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AKT1 — TSC2
Pathways - manually collected, often from reviews:
-
OpenBEL Selventa BEL large corpus:
Complex of TSC1-TSC2
→
AKT1
(decreases, AKT1 Activity, TSC1/TSC2 Activity)
Petroulakis et al., Br J Cancer 2006*
Evidence: In turn, Akt phosphorylates the tuberous scleorisis complex, TSC1/TSC2 (hamartin/tuberin) that serves as a GTPase activating protein (GAP) for the small G protein, Ras homolog enriched in brain (Rheb).
-
KEGG mTOR signaling pathway:
AKT1/AKT2/AKT3
→
TSC2
(protein-protein, inhibition)
-
KEGG Insulin signaling pathway:
AKT1/AKT2/AKT3
→
TSC2
(protein-protein, inhibition)
-
NCI Pathway Database mTOR signaling pathway:
AKT1 (AKT1)
→
TSC1/TSC2 complex (TSC1-TSC2)
(modification, activates)
Inoki et al., Nat Cell Biol 2002*, Garami et al., Mol Cell 2003, Sancak et al., Mol Cell 2007
Evidence: mutant phenotype, assay, physical interaction
-
Reactome Reaction:
AKT1
→
TSC2
(reaction)
Manning et al., Mol Cell 2002*, Inoki et al., Nat Cell Biol 2002*
-
WikiPathways Focal Adhesion-PI3K-Akt-mTOR-signaling pathway:
AKT1/AKT3/AKT2
→
TSC1/TSC2
(inhibition)
-
WikiPathways Angiopoietin Like Protein 8 Regulatory Pathway:
AKT1/AKT2
→
TSC2/TSC1
(inhibition)
Kwiatkowski et al., Hum Mol Genet 2005*, Vadlakonda et al., Frontiers in oncology 2013*
-
WikiPathways Insulin Signaling:
GSK3B/AKT2/AKT1/SGK3/SGK1/GSK3A/PDPK1/SGK2
→
TSC2/TSC1
(inhibition)
-
WikiPathways Angiopoietin Like Protein 8 Regulatory Pathway:
AKT1/AKT2
→
TSC2/TSC1
(inhibition)
-
WikiPathways PI3K-AKT-mTOR signaling pathway and therapeutic opportunities:
AKT1
→
TSC2
(mim-inhibition)
-
WikiPathways Signaling Pathways in Glioblastoma:
AKT1/AKT2/AKT3
→
Complex of TSC1-TSC2
(mim-inhibition)
-
WikiPathways Target Of Rapamycin (TOR) Signaling:
AKT1
→
Complex of TSC2-TSC1
(inhibition)
-
WikiPathways BDNF-TrkB Signaling:
AKT1
→
Complex of TSC1-TSC2
(mim-inhibition)
Protein-Protein interactions - manually collected from original source literature:
Studies that report less than 10 interactions are marked with *
-
IRef Bind_translation Interaction:
AKT1
—
TSC2
(coimmunoprecipitation)
Manning et al., Mol Cell 2002*
-
IRef Bind_translation Interaction:
AKT1
—
TSC2
(experimental interaction detection)
Manning et al., Mol Cell 2002*
-
IRef Biogrid Interaction:
AKT1
—
TSC2
(physical association, affinity chromatography technology)
Dan et al., J Biol Chem 2002*
-
IRef Biogrid Interaction:
AKT1
—
TSC2
(physical association, affinity chromatography technology)
Roux et al., Proc Natl Acad Sci U S A 2004
-
IRef Biogrid Interaction:
AKT1
—
TSC2
(direct interaction, pull down)
Dan et al., J Biol Chem 2002*
-
IRef Hprd Interaction:
AKT1
—
TSC2
(in vitro)
Manning et al., Mol Cell 2002*, Liu et al., Cancer Res 2002*
-
IRef Ophid Interaction:
AKT1
—
TSC2
(aggregation, interologs mapping)
Brown et al., Bioinformatics 2005
Text-mined interactions from Literome
Potter et al., Nat Cell Biol 2002
:
Akt regulates growth by directly phosphorylating
Tsc2 ... Stimulating
Akt/PKB signalling in vivo markedly
increases cell growth/size, disrupts the Tsc1-Tsc2 complex and disturbs the distinct subcellular localization of Tsc1 and
Tsc2
Potter et al., Biochem Soc Trans 2003
:
We have shown that
Akt regulates the
