| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Tuberin did not stimulate the GTPase activity of Rap 2 , Ha Ras , Rac , or Rho . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Phosphatidylinositol 3 kinase / Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin . ^^^ Expression of constitutively active PI3K or active Akt , including Akt 1 and Akt 2 , induces tuberin phosphorylation . ^^^ We further demonstrate that Akt / PKB associates with hamartin tuberin complexes , promoting phosphorylation of tuberin and increased degradation of hamartin tuberin complexes . ^^^ Akt also inhibits tuberin mediated degradation of p 27 ( kip 1 ) , thereby promoting CDK 2 activity and cellular proliferation . ^^^ Our results indicate that tuberin is a direct physiological substrate of Akt and that phosphorylation of tuberin by PI3K / Akt is a major mechanism controlling hamartin tuberin function . . ^^^ |
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| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| On growth factor stimulation , tuberin , the TSC 2 protein , is phosphorylated by Akt , thereby releasing its inhibitory effects on p70S6K . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Tuberin , the product of the tuberous sclerosis complex 2 tumor suppressor gene , is a phosphoprotein that negatively regulates phosphatidylinositol 3 ' kinase signaling downstream of Akt . ^^^ Several high stringency 14 3 3 binding sites that overlapped with Akt phosphorylation sites were identified in tuberin in silico . ^^^ Recognition of tuberin by an alpha 14 3 3 binding site specific antibody correlated with mitogen induced phosphorylation of tuberin and recognition of tuberin by an alpha Akt phosphorylation substrate antibody . ^^^ These data establish the presence of functional and overlapping 14 3 3 and Akt recognition site ( s ) in tuberin . . ^^^ |
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| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| TSC 2 , or tuberin , is the product of the tuberous sclerosis tumor suppressor gene TSC 2 and acts downstream of the phosphatidylinositol 3 kinase Akt signaling pathway to negatively regulate cellular growth . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Akt activation promotes degradation of tuberin and FOXO3a via the proteasome . ^^^ Expression of activated Akt triggered proteasome dependent declines in the protein levels of the Akt substrates tuberin , FOXO 1 , and FOXO3a . ^^^ The addition of proteasome inhibitors stabilized the phosphorylated forms of multiple Akt substrates , including tuberin and FOXO proteins . ^^^ |
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| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| PKB triggers a network that positively regulates G1 / S cell cycle progression through inactivation of GSK 3 beta , leading to increased cyclin D 1 , and inhibition of Forkhead family transcription factors and the tumor suppressor tuberin ( TSC 2 ) , leading to reduction of p27Kip1 . ^^^ |
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| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Inactivation of the tuberous sclerosis complex 1 and 2 gene products occurs by phosphoinositide 3 kinase / Akt dependent and independent phosphorylation of tuberin . ^^^ During mitogenic sufficiency , the phosphoinositide 3 kinase ( PI3K ) / Akt pathway phosphorylates tuberin on Ser 939 and Thr 1462 that inhibits the tumor suppressor function of the TSC complex . ^^^ PKC / MAPK signaling leads to phosphorylation of tuberin at sites that overlap with and are distinct from Akt phosphorylation sites . ^^^ |
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| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Our results define a signaling pathway in GCs whereby the inactivating phosphorylation of tuberin downstream of phosphatidylinositol ( PI ) 3 kinase / AKT activity leads to Rheb ( Ras homolog enriched in brain ) and subsequent mTOR ( mammalian target of rapamycin ) activation . mTOR then stimulates translation by phosphorylating p 70 S6 kinase and , consequently , the 40 S ribosomal protein S 6 . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Phosphatidylinositol 3 kinase ( PI3K ) inactivates the tumor suppressor complex and enhances mTOR signaling by means of phosphorylation of tuberin by Akt . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Tuberin , serving as a substrate of AKT and AMPK , mediates mTOR activity by coordinating inputs from growth factors and energy availability in the control of cell growth , proliferation , and survival . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Prostaglandin E 2 mediates phosphorylation and down regulation of the tuberous sclerosis 2 tumor suppressor ( tuberin ) in human endometrial adenocarcinoma cells via the Akt signaling pathway . ^^^ This study investigated the expression and localization of tuberin in neoplastic and normal endometrium and the effect of PGE 2 on phosphorylation of tuberin via the Akt pathway . ^^^ We investigated the effect of PGE 2 on phosphorylation of tuberin via the Akt pathway . ^^^ PGE 2 also phosphorylated Akt and tuberin in Ishikawa endometrial adenocarcinoma cells , leading to a reduction in expression of total tuberin protein . ^^^ Cotreatment of cells with wortmannin or LY 294002 inhibited the PGE 2 induced phosphorylation of Akt and tuberin . