MRC Centre for Developmental Neurobiology, King's College London, London, United Kingdom.
PLoS One. 2013 Aug 5;8(8):e71957. doi: 10.1371/journal.pone.0071957. Print 2013.
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.
肌动蛋白动力学的缺陷会影响突触传递和神经元可塑性的活性依赖性调节，并可能导致认知障碍。一种将突触功能障碍与认知缺陷联系起来的突出候选肌动蛋白结合蛋白是 Drebrin（DBN）。然而，DBN 在中枢突触中受到调控的具体方式在很大程度上仍是未知的。在这项研究中，我们确定并表征了 PTEN 肿瘤抑制因子与 DBN 的相互作用。我们的结果表明，PTEN 与 DBN 结合，并且这种相互作用导致 DBN C 末端丝氨酸 647 的磷酸化。PTEN 和 pS647-DBN 在神经元中分布在不同的、互补的隔室中，支持了 PTEN 负调控该位点 DBN 磷酸化的观点。我们进一步证明，神经元活性增加了体外培养的海马神经元和表现出癫痫活动的离体海马切片中 DBN 在 S647 处的磷酸化，这可能是通过诱导 PTEN:DBN 复合物的快速解离来实现的。我们的研究结果确定了一种新的机制，即 PTEN 是维持 DBN 在动态范围内磷酸化所必需的，这表明了一种与中枢神经系统突触处的认知衰退和退行性疾病相关的肌动蛋白结合蛋白的不寻常调控。
