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PKCε is a permissive link in integrin-dependent IFN-γ signalling that facilitates JAK phosphorylation of STAT1

Nature Cell Biology volume 5, pages 363–369 (2003)Cite this article

Abstract

The critical dependence of receptor-triggered signals on integrin-mediated cell–substrate interactions represents a fundamental biological paradigm in health and disease. However, the molecular connections of these permissive inputs, which operate through integrin–matrix interactions, has remained largely obscure. Here we show that the serine-threonine kinase protein kinase C ε (PKCε) functions as a signal integrator between cytokine and integrin signalling pathways. Integrins are shown to control PKCε phosphorylation acutely by determining complex formation with protein phosphatase 2A (PP2A) and the upstream kinase PDK1 (phosphoinositide-dependent kinase 1). The PP2A-induced loss of PKCε function results in attenuated interferon γ (INF-γ)-induced phosphorylation of STAT1 (signal transducer and activator of transcription 1) downstream of Janus kinase 1/2 (JAK1/2). PKCε function and the IFN-γ response can be recovered by inhibition of PP2A if PDK1 is associated with PKCε in this complex. More directly, a PP2A-resistant mutant of PKCε is sufficient for restoration of the IFN-γ response in suspension culture. Thus, PKCε functions as a central point of integration through which integrin engagement exerts a permissive input on IFN-γ signalling.

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Figure 1: Adhesion regulates IFN-γ-induced activation of STAT1.
Figure 2: PKCε positively regulates IFN-γ induced STAT1 activation downstream of JAKs.
Figure 3: Cell–matrix interactions regulate the phosphorylation state of PKCε.
Figure 4: Regulated formation of a PKCε–PDK1–PP2A complex.
Figure 5: Mutant PKCε can restore IFN-γ-induced STAT1 phosphorylation in detached cells.

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Acknowledgements

We wish to thank F. Watt and G. Schiavo for their valuable comments and J. Goris (Catholic University, Leuven, Belgium) for phosphorylated inhibitor-1. We also thank A. Costa-Pereira for technical advice. J.I. is an EMBO long-term fellow and is supported by grants from the Academy of Finland, Emil Aaltonen Foundation, Finnish Cancer Association, Finnish Cultural Foundation, Irja Karvonen Cancer Foundation, Leiras Research Foundation, HS100v foundation and Maud Kuistila's Foundation. This work was supported in part by the European Community, grant QLK3-CT-2000-01038.

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Authors and Affiliations

  1. Protein Phosphorylation Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

    Johanna Ivaska & Peter J. Parker

  2. Instituto de Bioquímica CSIC-UCM, Facultad de Farmacia, Madrid, 28040, Spain

    Lisardo Bosca

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  1. Johanna Ivaska
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Correspondence to Peter J. Parker.

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Supplementary Figure

Figure S1 Phosphatases that act on PKCe are activated upon cell detachment and in response to fibrillar collagen. (PDF 134 kb)

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Ivaska, J., Bosca, L. & Parker, P. PKCε is a permissive link in integrin-dependent IFN-γ signalling that facilitates JAK phosphorylation of STAT1. Nat Cell Biol 5, 363–369 (2003). https://doi.org/10.1038/ncb957

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