RICTOR

RPTOR independent companion of MTOR, complex 2
Identifiers
Symbols RICTOR ; AVO3; PIA; hAVO3
External IDs OMIM: 609022 MGI: 1926007 HomoloGene: 34317 ChEMBL: 1795179 GeneCards: RICTOR Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 253260 78757
Ensembl ENSG00000164327 ENSMUSG00000050310
UniProt Q6R327 Q6QI06
RefSeq (mRNA) NM_001285439 NM_030168
RefSeq (protein) NP_001272368 NP_084444
Location (UCSC) Chr 5:
38.94 – 39.07 Mb		 Chr 15:
6.71 – 6.8 Mb
PubMed search

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.[2]

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]

RICTOR is a subunit of the mTORC2 complex, which activates Akt/PKB signaling, leading to cell proliferation and survival.

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,[13] * MTOR[7][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 [19] *T cell costimulation [19]
*Cell migration [19] *actin cytoskeleton organization [19]
Strings represent evidence for the interaction of RICTOR with other proteins (other bubbles)

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, 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.[24]

See also

References

  1. ↑ Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA (Dec 2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc Natl Acad Sci U S A 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
  2. 1 2 "Entrez Gene: RICTOR rapamycin-insensitive companion of mTOR".
  3. ↑ "Gene & protein Summary: RICTOR". EMBL-EBI.
  4. ↑ "Homo sapiens rapamycin-insensitive companion of mTOR, mRNA (cDNA clone IMAGE:5787163), partial cds". UniGene.
  5. ↑ Sparks CA, Guertin DA (2010). "Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy". Oncogene 29 (26): 3733–44. doi:10.1038/onc.2010.139. PMC 3031870. PMID 20418915.
  6. ↑ Dibble CC, Asara JM, Manning BD (2009). "Characterization of RICTOR phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1". Mol. Cell. Biol. 29 (21): 5657–70. doi:10.1128/MCB.00735-09. PMC 2772744. PMID 19720745.
  7. 1 2 Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2004). "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. doi:10.1016/j.cub.2004.06.054. PMID 15268862.
  8. ↑ Harris TE, Lawrence JC (2003). "TOR signaling". Sci. STKE 2003 (212): re15. doi:10.1126/stke.2122003re15. PMID 14668532.
  9. ↑ Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005). "Phosphorylation and regulation of Akt/PKB by the RICTOR-mTOR complex". Science 307 (5712): 1098–101. doi:10.1126/science.1106148. PMID 15718470.
  10. ↑ Shiota C, Woo JT, Lindner J, Shelton KD, Magnuson MA (2006). "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. doi:10.1016/j.devcel.2006.08.013. PMID 16962829.
  11. ↑ Chen CC, Jeon SM, Bhaskar PT, Nogueira V, Sundararajan D, Tonic I, Park Y, Hay N (2010). "FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and RICTOR". Dev. Cell 18 (4): 592–604. doi:10.1016/j.devcel.2010.03.008. PMC 3031984. PMID 20412774.
  12. ↑ Fu L, Kim YA, Wang X, Wu X, Yue P, Lonial S, Khuri FR, Sun SY (2009). "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. doi:10.1158/0008-5472.CAN-09-2190. PMC 2789206. PMID 19920197.
  13. 1 2 Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B (Oct 2006). "SIN1/MIP1 maintains RICTOR-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity". Cell 127 (1): 125–37. doi:10.1016/j.cell.2006.08.033. PMID 16962653.
  14. ↑ Jacinto E, Loewith R, Schmidt A, Lin S, Rüegg MA, Hall A, Hall MN (Nov 2004). "Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive". Nat. Cell Biol. 6 (11): 1122–8. doi:10.1038/ncb1183. PMID 15467718.
  15. ↑ Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA, Sabatini DM (Sep 2006). "mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s". Curr. Biol. 16 (18): 1865–70. doi:10.1016/j.cub.2006.08.001. PMID 16919458.
  16. ↑ Yang Q, Inoki K, Ikenoue T, Guan KL (Oct 2006). "Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity". Genes Dev. 20 (20): 2820–32. doi:10.1101/gad.1461206. PMC 1619946. PMID 17043309.
  17. ↑ Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM (Apr 2006). "Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB". Mol. Cell 22 (2): 159–68. doi:10.1016/j.molcel.2006.03.029. PMID 16603397.
  18. ↑ Sarbassov DD, Sabatini DM (Nov 2005). "Redox regulation of the nutrient-sensitive raptor-mTOR pathway and complex". J. Biol. Chem. 280 (47): 39505–9. doi:10.1074/jbc.M506096200. PMID 16183647.
  19. 1 2 3 4 5 http://www.phosphosite.org/proteinAction.do?id
  20. ↑ Kumar A, Lawrence JC, Jung DY, Ko HJ, Keller SR, Kim JK, Magnuson MA, Harris TE (2010). "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. doi:10.2337/db09-1061. PMC 2874700. PMID 20332342.
  21. ↑ Guo Z, Zhou Y, Evers BM, Wang Q (2012). "RICTOR regulates FBXW7-dependent c-Myc and cyclin E degradation in colorectal cancer cells". Biochem. Biophys. Res. Commun. 418 (2): 426–32. doi:10.1016/j.bbrc.2012.01.054. PMC 3278531. PMID 22285861.
  22. ↑ Verreault M, Weppler SA, Stegeman A, Warburton C, Strutt D, Masin D, Bally MB (2013). "Combined RNAi-mediated suppression of RICTOR and EGFR resulted in complete tumor regression in an orthotopic glioblastoma tumor model". PLoS ONE 8 (3): e59597. doi:10.1371/journal.pone.0059597. PMC 3598699. PMID 23555046.
  23. ↑ Gibault L, Ferreira C, Pérot G, Audebourg A, Chibon F, Bonnin S, Lagarde P, Vacher-Lavenu MC, Terrier P, Coindre JM, Aurias A (2012). "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. doi:10.1038/modpathol.2011.163. PMID 22080063.
  24. ↑ Jia W, Sanders AJ, Jia G, Liu X, Lu R, Jiang WG (August 2013). "Expression of the mTOR pathway regulators in human pituitary adenomas indicates the clinical course". Anticancer Res. 33 (8): 3123–31. PMID 23898069.

Further reading

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