Mechanisms Connecting the Conserved Protein Kinases Ssp1, Kin1, and Pom1 in Fission Yeast Cell Polarity and Division.
Mechanisms Connecting the Conserved Protein Kinases Ssp1, Kin1, and Pom1 in Fission Yeast Cell Polarity and Division.
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DOI：
10.1016/j.cub.2017.11.034
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发表时间：
2018-01-08
期刊：
影响因子：
--
通讯作者：
Moseley JB
中科院分区：
文献类型：
--
作者：
Lee ME;Rusin SF;Jenkins N;Kettenbach AN;Moseley JB
在复杂的细胞极性网络中起作用的蛋白激酶之间的联系知之甚少。杆状分裂酵母细胞以高度极化的方式生长，遗传筛选已经鉴定出许多蛋白激酶，包括CaMKK样Ssp 1和MARK/PAR-1家族激酶Kin 1，它们是极化生长和细胞形状所需的，但它们的功能机制和连接尚不清楚。我们发现Ssp 1通过磷酸化Kin 1的激活环来促进细胞极性。Kin 1通过未知的机制调节细胞极性和胞质分裂。我们进行了大规模的磷酸化蛋白质组学筛选，发现Kin 1磷酸化自身和Pal 1以促进细胞尖端的生长，并且这些蛋白质对于生长的细胞尖端的定位是相互依赖的。细胞极性和胞质分裂的其他Kin 1底物（Tea 4，Mod 5，Cdc 15和Cyk 3）也被第二种激酶，DYRK家族成员Pom 1磷酸化。Kin 1和Pom 1富集在生长细胞的两端，它们在共享底物上的大部分非重叠位点磷酸化。Kin 1和Pom 1的联合抑制导致其共享底物Cdc 15和Cyk 3的合成缺陷，证实了通过共享底物的非冗余功能连接。这些发现揭示了一个新的Ssp 1-Kin 1信号通路，并确定其功能和机制与Pom 1信号细胞极性和胞质分裂。这些激酶在包括人类在内的许多真核生物中是保守的，这表明类似的连接和机制可能在广泛的细胞中起作用。
Connections between the protein kinases that function within complex cell polarity networks are poorly understood. Rod-shaped fission yeast cells grow in a highly polarized manner, and genetic screens have identified many protein kinases, including the CaMKK-like Ssp1 and the MARK/PAR-1 family kinase Kin1, that are required for polarized growth and cell shape, but their functional mechanisms and connections have been unknown. We found that Ssp1 promotes cell polarity by phosphorylating the activation loop of Kin1. Kin1 regulates cell polarity and cytokinesis through unknown mechanisms. We performed a large-scale phosphoproteomic screen and found that Kin1 phosphorylates itself and Pal1 to promote growth at cell tips, and these proteins are interdependent for localization to growing cell tips. Additional Kin1 substrates for cell polarity and cytokinesis (Tea4, Mod5, Cdc15 and Cyk3) were also phosphorylated by a second kinase, the DYRK-family member Pom1. Kin1 and Pom1 were enriched at opposite ends of growing cells, and they phosphorylated largely non-overlapping sites on shared substrates. Combined inhibition of both Kin1 and Pom1 led to synthetic defects in their shared substrates Cdc15 and Cyk3, confirming a non-redundant functional connection through shared substrates. These findings uncover a new Ssp1-Kin1 signaling pathway, and define its functional and mechanistic connection with Pom1 signaling for cell polarity and cytokinesis. These kinases are conserved in many eukaryotes including humans, suggesting that similar connections and mechanisms might operate in a broad range of cells.
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