Hoe Hyang-Sook, Rebeck G William
Department of Neuroscience, Georgetown University, 3970 Reservoir Road NW, Washington, DC 20057-1464, USA.
Brain Res Mol Brain Res. 2005 Jun 13;137(1-2):31-9. doi: 10.1016/j.molbrainres.2005.02.013. Epub 2005 Mar 23.
Two brain receptors for apolipoprotein E (apoE), the apoE receptor 2 (apoEr2) and the very low density lipoprotein receptor (VLDLr), are important in neuronal migration during development. Using a series of tagged constructs, we found that these two receptors undergo extracellular cleavages to release secreted forms of the receptors and intramembranous cleavages to degrade the C-terminal fragments. Release of the extracellular domains was blocked by an inhibitor of metalloproteinases and increased by PMA. Accumulation of the intracellular domain was increased by the presence of an inhibitor of gamma-secretase. ApoE binding to these receptors caused increased release of the extracellular domain and accumulation of the intracellular domains; similar increases in receptor proteolytic domains were observed from endogenous apoEr2 after treatment of primary neurons or rat hippocampus with an apoE-derived peptide. The human apoE isoforms promoted proteolysis to different degrees, with apoE2 resulting in a greater accumulation of the C-terminal fragments of apoEr2 compared with apoE4. These effects of apoE on receptor proteolysis were mediated by the ligand binding domain of the receptor. Similar promotion of receptor cleavage was seen with two other ligands, reelin and activated alpha2-macroglobulin. We suggest that signaling promoted by these receptors depends in part on these regulated proteolytic events.
载脂蛋白E（apoE）的两种脑受体，即apoE受体2（apoEr2）和极低密度脂蛋白受体（VLDLr），在发育过程中的神经元迁移中起重要作用。通过一系列标记构建体，我们发现这两种受体经历细胞外切割以释放受体的分泌形式，并经历膜内切割以降解C末端片段。细胞外结构域的释放被金属蛋白酶抑制剂阻断，并被佛波酯（PMA）增加。γ-分泌酶抑制剂的存在增加了细胞内结构域的积累。apoE与这些受体的结合导致细胞外结构域的释放增加和细胞内结构域的积累；在用apoE衍生肽处理原代神经元或大鼠海马后，内源性apoEr2的受体蛋白水解结构域也观察到类似的增加。人类apoE异构体促进蛋白水解的程度不同，与apoE4相比，apoE2导致apoEr2的C末端片段积累更多。apoE对受体蛋白水解的这些作用是由受体的配体结合结构域介导的。另外两种配体，即Reelin和活化的α2-巨球蛋白，也观察到类似的受体切割促进作用。我们认为，这些受体促进的信号传导部分取决于这些受调控的蛋白水解事件。
