◀ Back to AKT1
AKT1 — RICTOR
Pathways - manually collected, often from reviews:
-
NCI Pathway Database CXCR3-mediated signaling events:
mTORC2 complex (MTOR-RICTOR-MLST8-MAPKAP1)
→
AKT1 (AKT1)
(modification, activates)
Bonacchi et al., J Biol Chem 2001, Smit et al., Blood 2003
Evidence: assay
-
NCI Pathway Database Class I PI3K signaling events mediated by Akt:
mTORC2 complex (MTOR-RICTOR-MLST8-MAPKAP1)
→
AKT1 (AKT1)
(modification, activates)
Sarbassov et al., Science 2005, Frias et al., Curr Biol 2006, Jacinto et al., Cell 2006
Evidence: mutant phenotype, assay, physical interaction, other species
-
NCI Pathway Database CXCR4-mediated signaling events:
mTORC2 complex (MTOR-RICTOR-MLST8-MAPKAP1)
→
AKT1 (AKT1)
(modification, activates)
Sotsios et al., J Immunol 1999, Curnock et al., J Immunol 2003, Chen et al., Mol Biol Cell 2008
Evidence: assay
-
NCI Pathway Database Integrin-linked kinase signaling:
ILK/RICTOR complex (ILK-RICTOR)
→
AKT1 (AKT1)
(modification, activates)
McDonald et al., Cancer Res 2008*
Evidence: assay, physical interaction
-
NCI Pathway Database ErbB1 downstream signaling:
mTORC2 complex (MTOR-RICTOR-MLST8-MAPKAP1)
→
AKT1 (AKT1)
(modification, activates)
Sarbassov et al., Science 2005, Cao et al., Science signaling 2009
Evidence: genetic interaction
-
NCI Pathway Database mTOR signaling pathway:
mTORC2 complex (MTOR-MLST8-RICTOR-MAPKAP1-PRR5)
→
AKT1 (AKT1)
(modification, activates)
Sarbassov et al., Science 2005, Frias et al., Curr Biol 2006, Jacinto et al., Cell 2006, Yang et al., Genes Dev 2006, Guertin et al., Dev Cell 2006, Pearce et al., Biochem J 2007, Woo et al., J Biol Chem 2007, Huang et al., Mol Cell Biol 2008, Ikenoue et al., EMBO J 2008
Evidence: mutant phenotype, assay, physical interaction
-
Reactome Reaction:
AKT1
→
RICTOR
(reaction)
Scheid et al., Mol Cell Biol 2002*, Sarbassov et al., Science 2005, Carpten et al., Nature 2007*, Landgraf et al., Biochemistry 2008*
-
WikiPathways Angiopoietin Like Protein 8 Regulatory Pathway:
AKT1/AKT2
→
Complex of MTOR-MAPKAP1-RICTOR-MLST8
(activation)
-
WikiPathways PI3K-AKT-mTOR signaling pathway and therapeutic opportunities:
Complex of MTOR-RICTOR
→
AKT1
(activation)
-
WikiPathways Target Of Rapamycin (TOR) Signaling:
Complex of MLST8-MTOR-MAPKAP1-RICTOR
→
AKT1
(activation)
Protein-Protein interactions - manually collected from original source literature:
Studies that report less than 10 interactions are marked with *
-
IRef Biogrid Interaction:
AKT1
—
RICTOR
(direct interaction, enzymatic study)
Sarbassov et al., Science 2005
-
IRef Biogrid Interaction:
AKT1
—
RICTOR
(direct interaction, enzymatic study)
Sarbassov et al., Mol Cell 2006*
-
IRef Biogrid Interaction:
AKT1
—
RICTOR
(direct interaction, enzymatic study)
Ikenoue et al., EMBO J 2008
-
IRef Biogrid Interaction:
AKT1
—
RICTOR
(direct interaction, enzymatic study)
Murata et al., J Biol Chem 2011
-
IRef Biogrid Interaction:
AKT1
—
RICTOR
(physical association, affinity chromatography technology)
Woods et al., Science signaling 2012
-
IRef Biogrid Interaction:
AKT1
—
RICTOR
(physical association, affinity chromatography technology)
Kim et al., Oncogene 2011*
Text-mined interactions from Literome
Sarbassov et al., Mol Cell 2006
:
mTORC2 phosphorylates and
activates Akt/PKB , a key regulator of cell survival ...
