RICTOR

{{Short description|Protein-coding gene in the species Homo sapiens}}

Rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) is a protein that in humans is encoded by the RICTOR gene.{{cite journal |vauthors=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 | title = Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences | journal = Proc Natl Acad Sci U S A | volume = 99 | issue = 26 | pages = 16899–903 |date=Dec 2002 | pmid = 12477932 | pmc = 139241 | doi = 10.1073/pnas.242603899 | bibcode = 2002PNAS...9916899M | doi-access = free }}{{cite web | title = Entrez Gene: RICTOR rapamycin-insensitive companion of mTOR| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=253260| accessdate = }}

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.{{cite web | url = https://www.ebi.ac.uk/s4/summary/molecular?term=RICTOR&classification=9606 | title = Gene & protein Summary: RICTOR | publisher = EMBL-EBI }}{{cite web | url = https://www.ncbi.nlm.nih.gov/UniGene/seq.cgi?ORG=Hs&SID=15630523 | title = Homo sapiens rapamycin-insensitive companion of mTOR, mRNA (cDNA clone IMAGE:5787163), partial cds | format = | work = UniGene | accessdate = }} 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.{{cite journal |vauthors=Sparks CA, Guertin DA | title = Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy | journal = Oncogene | volume = 29 | issue = 26 | pages = 3733–44 | year = 2010 | pmid = 20418915 | pmc = 3031870 | doi = 10.1038/onc.2010.139 }} 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.{{cite journal |vauthors=Dibble CC, Asara JM, Manning BD | title = Characterization of RICTOR phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1 | journal = Mol. Cell. Biol. | volume = 29 | issue = 21 | pages = 5657–70 | year = 2009 | pmid = 19720745 | pmc = 2772744 | doi = 10.1128/MCB.00735-09 }}

Function

RICTOR is a subunit of the mammalian target of rapamycin complex 2 (mTORC2) which contains mTOR, GβL, RICTOR (this protein) and mSIN1.{{cite journal |vauthors=Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM | title = RICTOR, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton | journal = Curr. Biol. | volume = 14 | issue = 14 | pages = 1296–302 | year = 2004 | pmid = 15268862 | doi = 10.1016/j.cub.2004.06.054 | s2cid = 4658268 | doi-access = free | bibcode = 2004CBio...14.1296D }}

The mammalian target of rapamycin (mTOR) is a highly conserved Ser/Thr kinase that regulates cell growth and proliferation.{{cite journal |vauthors=Harris TE, Lawrence JC | title = TOR signaling | journal = Sci. STKE | volume = 2003 | issue = 212 | pages = re15 | year = 2003 | pmid = 14668532 | doi = 10.1126/stke.2122003re15 | s2cid = 10760217 }}

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.{{cite journal |vauthors=Sarbassov DD, Guertin DA, Ali SM, Sabatini DM | title = Phosphorylation and regulation of Akt/PKB by the RICTOR-mTOR complex | journal = Science | volume = 307 | issue = 5712 | pages = 1098–101 | year = 2005 | pmid = 15718470 | doi = 10.1126/science.1106148 | bibcode = 2005Sci...307.1098S | s2cid = 45837814 }}

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.{{cite journal |vauthors=Shiota C, Woo JT, Lindner J, Shelton KD, Magnuson MA | title = Multiallelic disruption of the gene RICTOR in mice reveals that mTOR complex 2 is essential for fetal growth and viability | journal = Dev. Cell | volume = 11 | issue = 4 | pages = 583–9 | year = 2006 | pmid = 16962829 | doi = 10.1016/j.devcel.2006.08.013 | doi-access = free }}

File:RICTOR action.JPG

= Regulation =

FoxO transcription factors can activate expression of RICTOR. FoxO has been shown to inhibit mTORC1, while activating Akt through RICTOR elevation.{{cite journal |vauthors=Chen CC, Jeon SM, Bhaskar PT, Nogueira V, Sundararajan D, Tonic I, Park Y, Hay N | title = FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and RICTOR | journal = Dev. Cell | volume = 18 | issue = 4 | pages = 592–604 | year = 2010 | pmid = 20412774 | pmc = 3031984 | doi = 10.1016/j.devcel.2010.03.008 }}

= Degradation =

Perifosine has been shown to interfere with mTOR activity by degrading its components, such as RICTOR.{{cite journal |vauthors=Fu L, Kim YA, Wang X, Wu X, Yue P, Lonial S, Khuri FR, Sun SY | title = Perifosine inhibits mammalian target of rapamycin signaling through facilitating degradation of major components in the mTOR axis and induces autophagy | journal = Cancer Res. | volume = 69 | issue = 23 | pages = 8967–76 | year = 2009 | pmid = 19920197 | pmc = 2789206 | doi = 10.1158/0008-5472.CAN-09-2190 }}

