SIN1/MIP1 Maintains rictor-mTOR Complex Integrity and Regulates Akt Phosphorylation and Substrate Specificity

@article{Jacinto2006SIN1MIP1MR,
  title={SIN1/MIP1 Maintains rictor-mTOR Complex Integrity and Regulates Akt Phosphorylation and Substrate Specificity},
  author={Estela Jacinto and Valeria Facchinetti and Dou Liu and Nelyn Soto and Shiniu Wei and Sung Yun Jung and Qiaojia Huang and Jun Qin and Bing Su},
  journal={Cell},
  year={2006},
  volume={127},
  pages={125-137}
}

Figures from this paper

mTORC1-Activated S6K1 Phosphorylates Rictor on Threonine 1135 and Regulates mTORC2 Signaling
TLDR
It is shown that growth factors promote the phosphorylation of Rictor (rapamycin-insensitive companion of mTOR), an essential subunit of m TORC2, and a new regulatory link between the two mTOR complexes is uncovered, whereby RictOr integrates mTORC1-dependent signaling.
CUL5-SOCS6 complex regulates mTORC2 function by targeting Sin1 for degradation
TLDR
To identify the SOCS box protein that specifically mediates CRL5-dependent Sin1 regulation, shRNA based screening and Co-IP experiments found that both proteasome inhibitor MG132 and NEDD8-activating enzyme inhibitor MLN4924 treatment increased Sin1protein levels in 293T cells, indicating that Sin1 protein is possibly governed by CRL family E3 ligases.
Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signaling to suppress tumorigenesis
TLDR
Results reveal a Sin1-phosphorylation-dependent mTORC2 regulation, providing a potential molecular mechanism by which mutations in the m TORC1–S6K–Sin1 signalling axis might cause aberrant hyper-activation of the mtorC2–Akt pathway, which facilitates tumorigenesis.
Regulation of mTOR Complex 1 (mTORC1) by Raptor Ser863 and Multisite Phosphorylation*
TLDR
It is reported that insulin promotes mTORC1-associated phosphorylation of raptor Ser863 via the canonical PI3K/TSC/Rheb pathway in a rapamycin-sensitive manner.
Phosphorylation of Rictor at Thr1135 impairs the Rictor/Cullin-1 complex to ubiquitinate SGK1
TLDR
It is illustrated that Rictor E3 ligase activity could be governed by specific signaling kinase cascades, and that misregulation of this process might contribute to SGK overexpression which is frequently observed in various types of cancers.
Regulation of the Mammalian Target Of Rapamycin Complex 2 (mTORC2)
TLDR
The results suggest that mTORC2 hyperactivation may contribute to the pathophysiology of diseases such as cancer and Tuberous Sclerosis Complex.
Dual phosphorylation of Sin1 at T86 and T398 negatively regulates mTORC2 complex integrity and activity
TLDR
Physiological and pathological evidence is provided to reveal the biological significance of Sin1 phosphorylation-mediated suppression of the mTOR/Akt oncogenic signaling, and it is suggested that misregulation of this process might contribute to Akt hyper-activation that is frequently observed in human cancers.
mTORC2 targets AGC kinases through Sin1-dependent recruitment.
TLDR
The mTORC2 subunit Sin1 is identified as a direct binding partner of the PKC (protein kinase C) ε kinase domain and map the interaction to the central highly conserved region of Sin1, providing evidence that Sin1 serves as a selectivity adaptor for the recruitment of m TORC2 targets.
mTORC2 Protein-mediated Protein Kinase B (Akt) Serine 473 Phosphorylation Is Not Required for Akt1 Activity in Human Platelets*
TLDR
It is demonstrated that mTORC2 is the kinase that phosphorylates Akt Ser473 in human platelets but that this phosphorylation is dispensable for Thr308 phosphorylated and Akt1 activity.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 78 REFERENCES
Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex
TLDR
It is shown that in Drosophila and human cells the target of rapamycin (TOR) kinase and its associated protein rictor are necessary for Ser473 phosphorylation and that a reduction in rictOr or mammalian TOR (mTOR) expression inhibited an Akt/PKB effector.
mTOR·RICTOR Is the Ser473 Kinase for Akt/Protein Kinase B in 3T3-L1 Adipocytes*
TLDR
It is concluded that mTOR complexed to RICTOR is the Ser-473 kinase in 3T3-L1 adipocytes, and the apparently disparate results reported in these studies are difficult to evaluate, given that different stimuli and cell types were examined.
Raptor, a Binding Partner of Target of Rapamycin (TOR), Mediates TOR Action
Akt regulates growth by directly phosphorylating Tsc2
TLDR
Drosophila melanogaster Tsc2 seems to be the critical target of Akt in mediating growth signals for the insulin signalling pathway, and Stimulating Akt/PKB signalling in vivo markedly increases cell growth/size, disrupts the Tsc1–Tsc2 complex and disturbs the distinct subcellular localization of T Sc2.
Conditional Knock-out of Integrin-linked Kinase Demonstrates an Essential Role in Protein Kinase B/Akt Activation*
TLDR
It is demonstrated that ILK is essential for the regulation of PKB/Akt activity by utilizing double-stranded RNA interference (siRNA) as well as conditional knock-out of ILK using the Cre-Lox system, to establish ILK as an essential upstream regulator of P KB/AKT activation.
Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive
TLDR
Two distinct TOR complexes constitute a primordial signalling network conserved in eukaryotic evolution to control the fundamental process of cell growth.
Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control.
...
1
2
3
4
5
...