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IGFBP5 induces cell adhesion, increases cell survival and inhibits cell migration in MCF-7 human breast cancer cells
Angara Sureshbabu, Hiroshi Okajima, Daisuke Yamanaka, Elizabeth Tonner, Surya Shastri, Joanna Maycock, Malgorzata Szymanowska, John Shand, Shin-Ichiro Takahashi, James Beattie, Gordon Allan, David Flint


Maintenance of tissue boundaries is crucial for control of metastasis. We describe a new signalling pathway in which epithelial cell disruption can be minimised and thereby restricts epithelial–mesenchymal transgressions. This involves the release of insulin-like growth factor (IGF)-binding protein 5 (IGFBP5) from apoptotic cells, which increases the adhesion of epithelial cells on mesenchymal but not epithelial extracellular matrix (ECM), and involves the direct interaction of IGFBP5 and α2β1 integrins. IGFBP5 also induced cell adhesion to vitronectin in the absence of αVβ3 integrin, the vitronectin receptor, again through an α2β1-integrin-dependent action, suggesting that IGFBP5 can induce spreading on matrices, even in the absence of the integrins normally used in this process. Using IGFBP5 mutants we demonstrate that the effect is IGF-independent but requires the heparin-binding domain in the C-terminus of IGFBP5. A truncated mutant containing only the C-terminal of IGFBP5 also induced adhesion. Adhesion induced by IGFBP5 was dependent on Cdc42 and resulted in activation of integrin-linked kinase (ILK) and Akt. Consistent with these changes, IGFBP5 facilitated prolonged cell survival in nutrient-poor conditions and decreased phosphorylation of the stress-activated kinase p38 MAPK (MAPK14). Whereas IGFBP5 enhanced adhesion, it inhibited cell migration, although this was not evident using the truncated C-terminal mutant, suggesting that effects of IGFBP5 on adhesion and migration involve different mechanisms. We anticipate that these responses to IGFBP5 would reduce the metastatic potential of cells.


  • Funding

    This research was funded by the Biotechnology and Biological Sciences Research Council [grant number BB\F00205X\1], Rural and Environment Research and Analysis Directorate (UK) and the University of Strathclyde.

  • Accepted December 9, 2011.
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