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| RECENT FINDINGS : These have been found in two major areas : genetic studies in Drosophila followed by studies in mammalian systems have identified the components of the Tuberous Sclerosis protein complex , a heterodimer of the proteins Hamartin and Tuberin , as inhibitors of TOR signaling , and as the major targets by which the insulin / IGF 1 signal transduction pathway , through the protein kinase PKB , and the energy status of the cell , through the AMP activated protein kinase , regulate the TOR signaling . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Inhibition of the phosphatidylinositol 3 kinase ( PI3K ) by wortmannin or overexpression of the kinase dead Akt mutant completely blocked the NGF induced tuberin phosphorylation and degradation . ^^^ Epidermal growth factor can similarly induce tuberin phosphorylation and degradation via a PI3K / Akt pathway in PC 12 cells , but these responses were insensitive to pertussis toxin treatment . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Nicotinic activation of Akt increased phosphorylation of multiple downstream substrates of Akt in a time dependent manner , including GSK 3 , FKHR , tuberin , mTOR and S6K1 . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| This aberrant activation depends on Ras and PI 3 kinase , and is mediated by the phosphorylation and inactivation of the TSC 2 encoded protein tuberin by AKT . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Additional experiments showed that CCh treatment augmented NGF induced phosphorylation and degradation of the Akt regulated translation regulator tuberin . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Triple antisense knock down of PKB alpha , beta , and gamma abrogated the insulin stimulated phosphorylation of WNK 1 , ATP citrate lyase , and tuberin . ^^^ Role of protein kinase B in phosphorylating glycogen synthase kinase 3 , tuberin , WNK 1 , and ATP citrate lyase . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| The complex of AS 250 with KIAA 1219 is notably similar to the important regulatory complex of the protein tuberin with hamartin ( the tuberous sclerosis complex ) , in the size of its subunits , the location of the GAP domain , and its phosphorylation by Akt . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| In response to growth signals , tuberin is phosphorylated by AKT and translocates to the cytosol , relieving Rheb repression . ^^^ Thus , tuberin bound by 14 3 3 in response to AKT phosphorylation is sequestered away from its membrane bound activation partner ( hamartin ) and its target GTPase ( Rheb ) to relieve the growth inhibitory effects of this tumor suppressor . . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| AKT phosphorylation negatively regulates tuberin ' s potential to trigger apoptosis . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Additional experiments showed that G alpha11QL , G alpha14QL , G alpha16QL , G alpha12QL and G alpha13QL , but not G alpha ( s ) QL , attenuated phosphorylation of the Akt regulated translation regulator tuberin . ^^^ Moreover , they were able to inhibit the epidermal growth factor induced Akt activation and tuberin phosphorylation . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Since phosphorylation of Bad occurred at serine 136 , the target of the serine / threonine kinase Akt , the effect of LAM on Akt kinase activity was tested . ^^^ Man LAM could activate Akt as evidenced from phosphorylation of Akt at Thr ( 308 ) and by the phosphorylation of the exogenous substrate histone 2B . ^^^ The phosphorylation of Bad by man LAM was abrogated in cells transfected with a kinase dead mutant of Akt . ^^^ These results establish that LAM mediated Bad phosphorylation occurs in a PI 3K / Akt dependent manner . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Accordingly , T47D cells grown on LAM had the greatest increase in ErbB 2 activation , PI3K activity , and phosphorylation of Akt . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Akt activity was unchanged in LAM cells . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| TSC 2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling . ^^^ Furthermore , TSC 2 is directly phosphorylated by Akt , which is involved in stimulating cell growth and is activated by growth stimulating signals , such as insulin . ^^^ TSC 2 is inactivated by Akt dependent phosphorylation , which destabilizes TSC 2 and disrupts its interaction with TSC 1 . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Akt regulates growth by directly phosphorylating Tsc 2 . ^^^ Here , we report that Drosophila melanogaster Akt / PKB stimulates growth by phosphorylating the tuberous sclerosis complex 2 ( Tsc 2 ) tumour suppressor and inhibiting formation of a Tsc 1 Tsc2 complex . ^^^ We show that Akt / PKB directly phosphorylates Drosophila Tsc 2 in vitro at the conserved residues , Ser 924 and Thr 1518 . ^^^ Mutation of these sites renders Tsc 2 insensitive to Akt / PKB signalling , increasing the stability of the Tsc 1 Tsc2 complex within the cell . ^^^ Stimulating Akt / PKB signalling in vivo markedly increases cell growth / size , disrupts the Tsc 1 Tsc2 complex and disturbs the distinct subcellular localization of Tsc 1 and Tsc 2 . