RICTOR explained

RICTOR should not be confused with Rictor.

Rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) is a protein that in humans is encoded by the RICTOR gene.^{[1] [2]}

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 chromosome 5 at 5p13.1 with a sequence length of 5440 bp, oriented on the minus strand.^{[3] [4]} 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.^[5] 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 S6K1.^[6]

Function

RICTOR is a subunit of the mammalian target of rapamycin complex 2 (mTORC2) which contains mTOR, GβL, RICTOR (this protein) and mSIN1.^[7]

The mammalian target of rapamycin (mTOR) is a highly conserved Ser/Thr kinase that regulates cell growth and proliferation.^[8]

mTOR may exist as mTOR complex 1 (mTORC1) or mTOR complex 2 (mTORC2). RICTOR is a key component of mTORC2, which, unlike mTORC1, is not directly inhibited by rapamycin. mTORC2, and RICTOR, specifically, has been shown to phosphorylate Akt/protein kinase B (PKB) on SER473. This phosphorylation activates Akt/PKB, where deregulation of Akt/PKB has been implicated in cancer and diabetes.^[9]

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 actin cytoskeleton organization.^[10]

Regulation

FoxO transcription factors can activate expression of RICTOR. FoxO has been shown to inhibit mTORC1, while activating Akt through RICTOR elevation.^[11]

Degradation

Perifosine has been shown to interfere with mTOR activity by degrading its components, such as RICTOR.^[12]

Interactions

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

KIAA1303,	MTOR^[13] ^[14] ^[15] ^[16] ^[17] ^[18]
EGFR	Fibroblast growth factor
Nerve growth factor receptor	Peptidyl-tyrosine phosphorylation ^[19]
TOR	Protein kinase B
Phosphoinositide-mediated signaling	T cell costimulation
Cell migration	actin cytoskeleton organization

Clinical relevance

Diseases associated with mutation in the RICTOR gene include foramen magnum meningioma and syringomyelia. Akt/PMB activation is also involved in glucose metabolism and activation of Akt by RICTOR has been shown to mediate glucose and lipid metabolism.^[20] Therefore, the influence of RICTOR and mTORC2 on Akt signaling has been associated with insulin resistance and 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 colorectal carcinoma, RICTOR has been shown to association with FBXW7 (outside of mTORC2) to mediate the ubiquitination of growth-promoting factors cyclin E and c-Myc. Furthermore, elevated growth factor signaling may suppress the ubiquitinating action of RICTOR-FBXW7, resulting in accumulation of cyclin E and c-Myc and subsequent progression through the cell cycle.^[21]

In 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.^[22]

RICTOR has been shown to be significantly overexpressed in well-differentiated leiomyosarcomas. Due to the influence of RICTOR on actin polymerization, RICTOR could play a role in allowing transcription and subsequent differentiation in these muscle cells.^[23]

mTOR subunits RICTOR and RAPTOR both showed increased expression, which increased with pituitary adenoma tumor staging. Therefore, mTOR, RPTOR 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.^[24]