mTORC2 phosphorylates and
activates Akt/PKB , a key regulator of cell survival
Zeng et al., Blood 2007
(Leukemia, Myeloid, Acute) :
Rapamycin derivatives reduce
mTORC2 signaling and
inhibit AKT activation in AML
Hietakangas et al., Genes Dev 2007
:
Here we analyze the role of
TORC2 mediated
AKT phosphorylation in Drosophila
Woo et al., J Biol Chem 2007
(Breast Neoplasms...) :
Despite no significant effect of PRR5 on
mTORC2 mediated
Akt phosphorylation, PRR5 silencing inhibits Akt and S6K1 phosphorylation and reduces cell proliferation rates, a result consistent with PRR5 roles in cell growth and tumorigenesis
Masri et al., Cancer Res 2007
(Brain Neoplasms...) :
mTORC2 has recently been shown to phosphorylate and
activate Akt
McDonald et al., Cancer Res 2008
(Breast Neoplasms...) :
Rictor and integrin linked kinase interact and
regulate Akt phosphorylation and cancer cell survival
Wang et al., Oncology 2007
(Disease Models, Animal...) :
Either siRNA Raptor or siRNA
Rictor suppressed TNF-alpha expression, but the latter
suppressed the effects of GM3 on TNF-alpha expression and
Akt phosphorylation at Ser ( 473 ), indicating the GM3 signal to be transduced via Rictor/mTOR and Akt ( Ser ( 473 ) ), leading to TNF-alpha stimulation
Hietakangas et al., BMC cancer 2008
(Breast Neoplasms...) :
TOR complex 2 (TORC2) activates
AKT by phosphorylating it on the ` hydrophobic motif ' site
Bentzinger et al., Cell Metab 2008
(Muscular Dystrophies) :
Finally, we show that activation of
PKB/Akt does not
require mTORC2 ... Finally, we show that activation of
PKB/Akt does not
require mTORC2
Werzowa et al., Br J Dermatol 2009
(Melanoma...) :
Inhibition of
mTORC2 led to reduced levels of phosphorylated
AKT
Balasubramanian et al., Cardiovasc Hematol Agents Med Chem 2009
(Cardiomegaly) :
mTORC2 regulates the actin cytoskeleton in addition to activating
Akt ( Protein kinase B ) for the subsequent removal of proapoptotic factors via the UPS for cell survival
Lodeiro et al., PloS one 2009
:
This beta-arrestin scaffolded complex leads to full
activation of
Akt through PDK1 and
mTORC2 , which are not associated to the complex
Wang et al., Science signaling 2009
(Cardiovascular Diseases...) :
Rapamycin treatment of diet induced obese mice or of transgenic mice with long-term activation of endothelial
Akt inhibits
activation of mammalian target of rapamycin
(mTOR)-rictor complex 2 and Akt, prevents vascular senescence without altering body weight, and reduces the severity of limb necrosis and ischemic stroke
Bozulic et al., Curr Opin Cell Biol 2009
(Neoplasms) :
This present review concerns
PKB regulation by
mTORC2 and DNA-PK in a stimulus dependent and context dependent manner and the possible implications of this for PKB activity, substrate specificity and therapeutic intervention
Breuleux et al., Mol Cancer Ther 2009
(Neoplasms) :
Rictor may also play a role because rictor kinase complexes ( including mTOR/rictor )
regulate AKT S473 phosphorylation
Dibble et al., Mol Cell Biol 2009
:
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
Julien et al., Mol Cell Biol 2010
:
While mTOR complex 1 (mTORC1) regulates mRNA translation and ribosome biogenesis,
mTORC2 plays an important role in the phosphorylation and subsequent activation of
Akt ... However, cells expressing a Rictor T1135A mutant were found to have increased
mTORC2 dependent phosphorylation of
Akt ... In addition, phosphorylation of the Akt substrates FoxO1/3a and glycogen synthase kinase 3 alpha/beta ( GSK3 alpha/beta ) was found to be increased in these cells, indicating that S6K1 mediated phosphorylation of
Rictor inhibits mTORC2 and
Akt signaling
Yu et al., Cancer Res 2010
