Ectodomain shedding, translocation and synthesis of SorLA are stimulated by its ligand head activator.
Ectodomain shedding, translocation and synthesis of SorLA are stimulated by its ligand head activator.
复制标题
SorLA 的胞外域脱落、易位和合成受到其配体头激活剂的刺激。
作者：
W. Hampe;I. Riedel;Julia Lintzel;Christian O. Bader;I. Franke;H. Schaller
单跨膜受体SorLA是来自水螅的头部激活物结合蛋白HAB的哺乳动物同源物。人神经前体细胞NT2和神经内分泌细胞系BON产生头部激活剂（head activator， HA），并通过进入有丝分裂和细胞增殖对HA作出反应。它们表达SorLA，并以纳米级亲和力结合HA。与Sepharose偶联的HA能够特异性沉淀SorLA，证明SorLA与HA结合。使用针对细胞外和细胞内表位的抗血清，我们发现SorLA作为膜受体和可溶性蛋白从细胞释放到培养基中。不同细胞系在SorLA的加工过程中差异很大，NT2细胞主要将SorLA作为膜受体表达，而BON细胞则以释放SorLA为主。可溶性SorLA缺乏胞内结构域，通过金属蛋白酶从跨膜蛋白上脱落。透明质酸和酚酯刺激细胞和脑切片的释放，金属蛋白酶抑制剂和降低温度至20℃可阻断SorLA的释放，SorLA反义寡核苷酸处理细胞可导致细胞增殖速率降低。由此我们得出SorLA介导内源性HA的有丝分裂作用是必要的。透明质酸促进SorLA从细胞膜到细胞表面的易位和内化。此外，HA刺激SorLA的合成暗示了一个自催化反馈回路，在这个反馈回路中配体激活其受体的生产、加工和易位。
The single transmembrane receptor SorLA is the mammalian orthologue of the head activator-binding protein, HAB, from hydra. The human neuronal precursor cell line NT2 and the neuroendocrine cell line BON produce head activator (HA) and respond to HA by entry into mitosis and cell proliferation. They express SorLA, and bind HA with nanomolar affinity. HA coupled to Sepharose is able to precipitate SorLA specifically proving that SorLA binds HA. Using antisera directed against extra- and intracellular epitopes we find SorLA as membrane receptor and as soluble protein released from cells into the culture medium. Cell lines differ strongly in processing of SorLA, with NT2 cells expressing SorLA mainly as membrane receptor, whereas release predominates in BON cells. Soluble SorLA lacks the intracellular domain and is shed from the transmembrane protein by a metalloprotease. Release from cells and brain slices is stimulated by HA and by phorbol ester, and it is blocked by a metalloprotease inhibitor and by lowering the temperature to 20 degrees C. Blockade of SorLA shedding and treatment of cells with SorLA antisense oligonucleotides lead to a decrease in the rate of cell proliferation. From this we conclude that SorLA is necessary to mediate the mitogenic effect of endogenous HA. HA enhances the translocation of SorLA from internal membranes to the cell surface and its internalization. In addition, HA stimulates SorLA synthesis hinting at an autocatalytic feedback loop in which the ligand activates production, processing, and translocation of its receptor.
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