Abstract
Mammalian target of rapamycin complex (mTORC) regulates a variety of cellular responses including proliferation, growth, differentiation and cell migration. In this study, we show that mammalian target of rapamycin complex 2 (mTORC2) regulates invasive cancer cell migration through selective activation of Akt1. Insulin-like growth factor-1 (IGF-1)-induced SKOV-3 cell migration was completely abolished by phosphatidylinositol 3-kinase (PI3K) (LY294002, 10 μM) or Akt inhibitors (SH-5, 50 μM), whereas inhibition of extracellular-regulated kinase by an ERK inhibitor (PD98059, 10 μM) or inhibition of mammalian target of rapamycin complex 1 (mTORC1) by an mTORC1 inhibitor (Rapamycin, 100 nM) did not affect IGF-1-induced SKOV-3 cell migration. Inactivation of mTORC2 by silencing Rapamycin-insensitive companion of mTOR (Rictor), abolished IGF-1-induced SKOV-3 cell migration as well as activation of Akt. However, inactivation of mTORC1 by silencing of Raptor had no effect. Silencing of Akt1 but not Akt2 attenuated IGF-1-induced SKOV-3 cell migration. Rictor was preferentially associated with Akt1 rather than Akt2, and over-expression of Rictor facilitated IGF-1-induced Akt1 activation. Expression of PIP3-dependent Rac exchanger1 (P-Rex1), a Rac guanosine exchange factor and a component of the mTOR complex, strongly stimulated activation of Akt1. Furthermore, knockdown of P-Rex1 attenuated Akt activation as well as IGF-1-induced SKOV-3 cell migration. Silencing of Akt1 or P-Rex1 abolished IGF-1-induced SKOV-3 cell invasion. Finally, silencing of Akt1 blocked in vivo metastasis, whereas silencing of Akt2 did not. Given these results, we suggest that selective activation of Akt1 through mTORC2 and P-Rex1 regulates cancer cell migration, invasion and metastasis.
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References
Alessi DR, Cohen P . (1998). Mechanism of activation and function of protein kinase B. Curr Opin Genet Dev 8: 55–62.
Bae SS, Cho H, Mu J, Birnbaum MJ . (2003). Isoform-specific regulation of insulin-dependent glucose uptake by Akt/protein kinase B. J Biol Chem 278: 49530–49536.
Barber MA, Welch HC . (2006). PI3K and RAC signalling in leukocyte and cancer cell migration. Bull Cancer 93: E44–E52.
Brazil DP, Yang ZZ, Hemmings BA . (2004). Advances in protein kinase B signalling: AKTion on multiple fronts. Trends Biochem Sci 29: 233–242.
Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A et al. (2008). Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 118: 3065–3074.
Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw III EB et al. (2001a). Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBβ). Science 292: 1728–1731.
Cho H, Thorvaldsen JL, Chu Q, Feng F, Birnbaum MJ . (2001b). Akt1/PKBα is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem 276: 38349–38352.
Chung CY, Lee S, Briscoe C, Ellsworth C, Firtel RA . (2000). Role of Rac in controlling the actin cytoskeleton and chemotaxis in motile cells. Proc Natl Acad Sci USA 97: 5225–5230.
Datta SR, Brunet A, Greenberg ME . (1999). Cellular survival: a play in three Akts. Genes Dev 13: 2905–2927.
Dunn SE, Ehrlich M, Sharp NJ, Reiss K, Solomon G, Hawkins R et al. (1998). A dominant negative mutant of the insulin-like growth factor-I receptor inhibits the adhesion, invasion, and metastasis of breast cancer. Cancer Res 58: 3353–3361.
Enomoto A, Murakami H, Asai N, Morone N, Watanabe T, Kawai K et al. (2005). Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev Cell 9: 389–402.
Grille SJ, Bellacosa A, Upson J, Klein-Szanto AJ, van Roy F, Lee-Kwon W et al. (2003). The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res 63: 2172–2178.
Hernandez-Negrete I, Carretero-Ortega J, Rosenfeldt H, Hernandez-Garcia R, Calderon-Salinas JV, Reyes-Cruz G et al. (2007). P-Rex1 links mammalian target of rapamycin signaling to Rac activation and cell migration. J Biol Chem 282: 23708–23715.
Higuchi M, Masuyama N, Fukui Y, Suzuki A, Gotoh Y . (2001). Akt mediates Rac/Cdc42-regulated cell motility in growth factor-stimulated cells and in invasive PTEN knockout cells. Curr Biol 11: 1958–1962.
Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A et al. (2004). Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6: 1122–1128.
Ju X, Katiyar S, Wang C, Liu M, Jiao X, Li S et al. (2007). Akt1 governs breast cancer progression in vivo. Proc Natl Acad Sci USA 104: 7438–7443.
Kim D, Kim S, Koh H, Yoon SO, Chung AS, Cho KS et al. (2001). Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. Faseb J 15: 1953–1962.
Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H et al. (2002). mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110: 163–175.
Kim EK, Tucker DF, Yun SJ, Do KH, Kim MS, Kim JH et al. (2008a). Linker region of Akt1/protein kinase Bα mediates platelet-derived growth factor-induced translocation and cell migration. Cell Signal 20: 2030–2037.
Kim EK, Yun SJ, Do KH, Kim MS, Cho M, Suh DS et al. (2008b). Lysophosphatidic acid induces cell migration through the selective activation of Akt1. Exp Mol Med 40: 445–452.
LeRoith D, Werner H, Beitner-Johnson D, Roberts Jr CT . (1995). Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev 16: 143–163.
O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D et al. (2006). mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66: 1500–1508.
Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H et al. (2004). Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14: 1296–1302.
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM . (2005). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307: 1098–1101.
Sheng S, Qiao M, Pardee AB . (2009). Metastasis and AKT activation. J Cell Physiol 218: 451–454.
van Golen CM, Schwab TS, Kim B, Soules ME, Su Oh S, Fung K et al. (2006). Insulin-like growth factor-I receptor expression regulates neuroblastoma metastasis to bone. Cancer Res 66: 6570–6578.
Wu Y, Yakar S, Zhao L, Hennighausen L, LeRoith D . (2002). Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis. Cancer Res 62: 1030–1035.
Yun SJ, Tucker DF, Kim EK, Kim MS, Do KH, Ha JM et al. (2009). Differential regulation of Akt/protein kinase B isoforms during cell cycle progression. FEBS Lett 583: 685–690.
Zhang H, Bajraszewski N, Wu E, Wang H, Moseman AP, Dabora SL et al. (2007). PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. J Clin Invest 117: 730–738.
Zhang J, Gao Z, Yin J, Quon MJ, Ye J . (2008). S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-(α) signaling through IKK2. J Biol Chem 283: 35375–35382.
Zhou GL, Tucker DF, Bae SS, Bhatheja K, Birnbaum MJ, Field J . (2006). Opposing roles for Akt1 and Akt2 in Rac/Pak signaling and cell migration. J Biol Chem 281: 36443–36453.
Acknowledgements
This work was supported partly by the MRC program of the NRF (2010-0001247), a National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2010-0015808), and the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family affairs, Republic of Korea (0920050).
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Kim, E., Yun, S., Ha, J. et al. Selective activation of Akt1 by mammalian target of rapamycin complex 2 regulates cancer cell migration, invasion, and metastasis. Oncogene 30, 2954–2963 (2011). https://doi.org/10.1038/onc.2011.22
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DOI: https://doi.org/10.1038/onc.2011.22
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