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Regulation of differentiation and morphogenesis through the protein kinase Cbk1.

机译：通过蛋白激酶Cbk1调控分化和形态发生。

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摘要

The Ndr/Lats kinase Cbk1 is an essential component of the RAM network, a conserved signaling pathway that integrates cell fate determination and morphogenesis in budding yeast. As the downstream-most component of the network, Cbk1 controls aspects of cell polarity, cell cycle-regulated transcription, and cell integrity. Loss of Cbk1 function is lethal in the presence of SSD1, a gene that is polymorphic in common lab strain backgrounds. Therefore, I sought to identify both upstream regulatory inputs and downstream targets of this kinase to better understand how Cbk1 functions in differentiation and morphogenesis.;I have shown that phosphoregulation of Cbk1 at conserved sites is critical for RAM network function. Intramolecular autophosphorylation within the activation loop is critical for kinase activity but is only partially required for cell separation and polarized growth. In contrast, phosphorylation of a C-terminal hydrophobic motif is required for Cbk1 function in vivo, but not for its kinase activity, suggesting a novel mechanism for control of this family of kinases. Phosphorylation of the C-terminal site is regulated over the cell cycle and requires all upstream RAM network components. In addition, phosphorylation at this site requires the Cbk1 target, Ace2, so that the downstream target reinforces the activation of its upstream regulator, suggesting a positive feedback loop.;I have also sought to identify downstream targets of Cbk1. I have demonstrated that Ssd1, a protein of unknown function, is a novel target of Cbk1. Mutation of the eight putative Cbk1 phosphorylation sites found in Ssd1 abolishes phosphorylation. Overexpression of this mutant Ssd1 protein is lethal, suggesting that Cbk1 antagonizes an unknown cell-lethal function of Ssd1. I find that Ssd1 binds to a specific subset of RNAs in vivo and represses the translation of these messages. In addition, Ssd1 acts as a potent stimulator global mRNA decay. Cbk1 inhibits both these functions. Many Ssd1 targets are daughter specific genes, whose expression are controlled in part by the transcription factor Ace2. Thus, Cbk1 functions at multiple points to precisely control gene expression in the daughter cell, acting as a novel mechanism for the integration of cell fate determination and morphogenesis.
机译：Ndr / Lats激酶Cbk1是RAM网络的重要组成部分，RAM网络是一种保守的信号传导途径，整合了发芽酵母中的细胞命运确定和形态发生。作为网络的最下游组件，Cbk1控制细胞极性，细胞周期调节的转录和细胞完整性等方面。在SSD1的存在下，Cbk1功能的丧失是致命的，该基因在普通实验室菌株的背景下是多态的。因此，我试图确定该激酶的上游调控输入和下游靶标，以更好地了解Cbk1在分化和形态发生中的功能。我已经表明，保守位点Cbk1的磷酸化对于RAM网络功能至关重要。激活环内的分子内自磷酸化对于激酶活性至关重要，但对于细胞分离和极化生长仅部分需要。相反，体内Cbk1功能需要C端疏水基序的磷酸化，但其激酶活性不是必需的，这提示了控制该激酶家族的新机制。 C末端位点的磷酸化在细胞周期中受到调节，并且需要所有上游RAM网络组件。此外，在该位点的磷酸化需要Cbk1靶Ace2，因此下游靶增强了其上游调节剂的激活，提示存在正反馈回路。我也试图确定Cbk1的下游靶。我已经证明Ssd1，​​一种功能未知的蛋白质，是Cbk1的新型靶标。 Ssd1中发现的八个假定的Cbk1磷酸化位点的突变消除了磷酸化。这种突变Ssd1蛋白的过表达是致命的，这表明Cbk1拮抗Ssd1的未知细胞致死功能。我发现Ssd1在体内与RNA的特定子集结合并抑制了这些信息的翻译。此外，Ssd1可以作为有效的刺激剂，使mRNA整体衰减。 Cbk1禁止这两个功能。许多Ssd1靶标是子代特异性基因，其表达部分受转录因子Ace2控制。因此，Cbk1在多个点起作用以精确地控制子细胞中的基因表达，这是整合细胞命运确定和形态发生的新机制。

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  • 作者

    Jansen, Jaclyn.;

  • 作者单位

    Northwestern University.;

  • 授予单位 Northwestern University.;
  • 学科 Biology Molecular.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 184 p.
  • 总页数 184
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-17 11:38:31

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