Rapamycin inhibits mSin1 phosphorylation independently of mTORC1 and mTORC2

Oncotarget

Volumn 6, Issue 6, 2015, Pages 4286-4298

  Luo, Yan ^a,b   Liu, Lei ^b   Wu, Yang ^a,b   Singh, Karnika ^b   Su, Bing ^c   Zhang, Nan ^a   Liu, Xiaowei ^a   Shen, Yangmei ^a   Huang, Shile ^b  

^a SICHUAN UNIVERSITY   (China)

^b LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER   (United States)

^c YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

MSin1; MTOR; Rapamycin; Raptor; Rictor

Indexed keywords

GUANINE NUCLEOTIDE BINDING PROTEIN BETA SUBUNIT; MAMMALIAN LETHAL WITH SEC 13 PROTEIN 8; MAMMALIAN STRESS ACTIVATED PROTEIN KINASE INTERACTING PROTEIN 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; PROTEIN KINASE B; RAPAMYCIN; S6 KINASE; UNCLASSIFIED DRUG; ANTINEOPLASTIC ANTIBIOTIC; CARRIER PROTEIN; MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 1; MSIN1 PROTEIN, HUMAN; MULTIPROTEIN COMPLEX; SMALL INTERFERING RNA; TARGET OF RAPAMYCIN KINASE; TOR COMPLEX 2;

ANIMAL CELL; ARTICLE; CONTROLLED STUDY; DOWN REGULATION; EMBRYO; FEMALE; GENE SILENCING; HUMAN; HUMAN CELL; MALE; MOUSE; NONHUMAN; PROTEIN DEPHOSPHORYLATION; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN TARGETING; CHEMISTRY; DRUG EFFECTS; GENETIC TRANSFECTION; METABOLISM; PHOSPHORYLATION; TUMOR CELL LINE; WESTERN BLOTTING;

ANTIBIOTICS, ANTINEOPLASTIC; BLOTTING, WESTERN; CARRIER PROTEINS; CELL LINE, TUMOR; HUMANS; MULTIPROTEIN COMPLEXES; PHOSPHORYLATION; RNA, SMALL INTERFERING; SIROLIMUS; TOR SERINE-THREONINE KINASES; TRANSFECTION;

EID: 84924230185     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.3006     Document Type: Article

References (64)

