S100B and S100A6 differentially modulate cell survival by interacting with distinct RAGE (receptor for advanced glycation end products) immunoglobulin domains
S100B and S100A6 differentially modulate cell survival by interacting with distinct RAGE (receptor for advanced glycation end products) immunoglobulin domains
复制标题
DOI：
10.1074/jbc.m703951200
复制
发表时间：
2007-10-26
影响因子：
4.8
通讯作者：
Galichet, Arnaud
中科院分区：
文献类型：
--
作者：
Leclerc, Estelle;Fritz, Gunter;Galichet, Arnaud
S100蛋白是EF-hand钙结合蛋白，具有多种细胞内功能，包括细胞增殖、分化、迁移和凋亡。一些S100蛋白也被分泌并发挥细胞外旁分泌和自分泌功能。实验结果表明，晚期糖基化终产物受体（RAGE）在介导S100蛋白诱导的细胞信号传导中起重要作用。本文通过体外实验和培养人SH-SY5Y神经母细胞瘤细胞，比较了S100蛋白S100B和S100A6与RAGE的相互作用。我们的体外结合数据显示，S100B和S100A6虽然结构非常相似，但与不同的RAGE胞外结构域相互作用。我们的细胞分析数据表明，S100B和S100A6对细胞存活的调节存在差异。在微摩尔浓度下，S100B促进细胞增殖，而在相同浓度下，S100A6触发细胞凋亡。尽管两种S100蛋白都诱导活性氧的形成，但S100B招募了磷脂酰肌醇3-激酶/AKT和nf - κ B，而S100A6激活了JNK。更重要的是，我们发现S100B和S100A6以rage依赖的方式调节细胞存活；S100B特异性地与RAGE V和C-1结构域相互作用，S100A6特异性地与C1和C-2 RAGE结构域相互作用。总之，这些结果突出了S100/RAGE细胞信号的复杂性。
S100 proteins are EF-hand calcium-binding proteins with various intracellular functions including cell proliferation, differentiation, migration, and apoptosis. Some S100 proteins are also secreted and exert extracellular paracrine and autocrine functions. Experimental results suggest that the receptor for advanced glycation end products (RAGE) plays important roles in mediating S100 protein-induced cellular signaling. Here we compared the interaction of two S100 proteins, S100B and S100A6, with RAGE by in vitro assay and in culture of human SH-SY5Y neuroblastoma cells. Our in vitro binding data showed that S100B and S100A6, although structurally very similar, interact with different RAGE extracellular domains. Our cell assay data demonstrated that S100B and S100A6 differentially modulate cell survival. At micromolar concentration, S100B increased cellular proliferation, whereas at the same concentration, S100A6 triggered apoptosis. Although both S100 proteins induced the formation of reactive oxygen species, S100B recruited phosphatidylinositol 3-kinase/AKT and NF-kappa B, whereas S100A6 activated JNK. More importantly, we showed that S100B and S100A6 modulate cell survival in a RAGE-dependent manner; S100B specifically interacted with the RAGE V and C-1 domains and S100A6 specifically interacted with the C1 and C-2 RAGE domains. Altogether these results highlight the complexity of S100/RAGE cellular signaling.