RICTOR

Rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) is a is_associated_with::protein that in humans is encoded by the RICTOR is_associated_with::gene.

RICTOR and MTOR are components of a protein complex that integrates nutrient- and growth factor-derived signals to regulate cell growth.

Structure
The gene RICTOR is located on is_associated_with::chromosome 5 at 5p13.1 with a sequence length of 5440 bp, oriented on the minus strand. The translated RICTOR protein contains 1709 amino acids and is present in the cytosol. RICTOR contains few conserved regions and function domains of RICTOR have yet to be observed. However, using liquid chromatography-tandem mass spectrometry analysis, 21 phosphorylation sites were identified on RICTOR. Of these sites, T1135 has been shown to undergo growth factor-responsive phosphorylation via is_associated_with::S6K1.

Function
RICTOR is a subunit of the mammalian target of rapamycin complex 2 (is_associated_with::mTORC2) which contains is_associated_with::mTOR, GβL, RICTOR (this protein) and mSIN1.

The mammalian target of rapamycin (is_associated_with::mTOR) is a highly conserved Ser/Thr is_associated_with::kinase that regulates cell growth and proliferation.

is_associated_with::mTOR may exist as mTOR complex 1 (is_associated_with::mTORC1) or mTOR complex 2 (is_associated_with::mTORC2). RICTOR is a key component of is_associated_with::mTORC2, which, unlike mTORC1, is not directly inhibited by is_associated_with::rapamycin. is_associated_with::mTORC2, and RICTOR, specifically, has been shown to phosphorylate is_associated_with::Akt/is_associated_with::protein kinase B (PKB) on SER473. This phosphorylation activates is_associated_with::Akt/PKB, where deregulation of is_associated_with::Akt/PKB has been implicated in cancer and diabetes.

RICTOR and mTORC2 have been shown to play an essential role in embryonic growth and development, perhaps due to the control that mTORC2 exerts on is_associated_with::actin cytoskeleton organization.



Regulation
FoxO transcription factors can activate expression of RICTOR. FoxO has been shown to inhibit mTORC1, while activating Akt through RICTOR elevation.

Degradation
is_associated_with::Perifosine has been shown to interfere with mTOR activity by degrading its components, such as RICTOR.

Interactions
RICTOR has been shown to interact with and play a role in:



Clinical relevance
Diseases associated with mutation in the RICTOR gene include foramen magnum is_associated_with::meningioma and is_associated_with::syringomyelia. Akt/PMB activation is also involved in is_associated_with::glucose metabolism and activation of Akt by RICTOR has been shown to mediate glucose and lipid metabolism. Therefore, the influence of RICTOR and mTORC2 on Akt signaling has been associated with insulin resistance and is_associated_with::type 2 diabetes.

Cancer
Akt/PMB activation leads to proliferation and survival, therefore over-activation of the Akt/PMB pathway by mTORC2 (including RICTOR) is implicated in cancerous growth.

In human is_associated_with::colorectal carcinoma, RICTOR has been shown to association with is_associated_with::FBXW7 (outside of mTORC2) to mediate the is_associated_with::ubiquitination of growth-promoting factors is_associated_with::cyclin E and is_associated_with::c-Myc. Furthermore, elevated growth factor signaling may suppress the ubiquitinating action of RICTOR-FBXW7, resulting in accumulation of is_associated_with::cyclin E and is_associated_with::c-Myc and subsequent progression through the cell cycle.

In is_associated_with::glioblastoma (GBM), RICTOR(along with EGFR) may serve as an effective therapeutic target for silencing RNA, leading to decreased cell proliferation. Co-silencing of RICTOR and EGFR lead to increased sensitivity to alkaloids and alkylating agents. For one particular PTEN-mutant cell line, co-silencing resulted in tumor eradication.

RICTOR has been shown to be significantly overexpressed in well-differentiated is_associated_with::leiomyosarcomas. Due to the influence of RICTOR on is_associated_with::actin polymerization, RICTOR could play a role in allowing transcription and subsequent differentiation in these muscle cells.

mTOR subunits RICTOR and RAPTOR both showed increased expression, which increased with is_associated_with::pituitary adenoma tumor staging. Therefore, is_associated_with::mTOR, is_associated_with::RAPTOR and RICTOR were significantly correlated with the growth and invasion of pituitary adenomas and may have an important predictive and prognostic value in such patients.