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MTOR SGK1 (1 - 10 of 10)
PMID: 18570873
mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation.
mTOR-raptor binds and activates SGK1 to ...   (details)

MTOR SGK1

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 18570873

mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation.
Source

Molecular cell (6/20/2008)

Abstract

mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation. 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-beta 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.

Cellular mTOR activation... activated SGK1 and ...   (details)

MTOR SGK1

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 18570873

mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation.
Source

Molecular cell (6/20/2008)

Abstract

mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation. 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-beta 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.

mTOR overexpression activated both ... and SGK1, ...   (details)

MTOR SGK1

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 18570873

mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation.
Source

Molecular cell (6/20/2008)

Abstract

mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation. 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-beta 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.

PMID: 19720745
Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1.
... regulate mTORC2-mediated effects on SGK1 or ...   (details)

MTOR SGK1

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC2   (MAPKAP1   MLST8   RICTOR   MTOR )

PMID: 19720745

Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1.
Source

Molecular and cellular biology (November 2009)

Abstract

Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. The mammalian target of rapamycin (mTOR) functions within two distinct complexes (mTORC1 and mTORC2) to control cell growth, proliferation, survival, and metabolism. While there has been great progress in our understanding of mTORC1 regulation, the signaling mechanisms that regulate mTORC2 have not been defined. In this study, we use liquid chromatography-tandem mass spectrometry analyses to identify 21 phosphorylation sites on the core mTORC2 component Rictor. We find that one site, T1135, undergoes growth factor-responsive phosphorylation that is acutely sensitive to rapamycin and is phosphorylated downstream of mTORC1. We find that Rictor-T1135 is directly phosphorylated by the mTORC1-dependent kinase S6K1. Although this phosphorylation event does not affect mTORC2 integrity or in vitro kinase activity, expression of a phosphorylation site mutant of Rictor (T1135A) in either wild-type or Rictor null cells causes an increase in the mTORC2-dependent phosphorylation of Akt on S473. However, Rictor-T1135 phosphorylation does not appear to regulate mTORC2-mediated effects on SGK1 or PKC alpha. While the precise molecular mechanism affecting Akt is unknown, phosphorylation of T1135 stimulates binding of Rictor to 14-3-3 proteins. We provide evidence that Rictor-T1135 phosphorylation acts in parallel with other mTORC1-dependent feedback mechanisms, such as those affecting IRS-1 signaling to PI3K, to regulate the response of Akt to insulin.

PMID: 20338997
mTOR complex-2 activates ENaC by phosphorylating SGK1.
... of mTOR blocked both SGK1 phosphorylation ...   (details)

MTOR SGK1

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 20338997

mTOR complex-2 activates ENaC by phosphorylating SGK1.
Source

Journal of the American Society of Nephrology : JASN (May 2010)

Abstract

mTOR complex-2 activates ENaC by phosphorylating SGK1. The serum- and glucocorticoid-induced kinase 1 (SGK1) plays a central role in hormone regulation of epithelial sodium (Na+) channel (ENaC) -dependent Na+ transport in the distal nephron. Phosphorylation within a carboxy-terminal domain, designated the hydrophobic motif (HM), determines the activity of SGK1, but the identity of the HM kinase is unknown. Here, we show that the highly conserved serine-threonine kinase mammalian target of rapamycin (mTOR) is essential for the phosphorylation of the HM of SGK1 and the activation of ENaC. We observed that mTOR, in conjunction with rictor (mTORC2), phosphorylated SGK1 and stimulated ENaC. In contrast, when mTOR assembled with raptor in the rapamycin-inhibited complex (mTORC1), it did not phosphorylate SGK1 or stimulate ENaC. Inhibition of mTOR blocked both SGK1 phosphorylation and ENaC-mediated Na+ transport, whereas specific inhibition of mTORC1 had no effect. Similarly, small hairpin RNA-mediated knockdown of rictor inhibited SGK1 phosphorylation and Na+ current, whereas knockdown of raptor had no effect. Finally, in co-immunoprecipitation experiments, SGK1 interacted selectively with rictor but not with raptor, suggesting selective recruitment of SGK1 to mTORC2. We conclude that mTOR, specifically mTORC2, is the HM kinase for SGK1 and is required for ENaC-mediated Na+ transport, thereby extending our understanding of the molecular mechanisms underlying Na+ balance.