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| TSC 2 is negatively regulated by Akt phosphorylation . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Using genetic and biochemical methods , we have shown that Tsc 1 and Tsc 2 function in the insulin / phosphoinositide 3 kinase ( PI3K ) / Akt pathway . ^^^ We have shown that Akt regulates the Tsc 1 Tsc2 complex by directly phosphorylating Tsc 2 . ^^^ |
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| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| There is a marked reduction in Akt activation in Tsc 2 ( / ) TP 53 ( / ) and Tsc 1 ( / ) cells in response to serum and PDGF , along with a reduction in cell ruffling . ^^^ PDGFRalpha and PDGFRbeta expression is markedly reduced in both the cell lines and Tsc mouse renal cystadenomas , and ectopic expression of PDGFRbeta in Tsc 2 null cells restores Akt phosphorylation in response to serum , PDGF , EGF , and insulin . ^^^ This activation of mTOR along with downregulation of PDGFR PI3K Akt signaling in cells lacking Tsc 1 or Tsc 2 may explain why these genes are rarely involved in human cancer . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Studies initiated in Drosophila have identified a role for the Tsc 1 and Tsc 2 genes in the regulation of cell and organ size , and genetic interaction studies have placed them in the PI3K Akt mTOR S6K pathway . ^^^ Biochemical studies have shown that activated Akt phosphorylates TSC 2 in the TSC1 / TSC2 protein complex , inactivating it ; while TSC1 / TSC2 has GAP activity for the Rheb GTPase ( a member of the ras family ) , and activated Rheb GTP activates mTOR . ^^^ |
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| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| The signaling pathway downstream of Akt leading to mTOR involves the protein products of the genes mutated in tuberous sclerosis , TSC 1 and TSC 2 , and the small guanosine triphosphatase , Rheb . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Tsc 2 was also identified as a novel Akt target , whose phosphorylation and inactivation by Akt may lead to an increase in cell size . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Downstream of PI3K , the survival kinase , Akt , is completely refractory to activation by IRS dependent growth factor pathways such as insulin or IGF 1 in TSC 1 or TSC 2 deficient cells but not to activation by IRS independent pathways such as those utilized by PDGF . ^^^ |
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| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Tsc 2 is not a critical target of Akt during normal Drosophila development . ^^^ It was reported that Akt , an essential component of the insulin pathway , stimulates growth by phosphorylating and inhibiting tuberous sclerosis complex 2 ( TSC 2 ) . ^^^ Here we evaluate this model genetically in Drosophila by engineering Tsc 2 mutants in which the Akt phosphorylation sites are changed to nonphosphorylatable or phospho mimicking residues . ^^^ Taken together , our data suggest that Tsc 2 is not a critical substrate of Akt in normal Drosophila development . . ^^^ |
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| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Our data support that RTP 801 and RTP801L work downstream of AKT and upstream of TSC 2 to inhibit mTOR functions . ^^^ |
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| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Selective activation of AMPK PGC 1alpha or PKB TSC 2 mTOR signaling can explain specific adaptive responses to endurance or resistance training like electrical muscle stimulation . ^^^ LFS had no effect on PKB phosphorylation but reduced TSC 2 phosphorylation at Thr 1462 and deactivated translational regulators . ^^^ In contrast , HFS acutely increased phosphorylation of PKB at Ser 473 5 . 3 fold and the phosphorylation of TSC 2 , mTOR , GSK 3beta at PKB sensitive sites . ^^^ HFS selectively activates the PKB TSC 2 mTOR cascade causing a prolonged activation of translational regulators , which is consistent with increased protein synthesis and muscle growth . ^^^ |
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| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| The known pathway by which Akt activates mTOR is via direct phosphorylation and inhibition of tuberous sclerosis complex 2 ( TSC 2 ) , which is a negative regulator of mTOR . ^^^ Here we establish an additional pathway by which Akt inhibits TSC 2 and activates mTOR . ^^^ We provide for the first time genetic evidence that Akt regulates intracellular ATP level and demonstrate that Akt is a negative regulator of the AMP activated protein kinase ( AMPK ) , which is an activator of TSC 2 . ^^^ Currently , the Akt mediated phosphorylation of TSC 2 and the inhibition of AMPK mediated phosphorylation of TSC 2 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 TSC 2 and activation of mTOR both through direct phosphorylation and by inhibition of AMPK mediated phosphorylation of TSC 2 . ^^^ |
