Multistep phosphorylation by oncogenic kinases enhances the degradation of the NF2 tumor suppressor merlin.

Mutations in the Neurofibromatosis 2 gene (NF2) predispose to tumors of the nervous system, mainly schwannomas and meningiomas. The NF2 gene encodes for the tumor suppressor protein merlin (moesin-ezrin-radixin-like protein), which functions as a linker between the plasma membrane and the cytoskeleton. Carboxyterminal phosphorylation affects merlin activity, but many open ...
questions on the regulation of merlin function still remain. The phosphoinositide 3-kinase/Akt pathway is activated in human vestibular schwannoma, suggesting a role for Akt-dependent merlin regulation in the formation of these tumors. In this study, we identify merlin serine 10 as a novel substrate for Akt phosphorylation. We demonstrate that this N-terminal phosphorylation directs merlin for proteasome-mediated degradation and affects merlin binding to the E3 ligase component DCAF1. Our data indicate that sequential phosphorylation of merlin C- and N-terminus by different oncogenic kinases targets merlin for degradation and thus downregulates its activity. On the basis of these findings, we propose a model for a posttranslational mechanism of merlin inactivation.
Mesh Terms:
Animals, COS Cells, Catalytic Domain, Cercopithecus aethiops, Humans, Models, Biological, Neurofibromin 2, Oncogenes, Phosphorylation, Phosphotransferases, Protein Processing, Post-Translational, Protein Structure, Tertiary, Signal Transduction, Transfection, Up-Regulation
Neoplasia
Date: Jul. 01, 2011
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