(Neoplasms) :
Importantly, consistent with genetic ablation of mTORC2, WYE-132 targeted P-AKT ( S473 ) and AKT function without significantly reducing the steady-state level of the PI3K/PDK1 activity biomarker P-AKT ( T308 ), highlighting a prominent and direct
regulation of
AKT by
mTORC2 in cancer cells
Yang et al., Cell cycle (Georgetown, Tex.) 2010
(Neoplasms) :
Akt activity is well-known
regulated through its phosphorylation at T308 and S473 by PDK1 and
mTOrC2 , respectively
Liao et al., J Cell Sci 2010
:
Chemotactic activation of Dictyostelium AGC-family kinases
AKT and PKBR1
requires separate but coordinated functions of PDK1 and
TORC2
Wu et al., Urol Oncol 2012
(Carcinoma, Transitional Cell...) :
Rictor dependent
AKT activation and inhibition of urothelial carcinoma by rapamycin
Sini et al., Autophagy 2010
(Neoplasms) :
mTORC2 activates
AKT directly by phosphorylating Serine 473
Chen et al., Mol Carcinog 2010
(Neoplasms) :
In this report, we focused on studying the
role of mTORC1 and
mTORC2 in rapamycin mediated
Akt and ERK phosphorylation, and the antitumor effect of rapamycin in cancer cells in combination with Akt and ERK inhibitors ... Collectively, we conclude that
mTORC2 plays a much more important role than mTORC1 in rapamycin mediated phosphorylation of
Akt and ERK, and cotargeting AKT and ERK signaling may be a new strategy for enhancing the efficacy of rapamycin based therapeutic approaches in cancer cells
Cleveland-Donovan et al., Endocrinology 2010
(Obesity) :
The mammalian target of rapamycin
(mTOR)-Rictor complex regulates phosphorylation of
AKT-serine ( 473 ) in 3T3-L1 adipocytes, but knockdown of Rictor by lentivirus delivered short hairpin RNA in sc preadipocytes did not affect AKT-serine ( 473 ) phosphorylation by IGF-I
Lee et al., Immunity 2010
:
mTORC2 promoted phosphorylation of
protein kinase B ( PKB, or Akt ) and PKC, Akt activity, and nuclear NF-kappaB transcription factors in response to T cell activation
Kim et al., J Lipid Res 2010
:
The lipogenic effects of GIP in the presence of insulin are therefore at least partially mediated by upregulation of adipocyte LPL gene transcription through a pathway involving
PI3-K/PKB/AMPK dependent
CREB/TORC2 activation
Lee et al., Genes Dev 2010
:
Collectively, these findings establish
mTOR/rictor mediated
Akt activation as a key driver of NSC proliferation and gliogenesis, and identify a unique mechanism for conferring brain region-specific responses to cancer causing genetic changes
Yamada et al., Histochem Cell Biol 2010
:
Silencing by Rictor siRNA resulted in the attenuation of
Akt phosphorylation on Ser473 and PKCa/ßII phosphorylation, as well as the
inhibition of
Rictor itself, suggesting that Rictor is an upstream regulator of both Akt and PKC ... Taken together, our results show that
Rictor associated with mTOR ( mTORC2 )
regulates the activity of both
Akt and PKC that are involved in cell functions such as NBT reduction and esterase activity induced by leukemia cell differentiation
Dunaway et al., Mol Cell Biol 2011
:
Slit2 stimulates angiogenesis through
mTORC2 dependent activation of
Akt and Rac GTPase, the activities of which are inhibited in the presence of ephrin-A1
Murata et al., J Biol Chem 2011
(Neuroblastoma...) :
A new cytosolic pathway from a Parkinson disease associated kinase, BRPK/PINK1 :
activation of
AKT via
mTORC2
Harston et al., Am J Physiol Heart Circ Physiol 2011
(Hypertrophy) :
Another molecular keystone involved in the hypertrophic growth process is the mammalian target of rapamycin (mTOR), which forms two distinct functional complexes : mTORC1 that activates p70S6 kinase-1 to enhance protein synthesis and
