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Negative regulation of EGFR signalling through integrin-α1β1-mediated activation of protein tyrosine phosphatase TCPTP

Nature Cell Biology volume 7, pages 78–85 (2005)Cite this article

Abstract

Integrin-mediated cell adhesion regulates a multitude of cellular responses, including proliferation, survival and cross-talk between different cellular signalling pathways1. So far, integrins have been mainly shown to convey permissive signals enabling anchorage-dependent receptor tyrosine kinase signalling2,3,4. Here we show that a collagen-binding integrin α1β1 functions as a negative regulator of epidermal growth factor receptor (EGFR) signalling through the activation of a protein tyrosine phosphatase. The cytoplasmic tail of α1 integrin selectively interacts with a ubiquitously expressed protein tyrosine phosphatase TCPTP (T-cell protein tyrosine phosphatase) and activates it after cell adhesion to collagen. The activation results in reduced EGFR phosphorylation after EGF stimulation. Introduction of the α1 cytoplasmic domain peptide into cells induces phosphatase activation and inhibits EGF-induced cell proliferation and anchorage-independent growth of malignant cells. These data are the first demonstration of the regulation of TCPTP activity in vivo and represent a new molecular paradigm of integrin-mediated negative regulation of receptor tyrosine kinase signalling.

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Figure 1: TCPTP associates with the cytoplasmic domain of the integrin α1-chain.
Figure 2: The integrin α1 cytoplasmic tail activates TCPTP.
Figure 3: Integrin α1β1 ligation attenuates EGFR phosphorylation through activation of TCPTP.
Figure 4: α1 cytoplasmic tail peptide induces phosphatase activity in vivo and inhibits anchorage-independent and EGF-induced cell growth.

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Acknowledgements

We thank P. J. Parker and M. Salmi for valuable comments; T. Tiganis for the TC45 construct; A. Pozzi for the α1 integrin construct; J. Durgan for help with the yeast-two-hybrid assay; C. Nylund for the RT–PCR analysis; S. Käkönen for help with the statistical analysis; J. Heino for the peptides and the α1−/− and α1+/+ fibroblasts; and H. Jalonen, P. Toivonen and A. Raita for technical assistance. This work was supported by grants from the Academy of Finland, the Sigrid Juselius Foundation, Emil Aaltonen Foundation, Finnish Cancer Organisations and Southwestern Finland's Culture Foundation.

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  1. VTT Technical Research Centre of Finland, Medical Biotechnology and University of Turku Centre for Biotechnology, Turku, FIN-20520, Finland

    Elina Mattila, Teijo Pellinen, Jonna Nevo, Karoliina Vuoriluoto, Antti Arjonen & Johanna Ivaska

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Correspondence to Johanna Ivaska.

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Mattila, E., Pellinen, T., Nevo, J. et al. Negative regulation of EGFR signalling through integrin-α1β1-mediated activation of protein tyrosine phosphatase TCPTP. Nat Cell Biol 7, 78–85 (2005). https://doi.org/10.1038/ncb1209

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