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Serine 518 phosphorylation modulates merlin intramolecular association and binding to critical effectors important for NF2 growth suppression

Oncogene volume 23, pages 8447–8454 (2004)Cite this article

Abstract

The neurofibromatosis 2 (NF2) tumor suppressor protein, merlin, functions as a negative growth regulator; however, the molecular mechanisms that underlie merlin regulation remain elusive. Recent studies have implicated merlin phosphorylation in regulating merlin subcellular localization and growth suppression. P21-activated kinase (PAK), a downstream target of Rac1/Cdc42, directly phosphorylates merlin at Serine 518. In this report, we show that PAK2 directly phosphorylates wild-type merlin, whereas merlin truncation mutants with impaired GST-amino-terminal domain (N-term or NTD)/GST-carboxy-terminal domain (C-term or CTD) intramolecular association exhibit impaired S518 phosphorylation. We directly demonstrate that PAK2 phosphorylation impairs merlin N-term/C-term binding in vitro and in vivo. Lastly, we show that PAK2 phosphorylation impairs the ability of merlin to bind to two interacting proteins, CD44 and hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), both critical for merlin growth suppression. These observations suggest that merlin S518 phosphorylation directly modulates merlin intramolecular and intermolecular associations important for the ability of merlin to function as a tumor suppressor.

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Acknowledgements

This work is supported by a New Investigator Award from Department of Defense (NF020013) to KY and funding from the National Institutes of Health (NS35848) to DHG We thank Drs Joseph L Kissil and Tyler Jacks at Department of Biology and Center for Cancer Research, Howard Hughes Medical Institute, MIT for the HM2175 phospho-S518 merlin antibody and helpful discussions.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, 30322, GA, USA

    Rong Rong & Keqiang Ye

  2. Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St Louis, 63110, MO, USA

    Ezequiel I Surace, Carrie A Haipek & David H Gutmann

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  1. Rong Rong
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  2. Ezequiel I Surace
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Correspondence to Keqiang Ye.

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Rong, R., Surace, E., Haipek, C. et al. Serine 518 phosphorylation modulates merlin intramolecular association and binding to critical effectors important for NF2 growth suppression. Oncogene 23, 8447–8454 (2004). https://doi.org/10.1038/sj.onc.1207794

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