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首页> 外文期刊>Journal of Molecular Biology >Translocation of Exogenous FGF1 and FGF2 Protects the Cell against Apoptosis Independently of Receptor Activation
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Translocation of Exogenous FGF1 and FGF2 Protects the Cell against Apoptosis Independently of Receptor Activation

机译：外源FGF1和FGF2的易位独立于受体激活保护细胞免受凋亡

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FGF1 and FGF2 bind to specific cell-surface tyrosine kinase receptors (FGFRs) and activate intracellular signaling that leads to proliferation, migration or differentiation of many cell types. Besides this classical mode of action, under stress conditions, FGF1 and FGF2 are translocated in a receptor-dependent manner via the endosomal membrane into the cytosol and nucleus of the cell. However, despite many years of research, the role of translocated FGF1 and FGF2 inside the cell remains unclear. Here, we reveal an anti-apoptotic activity of intracellular FGF1 and FGF2, which is independent of FGFR activation and downstream signaling. We observed an inhibition of cell apoptosis induced by serum starvation or staurosporine upon treatment with exogenous FGF1 or FGF2, despite the presence of highly potent FGFR inhibitors. Similar results were found when the tyrosine kinase of FGFR1 was completely blocked by a specific mutation. Moreover, the anti-apoptotic effect of the growth factors was abolished by known inhibitors of the translocation of FGF1 and FGF2 from the endosomes to the interior of the cell. Interestingly, FGF2 showed higher anti-apoptotic activity than FGF1. Since FGF2 is not phosphorylated by PKCδ and is present inside the nucleus longer than is FGF1, we speculated that the different activities could reflect their diverse nuclear export kinetics. Indeed, we observed that FGF1 mutations preventing binding to nucleolin and therefore phosphorylation in the nucleus affect the anti-apoptotic activity of FGF1. Taken together, our data indicate that the translocation of FGF1 and FGF2 protects cells against apoptosis and promotes cell survival.
机译：FGF1和FGF2与特异性细胞表面酪氨酸激酶受体（FGFRS）结合并激活细胞内信号，导致许多细胞类型的增殖，迁移或分化。除了这种经典作用模式之外，在应力条件下，FGF1和FGF2通过内体膜以受体依赖性方式转移到细胞的细胞溶质和细胞核中。然而，尽管有多年的研究，但在细胞内易位的FGF1和FGF2的作用仍然不清楚。在这里，我们揭示了细胞内FGF1和FGF2的抗凋亡活性，其与FGFR激活和下游信号传导无关。我们观察到在用外源FGF1或FGF2处理时，抑制血清饥饿剂或Staurosporine的细胞凋亡，尽管存在高效的FGFR抑制剂存在。当FGFR1的酪氨酸激酶被特定突变完全阻断时，发现了类似的结果。此外，通过已知的FGF1和FGF2从内体转移到细胞内部的已知抑制剂，废除了生长因子的抗凋亡效应。有趣的是，FGF2显示比FGF1更高的抗凋亡活动。由于FGF2不受PKCδ磷酸化并且存在于细胞核内的比FGF1长，因此我们推测不同的活动可以反映其各种核出口动力学。实际上，我们观察到，FGF1突变预防核素的结合，因此核中的磷酸化影响FGF1的抗凋亡活性。我们的数据结合在一起，表明FGF1和FGF2的易位保护细胞免受细胞凋亡并促进细胞存活。

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