Akt Phosphorylation and PI (3, 4, 5) P3 Binding Coordinately Inhibit the Tumor Suppressive Activity of Merlin

摘要

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 actin cytoskeleton. Merlin suppresses PI 3-kinase/Akt signaling through directly binding and inhibiting PIKE-L's stimulatory activity on PI 3-kinase. In Nature Cell Biology paper (2007), we have demonstrated that 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. In Cancer Research paper (2009), we show Akt phosphorylation and PI( 3, 4, 5) P3 binding mediate the tumor suppressive activity of merlin. The extreme Nterminus 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 pro-apoptotic actions. Further, Akt phosphorylation and phosphatidylinositols increase merlin binding to CD44. EGF treatment and Akt phosphorylation provoke merlin to aggregate in the ruffled plasma membrane and promote cell migration. Thus, these results suggest that PI 3-kinase signaling regulates merlin's tumor suppressive activity via both Akt phosphorylation and phosphatidylinositol lipids binding to merlin. Recently, we show that phosphorylation of merlin also regulates its sumoylation. The biological significance of this finding is under investigation.