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首页> 外文期刊>Oncogene >Identification of novel ERK-mediated feedback phosphorylation sites at the C-terminus of B-Raf
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Identification of novel ERK-mediated feedback phosphorylation sites at the C-terminus of B-Raf

机译：在B-Raf的C末端鉴定新型ERK介导的反馈磷酸化位点

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The extracellular signal-regulated kinase (ERK) pathway plays an important role during the development and activation of B lymphocytes. We have recently shown that B-Raf is a dominant ERK activator in B-cell antigen receptor signalling. We now show that B-Raf is hyperphosphorylated upon BCR engagement and undergoes a prominent electrophoretic mobility shift. This shift correlates with ERK activation and is prevented by the MEK inhibitor U0126. Syk-deficient DT40 B cells display neither dual ERK phosphorylation nor a mobility shift of B-Raf upon BCR engagement. The inducible expression of a constitutively active B-Raf in this mutant line restores dual ERK phosphorylation and the mobility shift of endogenous B-Raf, indicating that these two events are connected to each other. By site-directed mutagenesis studies, we demonstrate that the shift is due to an ERK2-mediated feedback phosphorylation of serine/threonine residues within an evolutionary conserved SPKTP motif at the C-terminus of B-Raf. Replacement of these residues by negatively charged amino acids causes a constitutive mobility shift and a reduction of PC12 cell differentiation. We discuss a model in which ERK-mediated phosphorylation of the SPKTP motif is involved in negative feedback regulation of B-Raf.
机译：细胞外信号调节激酶（ERK）通路在B淋巴细胞的发育和激活过程中起着重要作用。我们最近显示，B-Raf是B细胞抗原受体信号传导中的一种主要ERK激活剂。现在，我们显示B-Raf在BCR参与时被过度磷酸化，并经历显着的电泳迁移率变化。该移位与ERK激活相关，并且被MEK抑制剂U0126阻止。 Syk缺陷的DT40 B细胞在BCR参与后既不显示双重ERK磷酸化，也不显示B-Raf的迁移率变化。在此突变株系中组成型活性B-Raf的可诱导表达恢复了双重ERK磷酸化和内源性B-Raf的迁移率转移，表明这两个事件是相互关联的。通过定点诱变研究，我们证明了这种转变是由于E-2介导的丝氨酸/苏氨酸残基的ERK2介导的反馈磷酸化在B-Raf C端的进化保守SPKTP基序内。这些残基被带负电荷的氨基酸取代会导致组成型迁移率移动并降低PC12细胞分化。我们讨论一个模型，其中ERK介导的SPKTP主题的磷酸化参与B-Raf的负反馈调节。

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