Abstract
Defects in actin dynamics affect activity-dependent modulation of synaptic transmission and neuronal plasticity, and can cause cognitive impairment. A salient candidate actin-binding protein linking synaptic dysfunction to cognitive deficits is Drebrin (DBN). However, the specific mode of how DBN is regulated at the central synapse is largely unknown. In this study we identify and characterize the interaction of the PTEN tumor suppressor with DBN. Our results demonstrate that PTEN binds DBN and that this interaction results in the dephosphorylation of a site present in the DBN C-terminus - serine 647. PTEN and pS647-DBN segregate into distinct and complimentary compartments in neurons, supporting the idea that PTEN negatively regulates DBN phosphorylation at this site. We further demonstrate that neuronal activity increases phosphorylation of DBN at S647 in hippocampal neurons in vitro and in ex vivo hippocampus slices exhibiting seizure activity, potentially by inducing rapid dissociation of the PTEN:DBN complex. Our results identify a novel mechanism by which PTEN is required to maintain DBN phosphorylation at dynamic range and signifies an unusual regulation of an actin-binding protein linked to cognitive decline and degenerative conditions at the CNS synapse.
Highlights
PTEN (Phosphatase and tensin homolog) was originally identified as a tumor suppressor that negatively regulates the Phosphatidylinositol 3-kinase (PI3K) signaling pathway [1]
In this study we identify and characterize the interaction of the PTEN tumor suppressor with DBN, an actin-binding protein highly enriched in dendritic spines
Our results demonstrate that PTEN binds DBN and that this interaction results in the dephosphorylation of a site present in the DBN C-terminus serine 647
Summary
PTEN (Phosphatase and tensin homolog) was originally identified as a tumor suppressor that negatively regulates the Phosphatidylinositol 3-kinase (PI3K) signaling pathway [1]. Whilst most of the characterized neuronal responses can be credited to PTEN’s role in the regulation PI3K signaling [8,9,10], PTEN has other potential mechanisms of action including functions independent of the lipid phosphatase activity and functions in the nucleus [11,12]. In order to understand the spatial and temporal regulation of PTEN function in the brain, we searched for new PTEN protein–protein interactions using mass spectrometry. Our search identified a new binding partner: Drebrin (developmentally regulated brain protein, DBN), a protein that binds to actin filaments. DBN accumulates in regions highly enriched in F-actin, such as neuronal growth cones and dendritic spines, and modulates synaptic plasticity by affecting the spine morphology and by regulating neuronal transmission [13,14].
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