Gene interactions and pathways from curated databases and text-mining
Oncogene 2011, PMID: 21339740

Selective activation of Akt1 by mammalian target of rapamycin complex 2 regulates cancer cell migration, invasion, and metastasis.

Kim, E K; Yun, S J; Ha, J M; Kim, Y W; Jin, I H; Yun, J; Shin, H K; Song, S H; Kim, J H; Lee, J S; Kim, C D; Bae, S S

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.

Diseases/Pathways annotated by Medline MESH: Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasms
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Text Mining Data

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Manually curated Databases

  • IRef Biogrid Interaction: AKT1 — RICTOR (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: RICTOR — PREX1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: AKT1 — PREX1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: AKT1 — RPTOR (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: PREX1 — RPTOR (physical association, affinity chromatography technology)
  • IRef Intact Interaction: Complex of RICTOR-PREX1 (association, anti tag coimmunoprecipitation)
  • IRef Intact Interaction: PREX1 — RICTOR (physical association, anti tag coimmunoprecipitation)
  • IRef Intact Interaction: RPTOR — PREX1 (physical association, anti tag coimmunoprecipitation)
In total, 5 gene pairs are associated to this article in curated databases