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| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| The PTEN and TSC 2 tumor suppressors function to antagonize mTOR ( mammalian target of rapamycin ) activation by Akt ; hence , compound heterozygous inactivation of Pten and Tsc 2 in the mouse may in principle exacerbate the tumor phenotypes observed in the single mutants in a reciprocal manner . ^^^ |
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| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc 2 . ^^^ This study demonstrates that attenuation of the PI3K Akt pathway in tumors lacking TSC 2 contributes to their benign nature . . ^^^ |
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| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| The mTOR signaling network contains a number of tumor suppressor genes including PTEN , LKB 1 , TSC 1 , and TSC 2 , and a number of proto oncogenes including PI3K , Akt , and eIF4E , and mTOR signaling is constitutively activated in many tumor types . ^^^ |
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| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Overexpression of hVps 34 or the associated hVps 15 kinase activates S6K1 , and insulin stimulation of S6K1 is blocked by microinjection of inhibitory anti hVps 34 antibodies , overexpression of a FYVE domain construct that sequesters the hVps 34 product PI3P , or small interfering RNA mediated knock down of hVps 34 . hVps 34 is not part of the insulin input to S6K1 , as it is not stimulated by insulin , and inhibition of hVps 34 has no effect on phosphorylation of Akt or TSC 2 in insulin stimulated cells . ^^^ |
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| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Two recent studies used mouse genetics to assess the roles of PTEN and TSC 2 in cancer , underscoring the importance of Akt mTOR interplay for cancer progression and therapy . . ^^^ |
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| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| In this regard , AMPK PGC 1alpha signaling mediates several adaptations to endurance training , while up regulation of the Akt TSC 2 mTOR pathway may underlie increased protein synthesis after resistance exercise . ^^^ |
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| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| Mechanism of Akt 1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC 2 . ^^^ Here we show that overexpression of activated myr Akt 1 in human breast cancer cells phosphorylates and thereby targets the tumor suppressor tuberous sclerosis complex 2 ( TSC 2 ) for degradation , leading to reduced Rho GTPase activity , decreased actin stress fibers and focal adhesions , and reduced motility and invasion . ^^^ Overexpression of TSC 2 rescues the migration phenotype of myr Akt 1 expressing tumor cells , and high levels of TSC 2 in breast cancer patients correlate with increased metastasis and reduced survival . ^^^ |
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| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| PKB also phosphorylates the TSC 1 ( tuberous sclerosis complex 1 ) TSC 2 complex to relieve its inhibitory action on the mTOR ( mammalian target of rapamycin ) . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| The AMPK signalling network contains a number of tumour suppressor genes including LKB 1 , p 53 , TSC 1 and TSC 2 , and overcomes growth factor signalling from a variety of stimuli ( via growth factors and by abnormal regulation of cellular proto oncogenes including PI3K , Akt and ERK ) . ^^^ |
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| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| AKT activation in human glioblastomas enhances proliferation via TSC 2 and S 6 kinase signaling . ^^^ Within individual tumors , increased expression levels of p TSC 2 , p mTOR , p 4E BP 1 , p S6K , p S 6 , and p STAT 3 were found in regions defined by elevated AKT activation . ^^^ However , only TSC 2 , S6K , and S 6 activation levels correlated significantly with AKT activation and clustered together in multidimensional scaling analyses . ^^^ These findings provide the first in vivo evidence for a close correlation between AKT and TSC 2 phosphorylation levels in glioblastoma . ^^^ |
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| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| AKT independent phosphorylation of TSC 2 and activation of mTOR and ribosomal protein S 6 kinase signaling by prostaglandin F2alpha . ^^^ Treatment with PGF2alpha did not increase AKT phosphorylation but increased the phosphorylation of Erk and the tumor suppressor protein tuberous sclerosis complex 2 ( TSC 2 ) , an upstream regulator of mTOR . ^^^ |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P49815 and P31749 |
Pubmed |
SVM Score :0.0 |
| NA |
|