mTOR-Raptor Binds and Activates SGK1 to Regulate p27 Phosphorylation

Feng Hong, Michelle D. Larrea, Cheryl Doughty, David J. Kwiatkowski, Rachel Squillace, Joyce M Slingerland

Research output: Contribution to journalArticle

183 Citations (Scopus)

Abstract

The cell-cycle effects of mTORC1 are not fully understood. We provide evidence that mTOR-raptor phosphorylates SGK1 to modulate p27 function. Cellular mTOR activation, by refeeding of amino acid-deprived cells or by TSC2 shRNA, activated SGK1 and p27 phosphorylation at T157, and both were inhibited by short-term rapamycin treatment and by SGK1 shRNA. mTOR overexpression activated both Akt and SGK1, causing TGF-β resistance through impaired nuclear import and cytoplasmic accumulation of p27. Rapamycin or raptor shRNA impaired mTOR-driven p70 and SGK1 activation, but not that of Akt, and decreased cytoplasmic p27. mTOR/raptor/SGK1 complexes were detected in cells. mTOR phosphorylated SGK1, but not SGK1-S422A, in vitro. SGK1 phosphorylated p27 in vitro. These data implicate SGK1 as an mTORC1 (mTOR-raptor) substrate. mTOR may promote G1 progression in part through SGK1 activation and deregulate the cell cycle in cancers through both Akt- and SGK-mediated p27 T157 phosphorylation and cytoplasmic p27 mislocalization.

Original languageEnglish
Pages (from-to)701-711
Number of pages11
JournalMolecular Cell
Volume30
Issue number6
DOIs
StatePublished - Jun 20 2008

Fingerprint

Raptors
Phosphorylation
Small Interfering RNA
Sirolimus
Cell Cycle
Aminoacylation
Cell Nucleus Active Transport
Neoplasms
mechanistic target of rapamycin complex 1
In Vitro Techniques

Keywords

  • CELLCYCLE
  • SIGNALING

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Hong, F., Larrea, M. D., Doughty, C., Kwiatkowski, D. J., Squillace, R., & Slingerland, J. M. (2008). mTOR-Raptor Binds and Activates SGK1 to Regulate p27 Phosphorylation. Molecular Cell, 30(6), 701-711. https://doi.org/10.1016/j.molcel.2008.04.027

mTOR-Raptor Binds and Activates SGK1 to Regulate p27 Phosphorylation. / Hong, Feng; Larrea, Michelle D.; Doughty, Cheryl; Kwiatkowski, David J.; Squillace, Rachel; Slingerland, Joyce M.

In: Molecular Cell, Vol. 30, No. 6, 20.06.2008, p. 701-711.

Research output: Contribution to journalArticle

Hong, F, Larrea, MD, Doughty, C, Kwiatkowski, DJ, Squillace, R & Slingerland, JM 2008, 'mTOR-Raptor Binds and Activates SGK1 to Regulate p27 Phosphorylation', Molecular Cell, vol. 30, no. 6, pp. 701-711. https://doi.org/10.1016/j.molcel.2008.04.027
Hong, Feng ; Larrea, Michelle D. ; Doughty, Cheryl ; Kwiatkowski, David J. ; Squillace, Rachel ; Slingerland, Joyce M. / mTOR-Raptor Binds and Activates SGK1 to Regulate p27 Phosphorylation. In: Molecular Cell. 2008 ; Vol. 30, No. 6. pp. 701-711.
@article{2d58fbeae9874706984ee5f95ccfa137,
title = "mTOR-Raptor Binds and Activates SGK1 to Regulate p27 Phosphorylation",
abstract = "The cell-cycle effects of mTORC1 are not fully understood. We provide evidence that mTOR-raptor phosphorylates SGK1 to modulate p27 function. Cellular mTOR activation, by refeeding of amino acid-deprived cells or by TSC2 shRNA, activated SGK1 and p27 phosphorylation at T157, and both were inhibited by short-term rapamycin treatment and by SGK1 shRNA. mTOR overexpression activated both Akt and SGK1, causing TGF-β resistance through impaired nuclear import and cytoplasmic accumulation of p27. Rapamycin or raptor shRNA impaired mTOR-driven p70 and SGK1 activation, but not that of Akt, and decreased cytoplasmic p27. mTOR/raptor/SGK1 complexes were detected in cells. mTOR phosphorylated SGK1, but not SGK1-S422A, in vitro. SGK1 phosphorylated p27 in vitro. These data implicate SGK1 as an mTORC1 (mTOR-raptor) substrate. mTOR may promote G1 progression in part through SGK1 activation and deregulate the cell cycle in cancers through both Akt- and SGK-mediated p27 T157 phosphorylation and cytoplasmic p27 mislocalization.",
keywords = "CELLCYCLE, SIGNALING",
author = "Feng Hong and Larrea, {Michelle D.} and Cheryl Doughty and Kwiatkowski, {David J.} and Rachel Squillace and Slingerland, {Joyce M}",
year = "2008",
month = "6",
day = "20",
doi = "10.1016/j.molcel.2008.04.027",
language = "English",
volume = "30",
pages = "701--711",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",