Interactions

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

class="wikitable" \| * KIAA1303,	* MTOR{{cite journal \| date = Oct 2006 \|vauthors=Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B \| title = SIN1/MIP1 maintains RICTOR-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity \| journal = Cell \| volume = 127 \| issue = 1 \| pages = 125–37 \| pmid = 16962653 \| doi = 10.1016/j.cell.2006.08.033\|s2cid=230319 \| doi-access = free }}{{cite journal \| date = Nov 2004 \|vauthors=Jacinto E, Loewith R, Schmidt A, Lin S, Rüegg MA, Hall A, Hall MN \| title = Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive \| journal = Nat. Cell Biol. \| volume = 6 \| issue = 11 \| pages = 1122–8 \| pmid = 15467718 \| doi = 10.1038/ncb1183\|s2cid=13831153 }}{{cite journal \| date = Sep 2006 \|vauthors=Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA, Sabatini DM \| title = mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s \| journal = Curr. Biol. \| volume = 16 \| issue = 18 \| pages = 1865–70 \| pmid = 16919458 \| doi = 10.1016/j.cub.2006.08.001\|s2cid=8239162 \| doi-access = free \|bibcode=2006CBio...16.1865F }}{{cite journal \| date = Oct 2006 \|vauthors=Yang Q, Inoki K, Ikenoue T, Guan KL \| title = Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity \| journal = Genes Dev. \| volume = 20 \| issue = 20 \| pages = 2820–32 \| pmid = 17043309 \| pmc = 1619946 \| doi = 10.1101/gad.1461206}}{{cite journal \| date = Apr 2006 \|vauthors=Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM \| title = Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB \| journal = Mol. Cell \| volume = 22 \| issue = 2 \| pages = 159–68 \| pmid = 16603397 \| doi = 10.1016/j.molcel.2006.03.029\| doi-access = free }}{{cite journal \| date = Nov 2005 \|vauthors=Sarbassov DD, Sabatini DM \| title = Redox regulation of the nutrient-sensitive raptor-mTOR pathway and complex \| journal = J. Biol. Chem. \| volume = 280 \| issue = 47 \| pages = 39505–9 \| pmid = 16183647 \| doi = 10.1074/jbc.M506096200\| doi-access = free }}
*EGFR	*Fibroblast growth factor
*Nerve growth factor receptor	*Peptidyl-tyrosine phosphorylation {{Cite web\|url=http://www.phosphosite.org/proteinAction.do?id\|title = PhosphoSite Message}}
*TOR	*Protein kinase B
*Phosphoinositide-mediated signaling	*T cell costimulation
*Cell migration	*actin cytoskeleton organization

File:RICTOR interactions network.png

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.{{cite journal |vauthors=Kumar A, Lawrence JC, Jung DY, Ko HJ, Keller SR, Kim JK, Magnuson MA, Harris TE | title = Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism | journal = Diabetes | volume = 59 | issue = 6 | pages = 1397–406 | year = 2010 | pmid = 20332342 | pmc = 2874700 | doi = 10.2337/db09-1061 }} 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.{{cite journal |vauthors=Guo Z, Zhou Y, Evers BM, Wang Q | title = RICTOR regulates FBXW7-dependent c-Myc and cyclin E degradation in colorectal cancer cells | journal = Biochem. Biophys. Res. Commun. | volume = 418 | issue = 2 | pages = 426–32 | year = 2012 | pmid = 22285861 | pmc = 3278531 | doi = 10.1016/j.bbrc.2012.01.054 }}

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.{{cite journal |vauthors=Verreault M, Weppler SA, Stegeman A, Warburton C, Strutt D, Masin D, Bally MB | title = Combined RNAi-mediated suppression of RICTOR and EGFR resulted in complete tumor regression in an orthotopic glioblastoma tumor model | journal = PLOS ONE | volume = 8 | issue = 3 | pages = e59597 | year = 2013 | pmid = 23555046 | pmc = 3598699 | doi = 10.1371/journal.pone.0059597 | bibcode = 2013PLoSO...859597V | doi-access = free }}

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.{{cite journal |vauthors=Gibault L, Ferreira C, Pérot G, Audebourg A, Chibon F, Bonnin S, Lagarde P, Vacher-Lavenu MC, Terrier P, Coindre JM, Aurias A | title = From PTEN loss of expression to RICTOR role in smooth muscle differentiation: complex involvement of the mTOR pathway in leiomyosarcomas and pleomorphic sarcomas | journal = Mod. Pathol. | volume = 25 | issue = 2 | pages = 197–211 | year = 2012 | pmid = 22080063 | doi = 10.1038/modpathol.2011.163 | doi-access = free }}

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.{{cite journal |vauthors=Jia W, Sanders AJ, Jia G, Liu X, Lu R, Jiang WG | title = Expression of the mTOR pathway regulators in human pituitary adenomas indicates the clinical course | journal = Anticancer Res. | volume = 33 | issue = 8 | pages = 3123–31 |date=August 2013 | pmid = 23898069 }}