1. Huo Y, Iadevaia V, Proud CG. Differing effects of rapamycin and mTOR kinase inhibitors on protein synthesis. Biochem Soc Trans. 2011; 39:446-450.
2. Laplante M, Sabatini DM. mTOR Signaling in Growth Control and Disease. Cell. 2012; 149:274-293.
3. Fonseca BD, Smith EM, Lee VH, Mackintosh C, Proud CG. PRAS40 is a target for mammalian target of rapamycin complex 1 and is required for signaling downstream of this complex. J Biol Chem. 2007; 282:24514-24524.
4. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 2002; 110:177-189.
5. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002; 110:163-175.
6. Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P, Sabatini DM. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell. 2003; 11:895-904.
7. Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo JL, Bonenfant D, Oppliger W, Jenoe P, Hall MN. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell. 2002; 10:457-468.
8. Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, Carr SA, Sabatini DM. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell. 2007; 25:903-915.
9. Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol. 2007; 9:316-323.
10. 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. 2004; 6:1122-1128.
11. 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. 2004; 14:1296-1302.
12. 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. 2006; 16:1865-1870.
13. 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. 2006; 127:125-137.
14. 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. 2006; 20:2820-2832.
15. Pearce LR, Huang X, Boudeau J, Pawlowski R, Wullschleger S, Deak M, Ibrahim AF, Gourlay R, Magnuson MA, Alessi DR. Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem J. 2007; 405:513-522.
16. Woo SY, Kim DH, Jun CB, Kim YM, Haar EV, Lee SI, Hegg JW, Bandhakavi S, Griffin TJ, Kim DH. PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling. J Biol Chem. 2007; 282:25604-25612.
17. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005; 307:1098-1101.
18. 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. 2006; 22:159-168.
19. García-Martínez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum-and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J. 2008; 416:375-385.
20. Liu L, Chen L, Chung J, Huang S. Rapamycin inhibits F-actin reorganization and phosphorylation of focal adhesion proteins. Oncogene. 2008; 27:4998-5010.
21. Liu L, Luo Y, Chen L, Shen T, Xu B, Chen W, Zhou H, Han X, Huang S. Rapamycin inhibits cytoskeleton reorganization and cell motility by suppressing RhoA expression and activity. J Biol Chem. 2010; 285:38362-38373.
22. Gulhati P, Bowen KA, Liu J, Stevens PD, Rychahou PG, Chen M, Lee EY, Weiss HL, O'Connor KL, Gao T, Evers BM. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res. 2011; 71:3246-3256.
23. Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, Gray NS, Sabatini DM. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 2009; 137:873-886.
24. Kaizuka T, Hara T, Oshiro N, Kikkawa U, Yonezawa K, Takehana K, Iemura S, Natsume T, Mizushima N. Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J Biol Chem. 2010; 285:20109-20116.
25. Luo Y, Liu L, Rogers D, Su W, Odaka Y, Zhou H, Chen W, Shen T, Alexander JS, Huang S. Rapamycin inhibits lymphatic endothelial cell tube formation by downregulating vascular endothelial growth factor receptor 3 protein expression. Neoplasia. 2012; 14:228-237.
26. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012; 366:883-892.
27. Grabiner BC, Nardi V, Birsoy K, Possemato R, Shen K, Sinha S, Jordan A, Beck AH, Sabatini DM. A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov. 2014; 4:554-563.
28. Wagle N, Grabiner BC, Van Allen EM, Hodis E, Jacobus S, Supko JG, Stewart M, Choueiri TK, Gandhi L, Cleary JM, Elfiky AA, Taplin ME, Stack EC, Signoretti S, Loda M, Shapiro GI, Sabatini DM, Lander ES, Gabriel SB, Kantoff PW, Garraway LA, Rosenberg JE. Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discov. 2014; 4:546-553.
29. Dazert E, Hall MN. mTOR signaling in disease. Curr Opin Cell Biol. 2011; 23:744-755.
30. Inoki K, Kim J, Guan KL. AMPK and mTOR in cellular energy homeostasis and drug targets. Annu Rev Pharmacol Toxicol. 2012; 52:381-400.
31. Zhang YJ, Duan Y, Zheng XF. Targeting the mTOR kinase domain: the second generation of mTOR inhibitors. Drug Discov Today. 2011; 16:325-331.
32. Sun SY, Rosenberg LM, Wang X, Zhou Z, Yue P, Fu H. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 2005; 65:7052-7058.
33. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, Baselga J, Rosen N. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006; 66:1500-1508.
34. Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA, Lim D, Peterson TR, Choi Y, Gray NS, Yaffe MB, Marto JA, Sabatini DM. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science. 2011; 332:1317-1322.