}

TY - JOUR

T1 - mTOR-Raptor Binds and Activates SGK1 to Regulate p27 Phosphorylation

AU - Hong, Feng

AU - Larrea, Michelle D.

AU - Doughty, Cheryl

AU - Kwiatkowski, David J.

AU - Squillace, Rachel

AU - Slingerland, Joyce M

PY - 2008/6/20

Y1 - 2008/6/20

N2 - The cell-cycle effects of mTORC1 are not fully understood. We provide evidence that mTOR-raptor phosphorylates SGK1 to modulate p27 function. Cellular mTOR activation, by refeeding of amino acid-deprived cells or by TSC2 shRNA, activated SGK1 and p27 phosphorylation at T157, and both were inhibited by short-term rapamycin treatment and by SGK1 shRNA. mTOR overexpression activated both Akt and SGK1, causing TGF-β resistance through impaired nuclear import and cytoplasmic accumulation of p27. Rapamycin or raptor shRNA impaired mTOR-driven p70 and SGK1 activation, but not that of Akt, and decreased cytoplasmic p27. mTOR/raptor/SGK1 complexes were detected in cells. mTOR phosphorylated SGK1, but not SGK1-S422A, in vitro. SGK1 phosphorylated p27 in vitro. These data implicate SGK1 as an mTORC1 (mTOR-raptor) substrate. mTOR may promote G1 progression in part through SGK1 activation and deregulate the cell cycle in cancers through both Akt- and SGK-mediated p27 T157 phosphorylation and cytoplasmic p27 mislocalization.

AB - The cell-cycle effects of mTORC1 are not fully understood. We provide evidence that mTOR-raptor phosphorylates SGK1 to modulate p27 function. Cellular mTOR activation, by refeeding of amino acid-deprived cells or by TSC2 shRNA, activated SGK1 and p27 phosphorylation at T157, and both were inhibited by short-term rapamycin treatment and by SGK1 shRNA. mTOR overexpression activated both Akt and SGK1, causing TGF-β resistance through impaired nuclear import and cytoplasmic accumulation of p27. Rapamycin or raptor shRNA impaired mTOR-driven p70 and SGK1 activation, but not that of Akt, and decreased cytoplasmic p27. mTOR/raptor/SGK1 complexes were detected in cells. mTOR phosphorylated SGK1, but not SGK1-S422A, in vitro. SGK1 phosphorylated p27 in vitro. These data implicate SGK1 as an mTORC1 (mTOR-raptor) substrate. mTOR may promote G1 progression in part through SGK1 activation and deregulate the cell cycle in cancers through both Akt- and SGK-mediated p27 T157 phosphorylation and cytoplasmic p27 mislocalization.

KW - CELLCYCLE

KW - SIGNALING

UR - http://www.scopus.com/inward/record.url?scp=44949201143&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=44949201143&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2008.04.027

DO - 10.1016/j.molcel.2008.04.027

M3 - Article

C2 - 18570873

AN - SCOPUS:44949201143

VL - 30

SP - 701

EP - 711

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 6

ER -