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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Signaling dynamics of the KSR1 scaffold complex
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Signaling dynamics of the KSR1 scaffold complex

机译：KSR1支架复合物的信号动力学

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摘要

Scaffold proteins contribute to the spatiotemporal control of MAPK signaling and KSR1 is an ERK cascade scaffold that localizes to the plasma membrane in response to growth factor treatment. To better understand the molecular mechanisms of KSR1 function, we examined the interaction of KSR1 with each of the ERK cascade components, Raf, MEK, and ERK. Here, we identify a hydrophobic motif within the proline-rich sequence (PRS) of MEK1 and MEK2 that is required for constitutive binding to KSR1 and find that MEK binding and residues in the KSR1 CA1 region enable KSR1 to form a ternary complex with B-Raf and MEK following growth factor treatment that enhances MEK activation. We also find that docking of active ERK to the KSR1 scaffold allows ERK to phosphorylate KSR1 and B-Raf on feedback S/TP sites. Strikingly, feedback phos-phorylation of KSR1 and B-Raf promote their dissociation and result in the release of KSR1 from the plasma membrane. Together, these findings provide unique insight into the signaling dynamics of the KSR1 scaffold and reveal that through regulated interactions with Raf and ERK, KSR1 acts to both potentiate and attenuate ERK cascade activation, thus regulating the intensity and duration of ERK cascade signaling emanating from the plasma membrane during growth factor signaling.
机译：支架蛋白有助于MAPK信号的时空控制，KSR1是一种ERK级联支架，可响应生长因子治疗而定位于质膜。为了更好地了解KSR1功能的分子机制，我们检查了KSR1与每个ERK级联组分Raf，MEK和ERK的相互作用。在这里，我们确定了MEK1和MEK2富含脯氨酸序列（PRS）内与KSR1组成型结合所需的疏水基序，并发现MEK结合和KSR1 CA1区的残基使KSR1与B-形成三元复合物Raf和MEK经过生长因子处理后可增强MEK活化。我们还发现，活性ERK与KSR1支架的对接使ERK可以在反馈S / TP位点上磷酸化KSR1和B-Raf。引人注目的是，KSR1和B-Raf的反馈磷酸化促进了它们的解离，并导致KSR1从质膜释放。在一起，这些发现提供了对KSR1支架的信号传导动力学的独特见解，并揭示了通过与Raf和ERK的调控相互作用，KSR1既可增强也可减弱ERK级联信号的激活，从而调节由ESR级联信号产生的ERK级联信号的强度和持续时间。生长因子信号传导过程中的质膜。

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  • 作者

    Melissa M. McKay; Daniel A. Ritt; Deborah K. Morrison;

  • 作者单位

    Labpratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute-Frederick, P. O. Box B, Frederick, MD 21702;

    Labpratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute-Frederick, P. O. Box B, Frederick, MD 21702;

    Labpratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute-Frederick, P. O. Box B, Frederick, MD 21702;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    ERK cascade; protein scaffolds; signal tranduction;

    机译：ERK级联;蛋白质支架;信号转导;

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