See also

• RPTOR
• mTORC2

Further reading

• Cohen D, Scribner R, Clark J, Cory D . The potential role of custody facilities in controlling sexually transmitted diseases . American Journal of Public Health . 82 . 4 . 552–6 . 1992 . 1546771 . 10.2105/AJPH.82.4.552 . 1694115 .
• Ohara O, Nagase T, Mitsui G, etal . Characterization of size-fractionated cDNA libraries generated by the in vitro recombination-assisted method . DNA Res. . 9 . 2 . 47–57 . 2003 . 12056414 . 10.1093/dnares/9.2.47 . free .
• Ota T, Suzuki Y, Nishikawa T, etal . Complete sequencing and characterization of 21,243 full-length human cDNAs . Nat. Genet. . 36 . 1 . 40–5 . 2004 . 14702039 . 10.1038/ng1285 . free .
• Sarbassov DD, Ali SM, Kim DH, etal . Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton . Curr. Biol. . 14 . 14 . 1296–302 . 2004 . 15268862 . 10.1016/j.cub.2004.06.054 . 4658268 . free . 2004CBio...14.1296D .
• Beausoleil SA, Jedrychowski M, Schwartz D, etal . Large-scale characterization of HeLa cell nuclear phosphoproteins . Proc. Natl. Acad. Sci. U.S.A. . 101 . 33 . 12130–5 . 2004 . 15302935 . 10.1073/pnas.0404720101 . 514446 . 2004PNAS..10112130B . free .
• Jacinto E, Loewith R, Schmidt A, etal . Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive . Nat. Cell Biol. . 6 . 11 . 1122–8 . 2004 . 15467718 . 10.1038/ncb1183 . 13831153 .
• Kudchodkar SB, Yu Y, Maguire TG, Alwine JC . Human cytomegalovirus infection alters the substrate specificities and rapamycin sensitivities of raptor- and rictor-containing complexes . Proc. Natl. Acad. Sci. U.S.A. . 103 . 38 . 14182–7 . 2006 . 16959881 . 10.1073/pnas.0605825103 . 1599931 . 2006PNAS..10314182K . free .
• Jacinto E, Facchinetti V, Liu D, etal . SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity . Cell . 127 . 1 . 125–37 . 2006 . 16962653 . 10.1016/j.cell.2006.08.033 . 230319 . free .
• Yang Q, Inoki K, Ikenoue T, Guan KL . Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity . Genes Dev. . 20 . 20 . 2820–32 . 2006 . 17043309 . 10.1101/gad.1461206 . 1619946 .
• Fuchs BC, Finger RE, Onan MC, Bode BP . ASCT2 silencing regulates mammalian target-of-rapamycin growth and survival signaling in human hepatoma cells . Am. J. Physiol., Cell Physiol. . 293 . 1 . C55–63 . 2007 . 17329400 . 10.1152/ajpcell.00330.2006 . 22802061 .
• Pearce LR, Huang X, Boudeau J, etal . Identification of Protor as a novel Rictor-binding component of mTOR complex-2 . Biochem. J. . 405 . 3 . 513–22 . 2007 . 17461779 . 10.1042/BJ20070540 . 2267312 .

