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The Shb signalling scaffold binds to and regulates constitutive signals from the Epstein–Barr virus LMP2A membrane protein

Oncogene volume 26, pages 4908–4917 (2007)Cite this article

Abstract

The Epstein–Barr virus latency-associated membrane protein LMP2A has been shown to activate the survival kinase Akt in epithelial and B cells in a phosphoinositide 3-kinase-dependent fashion. In this study, we demonstrate that the signalling scaffold Shb associates through SH2 and PTB domain interactions with phosphorylated tyrosine motifs in the LMP2A N-terminal tail. Additionally, we show that mutation of tyrosines in these motifs as well as shRNA-mediated downregulation of Shb leads to a loss of constitutive Akt-activation in LMP2A-expressing cells. Furthermore, utilization by Shb of the LMP2A ITAM motif regulates stability of the Syk tyrosine kinase in LMP2A-expressing cells. Our data set the precedent for viral utilization of the Shb signalling scaffold and implicate Shb as a regulator of LMP2A-dependent Akt activation.

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Acknowledgements

We thank Michael Welsh for generous gifts of reagents and for stimulating discussions. Fabio Malavasi kindly contributed the agonistic anti CD38 antibody IB4. We thank W Rod Hardy for providing the pMSCVpuro vector. This work was supported by grants from The Swedish Research Council, Grant K2002-16X-14227-01A and The Swedish Children's Cancer Foundation, PROJ01/18, to GW and LM, and from the Canadian Institutes for Health Research (CIHR) to TP. RJI is a Fellow of the Leukemia & Lymphoma Society. CKL is supported in part by a fellowship from the Wenner-Gren Foundation.

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Authors and Affiliations

  1. Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden

    L V Matskova, C Helmstetter, I Ernberg & G Winberg

  2. Department of Biology, University of Victoria, Victoria, British Columbia, Canada

    R J Ingham

  3. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

    G Gish & T Pawson

  4. Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland

    C K Lindholm

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  1. L V Matskova
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Correspondence to L V Matskova.

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Matskova, L., Helmstetter, C., Ingham, R. et al. The Shb signalling scaffold binds to and regulates constitutive signals from the Epstein–Barr virus LMP2A membrane protein. Oncogene 26, 4908–4917 (2007). https://doi.org/10.1038/sj.onc.1210298

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