35. Yu Y, Yoon SO, Poulogiannis G, Yang Q, Ma XM, Villén J, Kubica N, Hoffman GR, Cantley LC, Gygi SP, Blenis J. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science. 2011; 332:1322-1326.
36. Akcakanat A, Singh G, Hung MC, Meric-Bernstam F. Rapamycin regulates the phosphorylation of rictor. Biochem Biophys Res Commun. 2007; 362:330-333.
37. Dibble CC, Asara JM, Manning BD. Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol Cell Biol. 2009; 29:5657-5670.
38. Rosner M, Hengstschläger M. Cytoplasmic and nuclear distribution of the protein complexes mTORC1 and mTORC2: rapamycin triggers dephosphorylation and delocalization of the mTORC2 components rictor and sin1. Hum Mol Genet. 2008; 17:2934-2948.
39. Chen CH, Sarbassov dos D. The mTOR (mammalian target of rapamycin) kinase maintains integrity of mTOR complex2. J Biol Chem. 2011; 286:40386-40394.
40. Smith MA, Morton CL, Phelps D, Girtman K, Neale G, Houghton PJ. SK-NEP-1 and Rh1 are Ewing family tumor lines. Pediatr Blood Cancer. 2008; 50:703-706.
41. Hosoi H, Dilling MB, Shikata T, Liu LN, Shu L, Ashmun RA, Germain GS, Abraham RT, Houghton PJ. Rapamycin causes poorly reversible inhibition of mTOR and induces p53-independent apoptosis in human rhabdomyosarcoma cells. Cancer Res. 1999; 59:886-894.
42. Erbay E, Chen J. The mammalian target of rapamycin regulates C2C12 myogenesis via a kinase-independent mechanism. J Biol Chem. 2001; 276:36079-36082.
43. Ge Y, Wu AL, Warnes C, Liu J, Zhang C, Kawasome H, Terada N, Boppart MD, Schoenherr CJ, Chen J. mTOR regulates skeletal muscle regeneration in vivo through kinase-dependent and kinase-independent mechanisms. Am J Physiol Cell Physiol. 2009; 297:C1434-C1444.
44. Shu L, Zhang X, Houghton PJ. Myogenic differentiation is dependent on both the kinase function and the N-terminal sequence of mammalian target of rapamycin. J Biol Chem. 2000; 277:16726-16732.
45. Shu L, Houghton PJ. The mTORC2 complex regulates terminal differentiation of C2C12 myoblasts. Mol Cell Biol. 2009; 29:4691-4700.
46. Julien LA, Carriere A, Moreau J, Roux PP. mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling. Mol Cell Biol. 2010; 30:908-921.
47. Treins C, Warne PH, Magnuson MA, Pende M, Downward J. Rictor is a novel target of p70 S6 kinase-1. Oncogene. 2010; 29:1003-1016.
48. Liu P, Gan W, Inuzuka H, Lazorchak AS, Gao D, Arojo O, Liu D, Wan L, Zhai B, Yu Y, Yuan M, Kim BM, Shaik S, Menon S, Gygi SP, Lee TH, Asara JM, Manning BD, Blenis J, Su B, Wei W. Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. Nat Cell Biol. 2013; 15:1340-1350.
49. Liu L, Li F, Cardelli JA, Martin KA, Blenis J, Huang S. Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways. Oncogene. 2006; 25:7029-7040.
50. Peterson RT, Desai BN, Hardwick JS, Schreiber SL. Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein. Proc Natl Acad Sci USA. 1999; 96:4438-4442.
51. Humphrey SJ, Yang G, Yang P, Fazakerley DJ, Stöckli J, Yang JY, James DE. Dynamic adipocyte phosphoproteome reveals that Akt directly regulates mTORC2. Cell Metab. 2013; 17:1009-1020.
52. Barquilla A, Saldivia M, Diaz R, Bart JM, Vidal I, Calvo E, et al. Third target of rapamycin complex negatively regulates development of quiescence in Trypanosoma brucei. Proc Natl Acad Sci USA. 2012; 109:14399-14404.
53. Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J. Rheb binds and regulates the mTOR kinase. Curr Biol. 2005; 15:702-713.
54. Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, Kozma SC, Hafen E, Bos JL, Thomas G. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell. 2003; 11:1457-1466.
55. Inoki K, Li Y, Xu T, Guan KL. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003; 17:1829-1834.
56. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol. 2003; 13:1259-1268.
57. Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat. Cell Biol. 2003; 5:578-581.
58. Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 2007; 8:774-785.
59. Corradetti MN, Inoki K, Bardeesy N, DePinho RA, Guan KL. Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev. 2004; 18:1533-1538.
60. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008; 30:214-226.
61. Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science. 2008; 320:1496-14501.
62. Kim E, Goraksha-Hicks P, Li L, Neufeld TP, Guan KL. Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol. 2008; 10:935-945.
63. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010; 141:290-303.
64. Chen CH, Kiyan V, Zhylkibayev AA, Kazyken D, Bulgakova O, Page KE, Bersimbaev RI, Spooner E, Sarbassov dos D. Autoregulation of the mechanistic target of rapamycin (mTOR) complex 2 integrity is controlled by an ATP-dependent mechanism. J Biol Chem. 2013; 288:27019-27030.