title: Selective activation of Akt1 by mammalian target of rapamycin complex 2 regulates cancer cell migration, invasion, and metastasis.
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.
authors.affiliation: MRC for Ischemic Tissue Regeneration and Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine,Yangsan-si, Republic of Korea.
authors.forename: E K
authors.initials: EK
authors.lastname: Kim
authors.forename: S J
authors.initials: SJ
authors.lastname: Yun
authors.forename: J M
authors.initials: JM
authors.lastname: Ha
authors.forename: Y W
authors.initials: YW
authors.lastname: Kim
authors.forename: I H
authors.initials: IH
authors.lastname: Jin
authors.forename: J
authors.initials: J
authors.lastname: Yun
authors.forename: H K
authors.initials: HK
authors.lastname: Shin
authors.forename: S H
authors.initials: SH
authors.lastname: Song
authors.forename: J H
authors.initials: JH
authors.lastname: Kim
authors.forename: J S
authors.initials: JS
authors.lastname: Lee
authors.forename: C D
authors.initials: CD
authors.lastname: Kim
authors.forename: S S
authors.initials: SS
authors.lastname: Bae
mesh_terms: D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D013379:Substrate Specificity; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism / Q000502:physiology
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C453280:PREX1 protein, human; D034741:RNA, Small Interfering; D007334:Insulin-Like Growth Factor I; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020830:rac1 GTP-Binding Protein