title: Multistep phosphorylation by oncogenic kinases enhances the degradation of the NF2 tumor suppressor merlin.
abstract: 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.
authors.affiliation: Biomedicum Helsinki, Department of Pathology, University of Helsinki, Helsinki, Finland. Minja.Pehrsson@helsinki.fi
authors.forename: Minja
authors.initials: M
authors.lastname: Laulajainen
authors.forename: Taru
authors.initials: T
authors.lastname: Muranen
authors.forename: Tuula A
authors.initials: TA
authors.lastname: Nyman
authors.forename: Olli
authors.initials: O
authors.lastname: Carpén
authors.forename: Mikaela
authors.initials: M
authors.lastname: Grönholm
mesh_terms: D000818:Animals; D019556:COS Cells; D020134:Catalytic Domain; D002522:Chlorocebus aethiops; D006801:Humans; D008954:Models, Biological; D025581:Neurofibromin 2 / Q000737:chemistry / Q000378:metabolism*; D009857:Oncogenes / Q000502:physiology*; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism* / Q000502:physiology; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D015854:Up-Regulation
chemical_list: D025581:Neurofibromin 2; D010770:Phosphotransferases