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Akt Phosphorylation of Merlin Enhances Its Binding to Phosphatidylinositols and Inhibits the Tumor-Suppressive Activities of Merlin

¹ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia and ² Dipartimento di Morfologia ed Embriologia, Universita' di Ferrara, Ferrara, Italy

Requests for reprints: Keqiang Ye, Emory University, Room 145, Whitehead Building, 615 Michael Street, Atlanta, GA 30322. Phone: 404-712-2814; Fax: 404-712-2979; E-mail: kye{at}emory.edu.

Key Words: NF2 • merlin • Akt • phosphorylation • phosphatidylinositols

The NF2 tumor suppressor gene encodes an intracellular membrane-associated protein, called merlin, which belongs to the band 4.1 family of cytoskeleton-associated proteins that link cell surface glycoproteins to the actin cytoskeleton. Merlin suppresses phosphatidylinositol 3-kinase (PI3K)/Akt signaling by directly binding and inhibiting the stimulatory activity of PIKE-L on PI3K. Akt feeds back and phosphorylates merlin and provokes its polyubiquitination and degradation. Here, we show that Akt phosphorylation and PI(3,4,5)P₃ binding mediate the tumor-suppressive activity of merlin. The extreme NH₂ terminus of merlin directly interacts with phosphatidylinositols, for which the unfolded conformation is required. Moreover, Akt phosphorylation enhances merlin binding affinity to phosphatidylinositols and inhibits its proapoptotic actions. Furthermore, Akt phosphorylation and phosphatidylinositols increase merlin binding to CD44. Epidermal growth factor treatment and Akt phosphorylation provoke merlin to aggregate in the ruffled plasma membrane and promote cell migration. Thus, these results suggest that PI3K signaling regulates the tumor-suppressive activity of merlin via both Akt phosphorylation and phosphatidylinositol lipids binding to merlin. [Cancer Res 2009;69(9):4043–51]