Notes and References

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2. Web site: Entrez Gene: RICTOR rapamycin-insensitive companion of mTOR.
3. Web site: Gene & protein Summary: RICTOR . EMBL-EBI .
4. Web site: Homo sapiens rapamycin-insensitive companion of mTOR, mRNA (cDNA clone IMAGE:5787163), partial cds . UniGene .
5. Sparks CA, Guertin DA . Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy . Oncogene . 29 . 26 . 3733–44 . 2010 . 20418915 . 3031870 . 10.1038/onc.2010.139 .
6. Dibble CC, Asara JM, Manning BD . Characterization of RICTOR phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1 . Mol. Cell. Biol. . 29 . 21 . 5657–70 . 2009 . 19720745 . 2772744 . 10.1128/MCB.00735-09 .
7. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM . RICTOR, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton . Curr. Biol. . 14 . 14 . 1296–302 . 2004 . 15268862 . 10.1016/j.cub.2004.06.054 . 4658268 . free . 2004CBio...14.1296D .
8. Harris TE, Lawrence JC . TOR signaling . Sci. STKE . 2003 . 212 . re15 . 2003 . 14668532 . 10.1126/stke.2122003re15 . 10760217 .
9. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM . Phosphorylation and regulation of Akt/PKB by the RICTOR-mTOR complex . Science . 307 . 5712 . 1098–101 . 2005 . 15718470 . 10.1126/science.1106148 . 2005Sci...307.1098S . 45837814 .
10. Shiota C, Woo JT, Lindner J, Shelton KD, Magnuson MA . Multiallelic disruption of the gene RICTOR in mice reveals that mTOR complex 2 is essential for fetal growth and viability . Dev. Cell . 11 . 4 . 583–9 . 2006 . 16962829 . 10.1016/j.devcel.2006.08.013 . free .
11. Chen CC, Jeon SM, Bhaskar PT, Nogueira V, Sundararajan D, Tonic I, Park Y, Hay N . FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and RICTOR . Dev. Cell . 18 . 4 . 592–604 . 2010 . 20412774 . 3031984 . 10.1016/j.devcel.2010.03.008 .
12. Fu L, Kim YA, Wang X, Wu X, Yue P, Lonial S, Khuri FR, Sun SY . Perifosine inhibits mammalian target of rapamycin signaling through facilitating degradation of major components in the mTOR axis and induces autophagy . Cancer Res. . 69 . 23 . 8967–76 . 2009 . 19920197 . 2789206 . 10.1158/0008-5472.CAN-09-2190 .
13. Oct 2006 . Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B . SIN1/MIP1 maintains RICTOR-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity . Cell . 127 . 1 . 125–37 . 16962653 . 10.1016/j.cell.2006.08.033. 230319 . free .
14. Nov 2004 . Jacinto E, Loewith R, Schmidt A, Lin S, Rüegg MA, Hall A, Hall MN . Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive . Nat. Cell Biol. . 6 . 11 . 1122–8 . 15467718 . 10.1038/ncb1183. 13831153 .
15. Sep 2006 . Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA, Sabatini DM . mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s . Curr. Biol. . 16 . 18 . 1865–70 . 16919458 . 10.1016/j.cub.2006.08.001. 8239162 . free . 2006CBio...16.1865F .
16. Oct 2006 . Yang Q, Inoki K, Ikenoue T, Guan KL . Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity . Genes Dev. . 20 . 20 . 2820–32 . 17043309 . 1619946 . 10.1101/gad.1461206.
17. Apr 2006 . Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM . Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB . Mol. Cell . 22 . 2 . 159–68 . 16603397 . 10.1016/j.molcel.2006.03.029. free .
18. Nov 2005 . Sarbassov DD, Sabatini DM . Redox regulation of the nutrient-sensitive raptor-mTOR pathway and complex . J. Biol. Chem. . 280 . 47 . 39505–9 . 16183647 . 10.1074/jbc.M506096200. free .
19. Web site: PhosphoSite Message.
20. Kumar A, Lawrence JC, Jung DY, Ko HJ, Keller SR, Kim JK, Magnuson MA, Harris TE . Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism . Diabetes . 59 . 6 . 1397–406 . 2010 . 20332342 . 2874700 . 10.2337/db09-1061 .
21. Guo Z, Zhou Y, Evers BM, Wang Q . RICTOR regulates FBXW7-dependent c-Myc and cyclin E degradation in colorectal cancer cells . Biochem. Biophys. Res. Commun. . 418 . 2 . 426–32 . 2012 . 22285861 . 3278531 . 10.1016/j.bbrc.2012.01.054 .
22. Verreault M, Weppler SA, Stegeman A, Warburton C, Strutt D, Masin D, Bally MB . Combined RNAi-mediated suppression of RICTOR and EGFR resulted in complete tumor regression in an orthotopic glioblastoma tumor model . PLOS ONE . 8 . 3 . e59597 . 2013 . 23555046 . 3598699 . 10.1371/journal.pone.0059597 . 2013PLoSO...859597V . free .
23. Gibault L, Ferreira C, Pérot G, Audebourg A, Chibon F, Bonnin S, Lagarde P, Vacher-Lavenu MC, Terrier P, Coindre JM, Aurias A . From PTEN loss of expression to RICTOR role in smooth muscle differentiation: complex involvement of the mTOR pathway in leiomyosarcomas and pleomorphic sarcomas . Mod. Pathol. . 25 . 2 . 197–211 . 2012 . 22080063 . 10.1038/modpathol.2011.163 . free .
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