PI3K induced actin filament remodeling through Akt and p70S6K1: implication of essential role in cell migration

Qian, Yong; Corum, Linda; Qiao, Meng; Blenis, John; Zheng, Jenny Z.; Shi, Xianglin; Flynn, Daniel C.; Jiang, Bing‐Hua

doi:10.1152/ajpcell.00142.2003

Cited by 175 publications

(152 citation statements)

References 37 publications

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“…In our previous studies, we showed that p70S6K1-KD inhibited endogenous p70S6K1 activities in CEF cells (Qian et al, 2004). Here, we show that overexpression of p70S6K1-KD partially inhibited ILK-induced cell migration and invasion (Figure 4e), indicating that p70S6K1 is involved in ILK-induced cell mobility.…”

Section: Disruption Of Either Akt or P70s6k1 Inhibits Ilk's Ability Bsupporting

confidence: 67%

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: Disruption Of Either Akt or P70s6k1 Inhibits Ilk's Ability Bsupporting

confidence: 67%

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

et al. 2005

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“…Oncogenic transformation by Ras and c-Myc is traditionally associated with alterations in the cytoskeletal architecture and overall cell morphology (Qian et al, 2004;Kharitonova et al, 2007). Phalloidin staining was performed to examine F-actin structures in Rb-proficient and -deficient cells (Figure 1d).…”

Section: Rb Loss Cooperates With Discrete Oncogenes Jl Dean Et Almentioning

confidence: 99%

Modeling the effect of the RB tumor suppressor on disease progression: dependence on oncogene network and cellular context

et al. 2009

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The retinoblastoma tumor suppressor, RB, is a key regulator of cellular proliferation that is functionally inactivated at high frequency in human cancer. Although RB has been extensively studied with regard to tumor etiology, loss of tumor-suppressor function often occurs relatively late in tumor progression. Therefore, inactivation of RB could have a profound impact on the behavior of tumors driven by discrete oncogenes. Here, collaboration between Ras or c-Myc deregulation and RB functional state was investigated in a model of conditional genetic deletion to decipher the effects related to disease progression. These studies showed that RB loss had a robust impact on mitogen dependence, anchorage dependence and overall survival, which was significantly modified by oncogene activation. Specifically, RB deficiency predisposed c-Myc-expressing cells to cell death and reduced overall tumorigenic proliferation. In contrast, RB deficiency exacerbated the tumorigenic behavior of Ras-transformed cells in both the model system and human tumor cell lines. As these tumors exhibited highly aggressive behavior, the possibility of exploiting the intrinsic sensitivity to cell death with RB loss was evaluated. Particularly, although Ras-transformed, RB-deficient cells bypassed the G1-checkpoint elicited by pharmacological activation of the p53 pathway, they were also highly sensitized to cell death. Altogether, these data suggest that the impact of RB deletion is dependent on the oncogene milieu, and can directly contribute to transformed phenotypes and response to therapeutic intervention.

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“…Recent reports have shown that PI3K induces actin filament remodeling through Akt and p70 S6K (15,16). When AGS cells were treated with 40 ng/mL rhTP or 40 Amol/L D-dRib, the level of phosphorylated Akt increased as early as 6 hours after treatment.…”

Section: Tp-related Invasion Activity Is Dependent On the Phosphatidymentioning

confidence: 90%

Angiogenic Factor Thymidine Phosphorylase Increases Cancer Cell Invasion Activity in Patients with Gastric Adenocarcinoma

Lee

Rha

et al. 2008

Molecular Cancer Research

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We investigated the biological role of thymidine phosphorylase (TP), an angiogenic factor, in gastric cancer cell migration and invasion and explored a therapeutic approach for high TP-expressing tumors using TP enzymatic inhibitor (TPI) and rapamycin. We established TP cDNA overexpressing gastric cancer cell lines (MKN-45/TP and YCC-3/TP) and did invasion and adhesion assays with Matrigel-coated transwell membranes. The related signal pathway using recombinant human TP (rhTP), deoxy-D-ribose (D-dRib), and signal pathway inhibitors (wortmannin, LY294002, and rapamycin) was investigated. First, AGS and MKN-1 gastric cancer cell lines showed dose-dependent up-regulation of invasiveness through Matrigel following treatment with rhTP or D-dRib. TP-overexpressing cancer cell lines displayed increased migration and invasion activity, which doubled with rhTP and D-dRib treatment. This activity depended on the enzymatic activity of TP, and TP stimulated the adhesion of cancer cells onto Matrigel and induced actin filament remodeling. Finally, we showed that this activity is related to increased phosphatidylinositol 3-kinase activity in TP-overexpressing cells and that combination treatment with rapamycin and TP enzymatic inhibitor produces an additive effect to abrogate TP-induced invasion. Taken together, TP increases the migration and invasion of gastric cancer cells, especially in TP-expressing cells. Therapies targeting TP might diminish the propensity for invasion and metastasis in gastric cancer. (Mol Cancer Res 2008;6(10):1554 -66)

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PI3K induced actin filament remodeling through Akt and p70S6K1: implication of essential role in cell migration

Cited by 175 publications

References 37 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

Modeling the effect of the RB tumor suppressor on disease progression: dependence on oncogene network and cellular context

Angiogenic Factor Thymidine Phosphorylase Increases Cancer Cell Invasion Activity in Patients with Gastric Adenocarcinoma

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