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

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). Merlin phosphorylation plays a critical part in dictating merlin NTD/CTD interactions as well as in controlling binding to its effector proteins. Merlin is partially regulated by phosphorylation of Ser 518, such that hyperphosphorylated merlin is inactive and fails to form productive intramolecular and intermolecular interactions. 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.

Protein kinase A-mediated phosphorylation of the NF2 tumor suppressor protein merlin at serine 10 affects the actin cytoskeleton

“…When serine 518 is dephosphorylated by the myosin phosphatase MYPT-1-PP1d, the tumor suppressor function of merlin is activated, inhibiting the Ras signaling pathway and leading to growth arrest (Morrison et al, 2001;Jin et al, 2006). Recently, also two Akt phosphorylation sites, threonine 230 and serine 315, were identified in the N terminus of merlin (Tang et al, 2007).…”

Epidermal Growth Factor Promotes Protein Degradation of Epithelial Protein Lost in Neoplasm (EPLIN), a Putative Metastasis Suppressor, during Epithelial-mesenchymal Transition

“…extracellular signals or stress is a common mechanism "priming" certain proteins for subsequent recruitment of degradation machinery (29,30). We investigated whether EGF could induce phosphorylation of EPLIN in ARCaP E cells, which may be a prerequisite for ubiquitination and degradation of EPLIN.…”

Human BRE1 Is an E3 Ubiquitin Ligase for Ebp1 Tumor Suppressor

“…Tumor suppressors are frequently degraded in cancer cells through polyubiquitination-mediated mechanism, including p53 (Maki et al, 1996), PTEN (Trotman et al, 2007;, and merlin (Tang et al, 2007). To investigate whether Ebp1 can also be modified by polyubiquitination, we cotransfected HA-ubiquitin into HEK293T cells with GST-tagged p42 and p48, followed by a proteasome inhibitor MG132 treatment for 4 h. GST-pull-down assay revealed that p42 but not p48 was potently polyubiquitinated, which was enhanced by MG132 treatment ( Figure 1A).…”