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Akt phosphorylation regulates the tumour-suppressor merlin through ubiquitination and degradation

Nature Cell Biology volume 9, pages 1199–1207 (2007)Cite this article

Abstract

The neurofibromatosis-2 (NF2) tumour-suppressor gene encodes an intracellular membrane-associated protein, called merlin, whose growth-suppressive function is dependent on its ability to form interactions through its intramolecular amino-terminal domain (NTD) and carboxy-terminal domain (CTD)1,2,3. Merlin phosphorylation plays a critical part in dictating merlin NTD/CTD interactions as well as in controlling binding to its effector proteins4,5,6,7. Merlin is partially regulated by phosphorylation of Ser 518, such that hyperphosphorylated merlin is inactive and fails to form productive intramolecular and intermolecular interactions8,9. Here, we show that the protein kinase Akt directly binds to and phosphorylates merlin on residues Thr 230 and Ser 315, which abolishes merlin NTD/CTD interactions and binding to merlin's effector protein PIKE-L and other binding partners. Furthermore, Akt-mediated phosphorylation leads to merlin degradation by ubiquitination. These studies demonstrate that Akt-mediated merlin phosphorylation regulates the function of merlin in the absence of an inactivating mutation.

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Figure 1: Merlin is a physiological substrate of Akt.
Figure 2: Merlin associates with Akt.
Figure 3: Akt phosphorylation disrupts the intramolecular and intermolecular binding of merlin.
Figure 4: Akt mediates merlin degradation through ubiquitination.
Figure 5: Akt phosphorylation of merlin increases its motility.

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Acknowledgements

This work was supported by a Research-Initiated Award from the Department of Defense (NF05009) and RO1 (CA117872) from NIH to K.Y. as well as an Investigator-Initiated Award from Department of Defense (DAMD-17-04-0266) to D.H.G.

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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

    Xiaoling Tang, Sung-Wuk Jang, Zhixue Liu, Daniel Brat & Keqiang Ye

  2. Winship Cancer Institute, Emory University School of Medicine, 615 Michael Street, Atlanta, 30322, GA, USA

    Xuerong Wang & Shi-Yong Sun

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

    Scott M. Bahr & David H. Gutmann

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Correspondence to Keqiang Ye.

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Tang, X., Jang, SW., Wang, X. et al. Akt phosphorylation regulates the tumour-suppressor merlin through ubiquitination and degradation. Nat Cell Biol 9, 1199–1207 (2007). https://doi.org/10.1038/ncb1641

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