PMID: 20735411
Dysregulation of epithelial Na+ absorption induced by inhibition of the kinases TORC1 and TORC2.
TORC2, ... also involved in... -induced SGK1 activation ...   (details)

MTOR SGK1

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  TORC2   (MLST8   RICTOR   MTOR )

PMID: 20735411

Dysregulation of epithelial Na+ absorption induced by inhibition of the kinases TORC1 and TORC2.
Source

British journal of pharmacology (December 2010)

Abstract

Dysregulation of epithelial Na+ absorption induced by inhibition of the kinases TORC1 and TORC2. [BACKGROUND AND PURPOSE] Although the serum and glucocorticoid-inducible protein kinase 1 (SGK1) appears to be involved in controlling epithelial Na (+) absorption, its role in this physiologically important ion transport process is undefined. As SGK1 activity is dependent upon target of rapamycin complex 2 (TORC2) -catalysed phosphorylation of SGK1-Ser (422), we have explored the effects of inhibiting TORC2 and/or TORC1 upon the hormonal control of Na (+) absorption. [EXPERIMENTAL APPROACH] Na (+) absorption was quantified electrometrically in mouse cortical collecting duct cells (mpkCCD) grown to confluence on permeable membranes. Kinase activities were assessed by monitoring endogenous protein phosphorylation, with or without TORC1/2 inhibitors (TORIN1 and PP242) and the TORC1 inhibitor: rapamycin. [KEY RESULTS] Inhibition of TORC1/2 (TORIN1, PP242) suppressed basal SGK1 activity, prevented insulin- and dexamethasone-induced SGK1 activation, and caused modest (10-20%) inhibition of basal Na (+) absorption and substantial (~80%) inhibition of insulin/dexamethasone-induced Na (+) transport. Inhibition of TORC1 did not impair SGK1 activation or insulin-induced Na (+) transport, but did inhibit (~80%) dexamethasone-induced Na (+) absorption. Arginine vasopressin stimulated Na (+) absorption via a TORC1/2-independent mechanism. [CONCLUSION AND IMPLICATIONS] Target of rapamycin complex 2, but not TORC1, is important to SGK1 activation. Signalling via phosphoinositide-3-kinase/TORC2/SGK1 can explain insulin-induced Na (+) absorption. TORC2, but not TORC1, is also involved in glucocorticoid-induced SGK1 activation but its role is permissive. Glucocorticoid-induced Na (+) transport displayed a requirement for TORC1 activity. Therefore, TORC1 and TORC2 contribute to the regulation of Na (+) absorption. Pharmacological manipulation of TORC1/2 signalling may provide novel therapies for Na (+) -sensitive hypertension.

PMID: 20884880
The mechanical stress-activated serum-, glucocorticoid-regulated kinase 1 contributes to neointima formation in vein grafts.
SGK-1 activation in ... and mammalian target of rapamycin complex ...   (details)

MTOR SGK1

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 20884880

The mechanical stress-activated serum-, glucocorticoid-regulated kinase 1 contributes to neointima formation in vein grafts.
Source

Circulation research (11/12/2010)

