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

Abstract

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 ILK-mediated 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 dominant-negative 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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Acknowledgements

We thank Dr John Blenis for providing p70S6K1 cDNA constructs. This work was supported by the National Institutes of Health Grants RR16440 (to DCF and BHJ), CA60731 (to DCF), GM65188, and DK54639 (to CW), by American Cancer Society Research Scholar Grant 04-076-01-TBE (to BHJ), and by West Virginia University Health Science Image Analysis Facility.

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Correspondence to Yong Qian or Bing-Hua Jiang.

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Qian, Y., Zhong, X., Flynn, D. et al. ILK mediates actin filament rearrangements and cell migration and invasion through PI3K/Akt/Rac1 signaling. Oncogene 24, 3154–3165 (2005). https://doi.org/10.1038/sj.onc.1208525

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