mTORC2 that
activates Akt to promote cell survival
Pearce et al., Biochem J 2011
:
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 )
Guo et al., Arterioscler Thromb Vasc Biol 2011
:
According to Western blot analysis and immunoprecipitation results, rHDL promoted mTOR phosphorylation, mTOR-rictor complex formation, and
mTOR-rictor dependent
Akt activation, which were accompanied by increased nuclear translocation of human telomerase reverse transcriptase and enhanced nuclear telomerase activity
Hiraoka et al., Oncogene 2011
:
A well conserved threonine in the turn motif ( TM ) is also constitutively phosphorylated by
mTORC2 and
contributes to the stability of
Akt
Moore et al., J Biol Chem 2011
(MAP Kinase Signaling System) :
In this study, we investigated the
role of the mammalian target of rapamycin complex (
mTORC)-2 in
Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1
Lazorchak et al., Protein & cell 2011
(Cell Transformation, Neoplastic) :
We also propose a novel strategy to treat cancers based on our recent discovery that
mTORC2 regulates
Akt protein stability
Boulbés et al., Biochem Biophys Res Commun 2011
:
Based on our study we suggest that the
mTORC2 dependent phosphorylation of
Akt on Ser-473 takes place on the surface of ER
Hwang et al., BMB Rep 2011
(Ischemia) :
The loss of TSC2, which is upstream of mTOR, activates S6K1, promotes cell growth and survival, activates mTOR kinase activities,
inhibits mTORC1 and
mTORC2 via mTOR inhibitors, and suppresses S6K1 and
Akt
Gupta et al., Blood 2012
(Lymphoma) :
Dual
mTORC1/mTORC2 inhibition
diminishes Akt activation and induces Puma dependent apoptosis in lymphoid malignancies
Koh et al., Endocr Relat Cancer 2012
(Carcinoma...) :
Cells treated with everolimus demonstrated
activation of
Akt and Ret via
TORC2 complex dependent and TORC2 complex independent mechanisms respectively
Fang et al., J Biol Chem 2012
(Prostatic Neoplasms) :
Significantly, androgen increased
TORC2 mediated
AKT S473 phosphorylation without affecting the PDK1 mediated AKT T308 phosphorylation or TORC1 activity ... This study reveals a pathway linking AR to a selective activation of
TORC2 , the subsequent
activation of
AKT , and phosphorylation of a discrete set of AKT substrates that regulate cellular proliferation and survival
Rodrik-Outmezguine et al., Cancer Discov 2011
:
mTOR kinase inhibitors block mTORC1 and mTORC2 and thus do not cause the
mTORC2 activation of
AKT observed with rapamycin ... Inhibition of
mTORC2 leads to AKT serine 473 ( S473 ) dephosphorylation and a rapid but transient inhibition of AKT T308 phosphorylation and
AKT signaling
Espona-Fiedler et al., Biochem Pharmacol 2012
(Melanoma) :
The inhibition of mTORC1 and
mTORC2 complexes by PG or OBX
resulted in a loss of
AKT phosphorylation at S473, preventing its full activation, with no significant effect on T308
Misra et al., J Cell Biochem 2012
(Prostatic Neoplasms) :
We measured
mTORC2 dependent
Akt phosphorylation at S473 in immunoprecipitates of mTOR or Rictor from 1-LN cells ... Silencing
Rictor gene expression by RNAi significantly
suppressed 8-CPT-2Me-cAMP induced phosphorylation of
Akt at Ser ( 473 ) ... These studies represent the first report that Epac1 mediates
mTORC2 dependent phosphorylation of
Akt ( S473 )
Rosel et al., J Cell Sci 2012
:
TORC1 is required for growth in response to growth factors, nutrients and the cellular energy state ;
TORC2 regulates
AKT signaling, which can modulate cytoskeletal polarization
Riaz et al., PloS one 2012
:
Receptor-specific mechanisms
regulate phosphorylation of
AKT at Ser473 : role of
RICTOR in ß1 integrin mediated cell survival ...
