Phosphatidylinositol 4,5-Bisphosphate (PI(4,5)P2)-dependent Oligomerization of Fibroblast Growth Factor 2 (FGF2) Triggers the Formation of a Lipidic Membrane Pore Implicated in Unconventional Secretion
Phosphatidylinositol 4,5-Bisphosphate (PI(4,5)P2)-dependent Oligomerization of Fibroblast Growth Factor 2 (FGF2) Triggers the Formation of a Lipidic Membrane Pore Implicated in Unconventional Secretion
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DOI：
10.1074/jbc.m112.381939
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发表时间：
2012-08-10
影响因子：
4.8
通讯作者：
Nickel, Walter
中科院分区：
文献类型：
--
作者：
Steringer, Julia P.;Bleicken, Stephanie;Nickel, Walter
成纤维细胞生长因子2（FGF 2）是一种重要的有丝分裂原，在肿瘤诱导的血管生成的特定步骤中起中心作用。已知它通过绕过内质网/高尔基体依赖性分泌途径的非常规方式分泌。然而，FGF 2膜易位到细胞外空间的机制仍然是难以捉摸的。在这里，我们表明，磷脂酰肌醇4，5-二磷酸依赖性膜招聘导致FGF 2寡聚化，这反过来又引发了一个假定的环形结构的血管膜孔的形成。该过程被FGF 2的酪氨酸磷酸化强烈上调。我们的研究结果解释了从活细胞中分泌FGF 2的关键要求，并提出了一种新的自我维持的蛋白质跨膜转运机制，其中细胞膜孔是短暂的转运中间体。
Fibroblast growth factor 2 (FGF2) is a critical mitogen with a central role in specific steps of tumor-induced angiogenesis. It is known to be secreted by unconventional means bypassing the endoplasmic reticulum/Golgi-dependent secretory pathway. However, the mechanism of FGF2 membrane translocation into the extracellular space has remained elusive. Here, we show that phosphatidylinositol 4,5-bisphosphate-dependent membrane recruitment causes FGF2 to oligomerize, which in turn triggers the formation of a lipidic membrane pore with a putative toroidal structure. This process is strongly up-regulated by tyrosine phosphorylation of FGF2. Our findings explain key requirements of FGF2 secretion from living cells and suggest a novel self-sustained mechanism of protein translocation across membranes with a lipidic membrane pore being a transient translocation intermediate.