K1 inhibition. Importantly, treating female mice in vivo with PF-4708671, a selective S6K1 inhibitor, stimulated corticospinal tract regeneration across a dorsal spinal hemisection between the cervical 5 and 6 cord segments (C5/C6), increasing axon counts for at least 3mmbeyond the injury site at 8 weeks after injury. Concomitantly, treatment withPF-4708671producedsignificantlocomotorrecovery. Pharmacological targeting ofS6K1maytherefore constituteanattractive strategy for promoting axon regeneration following CNS injury, especially given that S6K1 inhibitors are being assessed in clinical trials for nononcological indications.",
keywords = "Axon regeneration, Drug discovery, Drug target, Kinase, S6K, Spinal cord injury",
author = "Hassan Al-Ali and Ying Ding and Tatiana Slepak and Wei Wu and Yan Sun and Yania Martinez and Xu, {Xiao Ming} and Vance Lemmon and John Bixby",
year = "2017",
month = "7",
day = "26",
doi = "10.1523/JNEUROSCI.0931-17.2017",
language = "English (US)",
volume = "37",
pages = "7079--7095",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "30",

}

TY - JOUR

T1 - The mTOR substrate S6 kinase 1 (S6K1) is a negative regulator of axon regeneration and a potential drug target for central nervous system injury

AU - Al-Ali, Hassan

AU - Ding, Ying

AU - Slepak, Tatiana

AU - Wu, Wei

AU - Sun, Yan

AU - Martinez, Yania

AU - Xu, Xiao Ming

AU - Lemmon, Vance

AU - Bixby, John

PY - 2017/7/26

Y1 - 2017/7/26

N2 - Themammaliantarget of rapamycin(mTOR)positively regulatesaxongrowth in themammaliancentral nervous system (CNS). Althoughaxon regeneration and functional recovery from CNS injuries are typically limited, knockdown or deletion of PTEN, a negative regulator of mTOR, increases mTOR activity and induces robust axon growth and regeneration. It has been suggested that inhibition of S6 kinase 1 (S6K1, gene symbol: RPS6KB1), a prominent mTOR target, would blunt mTOR’s positive effect on axon growth. In contrast to this expectation, we demonstrate that inhibition of S6K1 inCNSneurons promotes neurite outgrowth in vitro by twofold to threefold. Biochemical analysis revealed that an mTOR-dependent induction of PI3K signaling is involved in mediating this effect of S6K1 inhibition. Importantly, treating female mice in vivo with PF-4708671, a selective S6K1 inhibitor, stimulated corticospinal tract regeneration across a dorsal spinal hemisection between the cervical 5 and 6 cord segments (C5/C6), increasing axon counts for at least 3mmbeyond the injury site at 8 weeks after injury. Concomitantly, treatment withPF-4708671producedsignificantlocomotorrecovery. Pharmacological targeting ofS6K1maytherefore constituteanattractive strategy for promoting axon regeneration following CNS injury, especially given that S6K1 inhibitors are being assessed in clinical trials for nononcological indications.

AB - Themammaliantarget of rapamycin(mTOR)positively regulatesaxongrowth in themammaliancentral nervous system (CNS). Althoughaxon regeneration and functional recovery from CNS injuries are typically limited, knockdown or deletion of PTEN, a negative regulator of mTOR, increases mTOR activity and induces robust axon growth and regeneration. It has been suggested that inhibition of S6 kinase 1 (S6K1, gene symbol: RPS6KB1), a prominent mTOR target, would blunt mTOR’s positive effect on axon growth. In contrast to this expectation, we demonstrate that inhibition of S6K1 inCNSneurons promotes neurite outgrowth in vitro by twofold to threefold. Biochemical analysis revealed that an mTOR-dependent induction of PI3K signaling is involved in mediating this effect of S6K1 inhibition. Importantly, treating female mice in vivo with PF-4708671, a selective S6K1 inhibitor, stimulated corticospinal tract regeneration across a dorsal spinal hemisection between the cervical 5 and 6 cord segments (C5/C6), increasing axon counts for at least 3mmbeyond the injury site at 8 weeks after injury. Concomitantly, treatment withPF-4708671producedsignificantlocomotorrecovery. Pharmacological targeting ofS6K1maytherefore constituteanattractive strategy for promoting axon regeneration following CNS injury, especially given that S6K1 inhibitors are being assessed in clinical trials for nononcological indications.

KW - Axon regeneration

KW - Drug discovery

KW - Drug target

KW - Kinase

KW - S6K

KW - Spinal cord injury

UR - http://www.scopus.com/inward/record.url?scp=85026391057&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85026391057&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.0931-17.2017

DO - 10.1523/JNEUROSCI.0931-17.2017

M3 - Article

C2 - 28626016

AN - SCOPUS:85026391057

VL - 37

SP - 7079

EP - 7095

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 30

ER -