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Selective regulation of tumor necrosis factor–induced Erk signaling by Src family kinases and the T cell protein tyrosine phosphatase

Nature Immunology volume 6, pages 253–260 (2005)Cite this article

Abstract

The proinflammatory cytokine tumor necrosis factor (TNF) modulates cellular responses through the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways, but the molecular mechanisms underlying MAPK activation are unknown. T cell protein tyrosine phosphatase (TCPTP) is essential for hematopoietic development and negatively regulates inflammatory responses. Using TCPTP-deficient fibroblasts, we show here that TCPTP regulates TNF-induced MAPK but not NF-κB signaling. TCPTP interacted with the adaptor protein TRAF2, and dephosphorylated and inactivated Src tyrosine kinases to suppress downstream signaling through extracellular signal–regulated kinases and production of interleukin 6. These results link TCPTP and Src tyrosine kinases to the selective regulation of TNF-induced MAPK signaling and identify a previously unknown mechanism for modulating inflammatory responses mediated by TNF.

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Figure 1: Enhanced TNF-induced Erk1/2 signaling in TCPTP-deficient cells.
Figure 2: Overexpressed TCPTP inhibits TNF-induced MAPK signaling.
Figure 3: TCPTP acts in the cytoplasm to inhibit TNF-induced MAPK signaling.
Figure 4: TCPTP acts upstream of MAP3Ks and interacts with TRAF2.
Figure 5: Enhanced TNF-induced IL-6 production in TCPTP-deficient cells.
Figure 6: TCPTP dephosphorylates and inactivates SFKs.
Figure 7: Enhanced SFK activation in TCPTP-deficient cells.

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Acknowledgements

We thank N. Tonks, A. Bennett and N. Court for critical reading of the manuscript and lab members for technical assistance and discussions. Supported by the National Health and Medical Research Council of Australia. T.T. is a Monash University Logan Fellow.

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  1. Michelle A Puryer

    Present address: Murdoch Children's Research Institute, Parkville, Victoria, 3052, Australia

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Monash University, 3800, Victoria, Australia

    Catherine van Vliet, Patricia E Bukczynska, Michelle A Puryer, Christine M Sadek, Benjamin J Shields & Tony Tiganis

  2. McGill Cancer Centre, McGill University, Montreal, H3G1Y6, Quebec, Canada

    Michel L Tremblay

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Supplementary information

Supplementary Fig. 1

Enhanced TNF-induced ERK1/2 signalling in TCPTP-deficient cells. (PDF 131 kb)

Supplementary Fig. 2

TNF-induced proliferation and cell death are not altered in TCPTP-deficient cells. (PDF 133 kb)

Supplementary Fig. 3

PP1 but not AG1478 or AG490 suppresses the enhanced TNF-induced activation of ERK1/2 in TCPTP-deficient cells. (PDF 136 kb)

Supplementary Fig. 4

Y418 phosphorylated Src-Y527F can be precipitated by the TCPTP-D182A “substrate-trapping” mutant. (PDF 110 kb)

Supplementary Fig. 5

Tyrosine phosphorylated SFKs can be precipitated by the TCPTP-D182A “substrate-trapping” mutant in response to TNF. (PDF 113 kb)

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van Vliet, C., Bukczynska, P., Puryer, M. et al. Selective regulation of tumor necrosis factor–induced Erk signaling by Src family kinases and the T cell protein tyrosine phosphatase. Nat Immunol 6, 253–260 (2005). https://doi.org/10.1038/ni1169

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