Abstract

The mechanical stress-activated serum-, glucocorticoid-regulated kinase 1 contributes to neointima formation in vein grafts. [RATIONALE] Mechanical stress plays an important role in proliferation of venous smooth muscle cells (SMCs) in neointima, a process of formation that contributes to failure of vein grafts. However, it is unknown what intracellular growth signal leads to proliferation of venous SMCs. [OBJECTIVE] The objective of this study is to identify mechanisms of mechanical stretch on neointima formation. [METHODS AND RESULTS] By a microarray analysis, we found that mechanical cyclic stretch (15% elongation) stimulated the transcription of SGK-1 (serum-, glucocorticoid-regulated kinase-1). Mechanical stretch-induced SGK-1 mRNA expression was blocked by actinomycin D. The mechanism for the SGK-1 expression involved MEK1 but not p38 or JNK signaling pathway. SGK-1 activation in response to stretch is blocked by insulin-like growth factor (IGF)-1 receptor inhibitor and mammalian target of rapamycin complex (mTORC)2 inhibitor (Ku-0063794) but not mTORC1 inhibitor (rapamycin). Mechanical stretch-induced bromodeoxyuridine incorporation was reduced by 83.5% in venous SMCs isolated from SGK-1 knockout mice. In contrast, inhibition of Akt, another downstream signal of PI3K resulted in only partial inhibition of mechanical stretch-induced proliferation of venous SMCs. Mechanical stretch also induced phosphorylation and nuclear exportation of p27 (kip1), whereas knockout of SGK-1 attenuated this effect of mechanical stretch on p27 (kip1). In vivo, we found that placement of a vein graft into artery increased SGK-1 expression. Knockout of SGK-1 effectively prevented neointima formation in vein graft. There is significant lower level of p27 (kip1) located in the nucleus of neointima cells in SGK-1 knockout mice compared with that of wild-type vein graft. In addition, we also found that wire injury of artery or growth factors in vitro increased expression of SGK-1. [CONCLUSIONS] These results suggest that SGK-1 is an injury-responsive kinase that could mediate mechanical stretch-induced proliferation of vascular cells in vein graft, leading to neointima formation.

PMID: 21413931
Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney.
... whereas mTORC2 regulates phosphorylation ... and SGK1 ...   (details)

MTOR SGK1

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC2   (MAPKAP1   MLST8   RICTOR   MTOR )

PMID: 21413931

Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney.
Source

The Biochemical journal (5/15/2011)

Abstract

Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney. The mTOR (mammalian target of rapamycin) protein kinase is an important regulator of cell growth and is a key target for therapeutic intervention in cancer. Two complexes of mTOR have been identified: complex 1 (mTORC1), consisting of mTOR, Raptor (regulatory associated protein of mTOR) and mLST8 (mammalian lethal with SEC13 protein 8) and complex 2 (mTORC2) consisting of mTOR, Rictor (rapamycin-insensitive companion of mTOR), Sin1 (stress-activated protein kinase-interacting protein 1), mLST8 and Protor-1 or Protor-2. Both complexes phosphorylate the hydrophobic motifs of AGC kinase family members: mTORC1 phosphorylates S6K (S6 kinase), whereas mTORC2 regulates phosphorylation of Akt, PKCa (protein kinase Ca) and SGK1 (serum- and glucocorticoid-induced protein kinase 1). To investigate the roles of the Protor isoforms, we generated single as well as double Protor-1- and Protor-2-knockout mice and studied how activation of known mTORC2 substrates was affected. We observed that loss of Protor-1 and/or Protor-2 did not affect the expression of the other mTORC2 components, nor their ability to assemble into an active complex. Moreover, Protor knockout mice display no defects in the phosphorylation of Akt and PKCa at their hydrophobic or turn motifs. Strikingly, we observed that Protor-1 knockout mice displayed markedly reduced hydrophobic motif phosphorylation of SGK1 and its physiological substrate NDRG1 (N-Myc downregulated gene 1) in the kidney. Taken together, these results suggest that Protor-1 may play a role in enabling mTORC2 to efficiently activate SGK1, at least in the kidney.

