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Pyk2 and FAK regulate neurite outgrowth induced by growth factors and integrins

Nature Cell Biology volume 2, pages 574–581 (2000)Cite this article

Abstract

Integration of signalling pathways initiated by receptor tyrosine kinases and integrins is essential for growth-factor-mediated biological responses. Here we show that co-stimulation of growth-factor receptors and integrins activates the focal-adhesion kinase (FAK) family to promote outgrowth of neurites in PC12 and SH-SY5Y cells. Pyk2 and FAK associate with adhesion-based complexes that contain epidermal growth factor (EGF) receptors, through their carboxy- and amino-terminal domains. Expression of the C-terminal domain of Pyk2 or of FAK is sufficient to block neurite outgrowth, but not activation of extracellular-signal-regulated kinase (ERK). Moreover, activation and autophosphorylation of Pyk2/FAK, as well as of effectors of their adhesion-targeting domains, such as paxillin, are important for propagation of signals that control neurite formation. Thus, Pyk2/FAK have important functions in signal integration proximal to integrin/growth-factor receptor complexes in neurons.

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Figure 1: Effect of integrin engagement on neurite outgrowth in PC12 or SH-SY5Y cells treated with EGF or IGF-1.
Figure 2: Activation of MAP kinase in PC12 and PC12-PDGFR cells plated on plastic or collagen I-coated dishes.
Figure 3: Activation of Pyk2 and FAK by growth factors in PC12 or SH-SY5Y cells.
Figure 4: Assembly of a signalling complex at adhesion sites.
Figure 5: Inhibition of Pyk2 or FAK blocks EGF and IGF-1-induced neurite outgrowth.
Figure 6: Paxillin is involved in Pyk2-mediated neurite formation.

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Acknowledgements

We thank L. Claesson-Welsh, F. Giancotti, T. Hunter, E. Nånberg, L. Rönnstrand, D. Schlaepfer, J. Schlessinger, S. Thomas, K. Vuori and A. Yoshimura for reagents. We also thank L. Claesson-Welsh and J. Dixelius for help with immunofluorescence microscopy. We are grateful to C-H. Heldin, L. Claesson-Welsh and A. Moustakas for comments on the manuscript. A.B. was supported by a postdoctoral fellowship from the Deutsche Forschungsgemeinschaft (DFG) and I.D. is a Boehringer Ingelheim Fonds Research Fellow.

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  1. Ludwig Institute for Cancer Research, Box 595, Husargatan 3, Uppsala, S- 75124, Sweden

    Inga Ivankovic-Dikic, Eva Grönroos, Andree Blaukat, Bernd-Uwe Barth & Ivan Dikic

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Ivankovic-Dikic, I., Grönroos, E., Blaukat, A. et al. Pyk2 and FAK regulate neurite outgrowth induced by growth factors and integrins. Nat Cell Biol 2, 574–581 (2000). https://doi.org/10.1038/35023515

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