Letter abstract
Nature Cell Biology 9, 1199 - 1207 (2007)
Published online: 23 September 2007 | doi:10.1038/ncb1641
Akt phosphorylation regulates the tumour-suppressor merlin through ubiquitination and degradation
Xiaoling Tang1, Sung-Wuk Jang1, Xuerong Wang2, Zhixue Liu1, Scott M. Bahr3, Shi-Yong Sun2, Daniel Brat1, David H. Gutmann3 & Keqiang Ye1
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.
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
- Winship Cancer Institute, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
- Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St Louis, MO 63110, USA.
Correspondence to: Keqiang Ye1 e-mail: kye@emory.edu
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