Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Center for Molecular Medicine, Samsung Biomedical Research Institute, 300, Cheoncheon-dong Jangan-gu, Suwon 440-746, Republic of Korea.
Neurochem Int. 2011 Feb;58(2):215-23. doi: 10.1016/j.neuint.2010.12.001. Epub 2010 Dec 8.
Two Ebp1 isoproteins, p48 and p42, regulate cell survival and differentiation distinctively. Here we show that p48 is the major isoform in hippocampal neurons and is localized throughout the entire neuron. Notably, reduction of p48 Ebp1 expression inhibited BDNF-mediated neurite outgrowth in hippocampal neurons. The p48 protein acts as a downstream effector of the Trk receptor, which mediates the functions of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in hippocampal cells. Trk receptor activation by both NGF and BDNF induced phosphorylation of Ebp1 at the S360 upon the activation of protein kinase Cδ (PKCδ) and triggered dissociation of p48 from retinoblastoma (Rb). Although both NGF and BDNF activate mitogen-activated protein kinase (MAPK; extracellular signal-related kinase (ERK)) as well as phosphatidylinositide 3-kinase (PI3K)/Akt, their activation is regulated in different time-frame upon growth factor specificity, especially, eliciting PKCδ mediated p48 S360 phosphorylation. Thus, p48 Ebp1 contributes to neuronal cell differentiation and growth factor specificity through the activation of PKCδ, acting as a crucial downstream effector of neurotrophin signaling.
两种 Ebp1 同工型蛋白，p48 和 p42，在细胞存活和分化方面具有不同的调节作用。在这里，我们发现 p48 是海马神经元中的主要同工型蛋白，并且分布于整个神经元中。值得注意的是，降低 p48 Ebp1 的表达水平会抑制 BDNF 介导的海马神经元的突起生长。p48 蛋白是 Trk 受体的下游效应物，Trk 受体介导神经生长因子（NGF）和脑源性神经营养因子（BDNF）在海马细胞中的功能。NGF 和 BDNF 均可通过激活蛋白激酶 Cδ（PKCδ）使 Ebp1 在 S360 磷酸化，从而触发 p48 从视网膜母细胞瘤（Rb）上解离。虽然 NGF 和 BDNF 均可激活丝裂原活化蛋白激酶（MAPK；细胞外信号相关激酶（ERK））和磷脂酰肌醇 3-激酶（PI3K）/Akt，但它们的激活受到生长因子特异性的不同时间框架的调节，特别是通过 PKCδ 介导的 p48 S360 磷酸化。因此，p48 Ebp1 通过激活 PKCδ 促进神经元细胞分化和生长因子特异性，作为神经营养因子信号转导的关键下游效应物。