RICTOR-mTOR was
required also for LPA induced
AKT Ser473 phosphorylation in MCF7 cells, but, interestingly, not in HeLa cells
Wang et al., Mol Cell Biol 2012
(Dermatitis, Seborrheic) :
Surprisingly, however,
TORC2 does not
regulate cell growth via its best characterized target,
AKT
Kaur et al., Proc Natl Acad Sci U S A 2012
:
We provide evidence that
mTORC2 complexes
control IFN induced phosphorylation of
AKT on serine 473 and their function is ultimately required for IFN dependent gene transcription via interferon stimulated response elements
Chang et al., Eur J Immunol 2012
:
Sin1 deficiency blocks the
mTORC2 dependent
Akt phosphorylation in T cells during development and activation
Floc'h et al., Cancer Res 2012
(Disease Models, Animal...) :
In human prostate cancer cell lines, although not in the mouse model, the synergistic actions of MK-2206 and ridaforolimus ( MK-8669 ) are due in part to limiting the
mTORC2 feedback
activation of
Akt
Najafov et al., Biochem J 2012
(Neoplasms) :
Akt is
activated by phosphorylation of its T-loop residue ( Thr ( 308 ) ) by PDK1 ( 3-phosphoinositide dependent kinase-1 ) and its C-terminal hydrophobic motif ( Ser ( 473 ) ) by
mTORC2 [ mTOR ( mammalian target of rapamycin ) complex 2 ]
Matheny et al., Growth Factors 2012
:
Enhanced
Akt phosphorylation and myogenic differentiation in PI3K p110ß-deficient myoblasts is
mediated by PI3K p110a and
mTORC2
Parrales et al., Cell Signal 2013
:
Since
Akt functions as an upstream activator of mechanistic target of rapamycin complex 1 ( mTORC1 ) and is also a downstream
target for
mTORC2 , the aim of this work was to determine whether mTOR is involved in thrombin induced RPE cell proliferation by regulating cyclin D1 expression in immortalized rat RPE-J cell line
Yao et al., Science signaling 2013
:
BSTA promotes
mTORC2 mediated phosphorylation of
Akt1 to suppress expression of FoxC2 and stimulate adipocyte differentiation ... The mammalian target of rapamycin complex 2 ( mTORC2 ) facilitated the phosphorylation of BSTA and its association with Akt1, and the
BSTA-Akt1 interaction
promoted the association of
mTORC2 with Akt1 and phosphorylation of Akt1 at Ser473 in response to growth factor stimulation
Razmara et al., Cell communication and signaling : CCS 2013
:
Platelet derived growth factor induced
Akt phosphorylation
requires mTOR/Rictor and phospholipase C-?1, whereas S6 phosphorylation depends on mTOR/Raptor and phospholipase D ... mTORC1 is activated in a PLD dependent manner and promotes phosphorylation of the S6 protein, whereas
mTORC2 , in concert with PLC? signaling,
promotes Akt phosphorylation
Shortt et al., Blood 2013
(Lymphoma, B-Cell) :
Moreover, apoptosis was initiated at drug concentrations insufficient to antagonize
PI3K/mTORC2 regulated
AKT phosphorylation
Wolin et al., Cancer Lett 2013
(Neuroendocrine Tumors...) :
The mTOR inhibitor everolimus has been approved by the FDA for the treatment of pNET, but its efficacy may be limited by its inability to prevent
mTORC2 mediated activation of
Akt
Riaz et al., J Biol Chem 2013
:
Protein suppression using specific siRNAs revealed that heparanase induced phosphorylation of
AKT at Ser-473 was
RICTOR-mTOR dependent , whereas ILK and PAK1/2 were dispensable
Moschella et al., Cell Signal 2013
:
Since mTORC2 is known to mediate the activation of a prosurvival kinase, Akt, we analyzed whether
mTORC2 directly
mediates Akt activation or whether it requires the participation of another prosurvival kinase, PKCe ( epsilon isoform of protein kinase-C )
Jeon et al., Biochim Biophys Acta 2013
(Breast Neoplasms...) :
When SelW was down-regulated,
mTORC2 dependent phosphorylation of
Akt at Ser473 was decreased
Melnik et al., Exp Dermatol 2013
:
Antiandrogens may attenuate mTORC1 by suppressing
mTORC2 mediated
Akt/TSC2 signalling
Wang et al., PloS one 2013
:
Western blotting showed that the PP242 inhibition of
mTORC2 mediated
AKT phosphorylation at Ser 473 ( AKT ( S473 ) ) was transient only in the first few hours of the PP242 treatment