A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt

Aoki, Masahiro; Blazek, Erik; Vogt, Peter K.

doi:10.1073/pnas.98.1.136

Cited by 256 publications

(122 citation statements)

References 85 publications

(57 reference statements)

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“…Our results have demonstrated that the overexpression of ILK activated p70S6K1, which is downstream of PI3K/Akt. Our results are consistent with the observations in either PI3K-or Aktinduced cell transformation, which demonstrated that the cell transformation was mediated via the phosphorylation and activation of p70S6K1 (Aoki et al, 2001). Our results are also consistent with the recent observation that p70S6K1 is activated in insulin, PDGF, and EGF signaling (Burgering and Coffer, 1995).…”

Section: Discussionsupporting

confidence: 83%

ILK mediates actin filament rearrangements and cell migration and invasion through PI3K/Akt/Rac1 signaling

et al. 2005

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One of the hallmarks of integrin signaling is an increase in cell migration and invasion, both of which are associated with actin filament rearrangements. Integrin-linked kinase (ILK) is a cytoplasmic effector of integrin receptors. ILK is known to be involved in multiple cellular functions. However, the signaling pathways involved in ILKmediated cellular structure and motility remain to be elucidated. Here, we have demonstrated that overexpression of ILK was sufficient to induce actin filament rearrangements, to form cell motility structures, and to increase cell migration and invasion in a phosphatidylinositol 3-kinase (PI3K)-dependent manner. This corresponds with the activation of both Akt and p70 ribosomal protein S6 kinase (p70S6K1). Overexpression of dominantnegative mutants of Akt inhibited ILK-dependent activation of p70S6K1, indicating that Akt is upstream of p70S6K1 in response to ILK signaling. Overexpression of ILK was sufficient to induce Rac1 activation, which was abolish by a PI3K inhibitor, indicating that Rac1 activity is involved in ILK signaling in a PI3K dependent manner. Inhibition of Akt, Rac1, or p70S6K1 inhibited the effects of ILK on actin filaments and cell migration, suggesting a regulatory role of the PI3K/Akt/p70S6K1/Rac1 signaling pathway in response to ILK signaling. We have shown that overexpression of a dominant-negative ILK was sufficient to abolish fibronectin peptide (PHSRN)-induced rearrangements of actin filaments and cell migration and invasion. Taken together, our results identify a mechanism through which ILK can regulate both integrin-associated rearrangements of actin filaments and cell migration and invasion at the integrin receptor-proximal region.

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Section: Discussionsupporting

confidence: 83%

ILK mediates actin filament rearrangements and cell migration and invasion through PI3K/Akt/Rac1 signaling

et al. 2005

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“…Coordinated with cell division, an increase in cell size is required for cellular proliferation. Like 4E-BP1, STAT-3 is constitutively activated in a number of human tumors and possesses oncogenic potential and antiapoptotic activities (Garcia and Jove, 1998;Bromberg et al, 1999;Catlett-Falcone et al, 1999;Aoki et al, 2001). Transcriptional activation of STAT-3 is regulated by serine phosphorylation at Ser-727 via the MAPK or mTOR pathways (Yokogami et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

PKC-η mediates glioblastoma cell proliferation through the Akt and mTOR signaling pathways

et al. 2004

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“…Phosphorylation of the tumor suppressor TSC2 by Akt results in its inactivation, thereby promoting the accumulation of (active) Rheb-GTP and the induction of mTOR activity. mTOR then triggers the phosphorylation of key regulators of the cellular translation machinery, including ribosomal p70 S6 kinase (p70 S6K) and eukaryote initiation factor 4E binding protein 1 (4EBP1) [Aoki et al, 2001; Gingras et al, 1998]. Of interest, mutations in different signaling proteins of the TSC/mTOR pathway are associated with the onset of other human diseases characterized by the development of vascular tumors (i.e.…”

Section: Introductionmentioning

confidence: 99%

The Kaposi's sarcoma‐associated herpesvirus G protein‐coupled receptor: Lessons on dysregulated angiogenesis from a viral oncogene

Jham

Montaner

2010

J of Cellular Biochemistry

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Tumor viruses can induce cell transformation by overcoming cellular defense mechanisms and promoting the ungoverned proliferation of infected cells. To this end, functionally related viral oncogenes have evolved in disparate viruses to override key proliferative and survival intracellular pathways, thus assuring efficient viral replication and contributing to tumor formation. Indeed, the study of viral oncogenes has been a powerful tool for disclosing fundamental insights into these basic cellular processes. In this regard, the Kaposi’s sarcoma-associated Herpesvirus (KSHV or HHV8), the etiological agent of Kaposi’s sarcoma (KS), is an exemplary model of an oncogenic virus that includes within its genome several homologues of cellular genes implicated in the regulation of cell proliferation and apoptosis. However, emerging evidence now points to a single KSHV gene, ORF74, encoding for the viral G protein-coupled receptor (vGPCR), as essential for KS development. Expressed in only a fraction of cells within KS lesions, this viral receptor induces tumorigenesis through both autocrine and paracrine mechanisms. Indeed, work from several labs has demonstrated that vGPCR can promote cell proliferation, enhance cell survival, modulate cell migration, stimulate angiogenesis, and recruit inflammatory cells, both in expressing cells, as well as in neighboring (bystander) cells. Examination of this powerful viral oncogene may expose novel targets for the treatment of patients with KS and could ultimately provide a unique perspective into how GPCRs, and specifically chemokine receptors, contribute to angiogenesis and tumorigenesis.

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A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt

Cited by 256 publications

References 85 publications

ILK mediates actin filament rearrangements and cell migration and invasion through PI3K/Akt/Rac1 signaling

ILK mediates actin filament rearrangements and cell migration and invasion through PI3K/Akt/Rac1 signaling

PKC-η mediates glioblastoma cell proliferation through the Akt and mTOR signaling pathways

The Kaposi's sarcoma‐associated herpesvirus G protein‐coupled receptor: Lessons on dysregulated angiogenesis from a viral oncogene

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