Abstract
Neurofibromin 2 (NF2, also known as merlin) is a tumor suppressor protein encoded by the neurofibromatosis type 2 gene NF2. NF2 is also an actin-binding protein that functions in an intrinsic signaling network critical for actin dynamics. Although protein kinase A (PKA)-mediated NF2-serin (S) 10 phosphorylation stabilizes filamentous actin (F-actin), the underlying mechanisms of NF2-S10 dephosphorylation and the role of NF2 in seizures have been elusive. Here, we demonstrate that pyridoxal-5′-phosphate phosphatase/chronophin (PLPP/CIN) dephosphorylated NF2-S10 site as well as cofilin-S3 site. In addition, NF2-S10 dephosphorylation reversely regulated murine double minute-2 (Mdm2) and postsynaptic density 95 (PSD95) degradations in an activity-dependent manner, which increased seizure intensity and its progression in response to kainic acid (KA). In addition, NF2 knockdown facilitated seizure intensity and its progress through F-actin instability independent of cofilin-mediated actin dynamics. Therefore, we suggest that PLPP/CIN may be a potential therapeutic target for epileptogenesis and NF2-associated diseases.
Highlights
Neurofibromin 2 [NF2, known as merlin or schwannomin] is a tumor suppressor protein encoded by the neurofibromatosis type 2 gene NF2
Coimmunoprecipitation demonstrated that PLPP/CIN bound to NF2, when PKA catabolic subunit (PKAc) was present (F(2,18) = 1721.3, p < 0.00001, one-way ANOVA, n = 7, respectively; Fig. 1d and e)
In vivo study demonstrated that no differences in NF2-PKAc binding between WT and PLPP/CINTg mice under physiological conditions (Fig. 1f, g)
Summary
Neurofibromin 2 [NF2, known as merlin (moesinezrin-radixin-like protein) or schwannomin] is a tumor suppressor protein encoded by the neurofibromatosis type 2 gene NF2. Deletion or loss-of-function mutation of NF2 causes neurofibromatosis type 2, which is a dominant inherited disorder characterized by the development of multiple benign tumors in the nervous system. Filamentous actin (F-actin) plays an important role in stabilization and structural modification of dendritic spines that are critical structural and functional components of neurons receiving and integrating the majority of excitatory synaptic inputs[7,8,9,10,11]. C.428_430delCTTdel mutation in Nf2 is associated with a predisposition to development of benign brain tumors in which the on-set of symptoms is characterized by status epilepticus (SE, a prolonged seizure activity) in humans[19]. With respect to NF2–actin interactions4–6. it is likely that NF2-
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