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首页> 外文期刊>Molecular and Cellular Biology >Phosphorylation of Fibroblast Growth Factor (FGF) Receptor 1 at Ser777 by p38 Mitogen-Activated Protein Kinase Regulates Translocation of Exogenous FGF1 to the Cytosol and Nucleus
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Phosphorylation of Fibroblast Growth Factor (FGF) Receptor 1 at Ser777 by p38 Mitogen-Activated Protein Kinase Regulates Translocation of Exogenous FGF1 to the Cytosol and Nucleus

机译：p38丝裂原活化蛋白激酶在Ser777上的成纤维细胞生长因子（FGF）受体1的磷酸化调节外源FGF1向细胞质和细胞核的转运。

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Exogenous fibroblast growth factor 1 (FGF1) signals through activation of transmembrane FGF receptors (FGFRs) but may also regulate cellular processes after translocation to the cytosol and nucleus of target cells. Translocation of FGF1 occurs across the limiting membrane of intracellular vesicles and is a regulated process that depends on the C-terminal tail of the FGFR. Here, we report that translocation of FGF1 requires activity of the α isoform of p38 mitogen-activated protein kinase (MAPK). FGF1 translocation was inhibited after chemical inhibition of p38 MAPK or after small interfering RNA knockdown of p38α. Translocation was increased after stimulation of p38 MAPK with anisomycin, mannitol, or H2O2. The activity level of p38 MAPK was not found to affect endocytosis or intracellular sorting of FGF1/FGFR1. Instead, we found that p38 MAPK regulates FGF1 translocation by phosphorylation of FGFR1 at Ser777. The FGFR1 mutation S777A abolished FGF1 translocation, while phospho-mimetic mutations of Ser777 to Asp or Glu allowed translocation to take place and bypassed the requirement for active p38 MAPK. Ser777 in FGFR1 was directly phosphorylated by p38α in a cell-free system. These data demonstrate a crucial role for p38α MAPK in the regulated translocation of exogenous FGF1 into the cytosolucleus, and they reveal a specific role for p38α MAPK-mediated serine phosphorylation of FGFR1.
机译：外源成纤维细胞生长因子1（FGF1）通过跨膜FGF受体（FGFR）的激活发出信号，但也可能在易位至靶细胞的细胞质和细胞核后调节细胞过程。 FGF1的转运发生在细胞内小泡的限制膜上，并且是一个受调节的过程，取决于FGFR的C末端尾巴。在这里，我们报告FGF1易位需要p38丝裂原活化蛋白激酶（MAPK）的α同工型的活性。在化学抑制p38 MAPK或小的干扰性p38αRNA敲低后，FGF1易位被抑制。茴香霉素，甘露醇或H 2 O 2 刺激p38 MAPK后，易位增加。未发现p38 MAPK的活性水平影响FGF1 / FGFR1的内吞作用或细胞内分选。相反，我们发现p38 MAPK通过在Ser777处使FGFR1磷酸化来调节FGF1易位。 FGFR1突变S777A消除了FGF1易位，而Ser777的模拟磷酸突变为Asp或Glu允许发生易位，并绕开了对活性p38 MAPK的需求。 FGFR1中的Ser777在无细胞系统中被p38α直接磷酸化。这些数据证明了p38αMAPK在外源性FGF1向细胞质/细胞核的调节转运中的关键作用，并且它们揭示了p38αMAPK介导的FGFR1丝氨酸磷酸化的特定作用。

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