Tsc1-Tsc2 complex by directly phosphorylating Tsc2 ... We have shown that
Akt regulates the Tsc1-Tsc2 complex by directly phosphorylating
Tsc2
Hahn-Windgassen et al., J Biol Chem 2005
:
Here we establish an additional pathway by which
Akt inhibits
TSC2 and activates mTOR ... Currently, the
Akt mediated phosphorylation of TSC2 and the inhibition of AMPK mediated phosphorylation of
TSC2 are viewed as two separate pathways, which activate mTOR ... Our results demonstrate that
Akt lies upstream of these two pathways and
induces full inhibition of
TSC2 and activation of mTOR both through direct phosphorylation and by inhibition of AMPK mediated phosphorylation of TSC2
Kayampilly et al., Endocrinology 2007
(MAP Kinase Signaling System) :
Because
Akt is the upstream
activator of
TSC2 phosphorylation, the effect of Akt inhibition was examined to test whether FSH mediated TSC2 phosphorylation proceeds through an Akt dependent pathway ... These results demonstrate the
involvement of ERK rather than
Akt in FSH mediated
TSC2 phosphorylation in granulosa cells
Vojtechová et al., Neoplasia (New York, N.Y.) 2008
:
The ectopic, active
Akt1 that was expressed in Src-deficient cells significantly
enhanced phosphorylation of
TSC2 in these cells, but it failed to activate the inhibited components of the mTOR pathway that are downstream of TSC2
Dan et al., J Immunol 2008
:
mTOR is negatively controlled by the tuberous sclerosis complex 1/2 (TSC1/2), and activation of
Akt induces phosphorylation of
TSC2 , which blocks the repressive TSC1/2 activity
Huang et al., Biochem Soc Trans 2009
:
Akt/PKB ( protein kinase B ) both regulates and is
regulated by the TSC ( tuberous sclerosis complex )
1-TSC2 complex ...
Akt/PKB ( protein kinase B ) both regulates and is
regulated by the TSC ( tuberous sclerosis complex )
1-TSC2 complex
Codeluppi et al., J Neurosci 2009
(Disease Models, Animal...) :
This occurs through
Akt mediated phosphorylation of the GTPase activating protein
Tuberin , which inhibits Tuberin 's ability to inactivate the small GTPase Rheb
Pollizzi et al., Molecular cancer 2009
(Disease Models, Animal...) :
Loss of either TSC1 or
TSC2 in TSC hamartomas
leads to activation of mTORC1 and suppression of
AKT
Zhang et al., PloS one 2009
:
Loss of function of the
TSC1-TSC2 complex results in constitutive mTORC1 signaling and, through mTORC1 dependent feedback mechanisms and loss of mTORC2 activity,
leads to a concomitant block of
Akt signaling to its other downstream targets
Blancquaert et al., Mol Endocrinol 2010
:
Unlike insulin, TSH/cAMP did not activate
protein kinase B or
induce tuberous sclerosis complex 2 phosphorylation at T1462 and Y1571
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
Das et al., J Biol Chem 2012
(Tuberous Sclerosis) :
TSC2 deficiency
induces constitutive activation of mTOR, leading to a state of insulin resistance due to a negative feedback regulation, resulting in reduced
Akt phosphorylation
Zurashvili et al., Mol Cell Biol 2013
:
In contrast,
PKB mediated phosphorylation of PRAS40 and
TSC2 , allowing optimal mTORC1 activation and brain-specific kinase (BRSK) protein synthesis, was markedly reduced in the mutant mice, leading to impaired neuronal growth and differentiation