... enabling mTORC2 to efficiently activate SGK1, ...   (details)

MTOR SGK1

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC2   (MAPKAP1   MLST8   RICTOR   MTOR )

PMID: 21413931

Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney.
Source

The Biochemical journal (5/15/2011)

Abstract

Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney. The mTOR (mammalian target of rapamycin) protein kinase is an important regulator of cell growth and is a key target for therapeutic intervention in cancer. Two complexes of mTOR have been identified: complex 1 (mTORC1), consisting of mTOR, Raptor (regulatory associated protein of mTOR) and mLST8 (mammalian lethal with SEC13 protein 8) and complex 2 (mTORC2) consisting of mTOR, Rictor (rapamycin-insensitive companion of mTOR), Sin1 (stress-activated protein kinase-interacting protein 1), mLST8 and Protor-1 or Protor-2. Both complexes phosphorylate the hydrophobic motifs of AGC kinase family members: mTORC1 phosphorylates S6K (S6 kinase), whereas mTORC2 regulates phosphorylation of Akt, PKCa (protein kinase Ca) and SGK1 (serum- and glucocorticoid-induced protein kinase 1). To investigate the roles of the Protor isoforms, we generated single as well as double Protor-1- and Protor-2-knockout mice and studied how activation of known mTORC2 substrates was affected. We observed that loss of Protor-1 and/or Protor-2 did not affect the expression of the other mTORC2 components, nor their ability to assemble into an active complex. Moreover, Protor knockout mice display no defects in the phosphorylation of Akt and PKCa at their hydrophobic or turn motifs. Strikingly, we observed that Protor-1 knockout mice displayed markedly reduced hydrophobic motif phosphorylation of SGK1 and its physiological substrate NDRG1 (N-Myc downregulated gene 1) in the kidney. Taken together, these results suggest that Protor-1 may play a role in enabling mTORC2 to efficiently activate SGK1, at least in the kidney.

PMID: 22842983
Serum and glucocorticoid-regulated kinase 1 (SGK1) activation in breast cancer: requirement for mTORC1 activity associates with ER-alpha expression.
... either mTORC1 or ... exclusively required for SGK1's ...   (details)

MTOR SGK1

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 22842983

Serum and glucocorticoid-regulated kinase 1 (SGK1) activation in breast cancer: requirement for mTORC1 activity associates with ER-alpha expression.
Source

Breast cancer research and treatment (September 2012)

Abstract

Serum and glucocorticoid-regulated kinase 1 (SGK1) activation in breast cancer: requirement for mTORC1 activity associates with ER-alpha expression. Mammalian target of rapamycin (mTOR) is an attractive target for cancer treatment. While rapamycin and its derivatives (e.g., everolimus) have been shown to inhibit mTOR signaling and cell proliferation in preclinical models of breast cancer, mTOR inhibition has demonstrated variable clinical efficacy with a trend toward better responses in estrogen receptor alpha positive (ERa+) compared to ERa negative (ERa-) tumors. Recently, serum- and glucocorticoid-regulated kinase 1 (SGK1) was identified as a substrate of mTOR kinase activity. Previous studies have alternatively suggested that either mTORC1 or mTORC2 is exclusively required for SGK1's Ser422 phosphorylation and activation in breast cancer cells. We investigated the effect of rapamycin on the growth of several ERa+ and ERa- breast cancer cell lines and examined differences in the phosphorylation of mTOR substrates (SGK1, p70S6K, and Akt) that might account for the differing sensitivity of these cell lines to rapamycin. We also examined which mTOR complex contributes to SGK1-Ser422 phosphorylation in ERa+ versus ERa- breast cell lines. We then assessed whether inhibiting SGK1 activity added to rapamycin-mediated cell growth inhibition by either using the SGK1 inhibitor GSK650394A or expressing an SGK1 shRNA. We observed sensitivity to rapamycin-mediated growth inhibition and inactivation of insulin-mediated SGK1-Ser422 phosphorylation in ERa+ MCF-7 and T47D cells, but not in ERa- MDA-MB-231 or MCF10A-Myc cells. In addition, either depleting SGK1 with shRNA or inhibiting SGK1 with GSK650394A preferentially sensitized MDA-MB-231 cells to rapamycin. Finally, we found that rapamycin-sensitive SGK1-Ser422 phosphorylation required ERa expression in MCF-7 derived cell lines. Therefore, targeting SGK1 activity may improve the efficacy of rapamycin and its analogs in the treatment of ERa- breast cancer.