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Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis

Nature Cell Biology volume 5, pages 733–740 (2003)Cite this article

Abstract

Epithelial cells must adhere to the extracellular matrix (ECM) for survival, as detachment from matrix triggers apoptosis or anoikis1. Integrins are major mediators of adhesion between cells and ECM proteins, and transduce signals required for cell survival2. Recent evidence suggests that integrin receptors are coupled to growth factor receptors in the regulation of multiple biological functions2; however, mechanisms involved in coordinate regulation of cell survival are poorly understood and mediators responsible for anoikis have not been well characterized. Here, we identify the pro-apoptotic protein Bim as a critical mediator of anoikis in epithelial cells. Bim is strongly induced after cell detachment and downregulation of Bim expression by RNA interference (RNAi) inhibits anoikis. Detachment-induced expression of Bim requires a lack of β1-integrin engagement, downregulation of EGF receptor (EGFR) expression and inhibition of Erk signalling. Overexpressed EGFR was uncoupled from integrin regulation, resulting in the maintenance of Erk activation in suspension, and a block in Bim expression and anoikis. Thus, Bim functions as a key sensor of integrin and growth factor signals to the Erk pathway, and loss of such coordinate regulation may contribute to tumour progression.

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Figure 1: Bim is upregulated by cell detachment and contributes to anoikis.
Figure 2: Regulation of Bim by integrins and EGFR signalling.
Figure 3: EGFR overexpression blocks Bim induction and apoptosis during cell detachment.
Figure 4: Erk signalling regulates Bim expression and anoikis.

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Acknowledgements

We would like to thank O. Gozani, R. Greenberg and members of the Brugge lab for stimulating discussions. We would like to thank Ariad Pharmaceuticals for providing AP1510 (www.ariad.com/regulationkits). This work was supported by grants from National Cancer Institute, Aventis Pharmaceuticals and the American Cancer Society (to J.S.B.); a Susan Komen Breast Cancer Postdoctoral Fellowship (to M.J.R.); an HHMI Physician Postdoctoral Fellowship (to J.D.); a Massachusetts Breast Cancer Research Award (to S.K.M.).

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Author notes

  1. Senthil K. Muthuswamy

    Present address: Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11274, USA

Authors and Affiliations

  1. Department of Cell Biology, Harvard Medical School, Boston, 02115, MA, USA

    Mauricio J. Reginato, Kenna R. Mills, Jessica K. Paulus, Danielle K. Lynch, Jayanta Debnath, Senthil K. Muthuswamy & Joan S. Brugge

  2. Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston, 02129, MA, USA

    Dennis C. Sgroi

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Reginato, M., Mills, K., Paulus, J. et al. Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis. Nat Cell Biol 5, 733–740 (2003). https://doi.org/10.1038/ncb1026

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