Polar gradients of the DYRK-family kinase Pom1 couple cell length with the cell cycle
Polar gradients of the DYRK-family kinase Pom1 couple cell length with the cell cycle
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DOI：
10.1038/nature08054
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发表时间：
2009-06-11
期刊：
影响因子：
64.8
通讯作者：
Berthelot-Grosjean, Martine
中科院分区：
文献类型：
--
作者：
Martin, Sophie G.;Berthelot-Grosjean, Martine
细胞通常在进入有丝分裂和分裂之前生长到一定大小。进入有丝分裂取决于Cdk 1的活性，其被Wee 1激酶抑制并被Cdc 25磷酸酶激活（1）。然而，细胞如何感知它们的大小以进行有丝分裂承诺仍然是未知的。在这里，我们表明，细胞内的双特异性酪氨酸磷酸化调节激酶（DYRK）Pom 1，它从杆状裂殖酵母细胞的末端发出的梯度，用于测量细胞长度和控制有丝分裂进入。Pom 1提供了极化生长和抑制细胞末端细胞分裂的位置信息（2-5）。我们发现Pom 1也是一种剂量依赖性的G2-M抑制剂。遗传分析表明，Pom 1负调节Cdr 1和Cdr 2，这两种先前描述的SAD激酶家族的Wee 1抑制剂（6-10）。这种抑制可能是直接的，因为体内和体外证据表明Pom 1磷酸化Cdr 2。而Cdr 1和Cdr 2定位于内侧皮质区域，Pom 1形成浓度梯度从细胞尖端，重叠Cdr 1和Cdr 2在短细胞，但不是在长细胞。扰乱这些Pom 1梯度导致Cdr 2磷酸化并施加G2延迟。在短细胞中，Pom 1阻止早熟M期进入，这表明较高的中间Pom 1水平抑制Cdr 2并促进G2延迟。因此，Pom 1从细胞末端的梯度提供了细胞长度的测量以调节M期进入。
Cells normally grow to a certain size before they enter mitosis and divide. Entry into mitosis depends on the activity of Cdk1, which is inhibited by the Wee1 kinase and activated by the Cdc25 phosphatase(1). However, how cells sense their size for mitotic commitment remains unknown. Here we show that an intracellular gradient of the dual-specificity tyrosine-phosphorylation regulated kinase (DYRK) Pom1, which emanates from the ends of rod-shaped Schizosaccharomyces pombe cells, serves to measure cell length and control mitotic entry. Pom1 provides positional information both for polarized growth and to inhibit cell division at cell ends(2-5). We discovered that Pom1 is also a dose-dependent G2-M inhibitor. Genetic analyses indicate that Pom1 negatively regulates Cdr1 and Cdr2, two previously described Wee1 inhibitors of the SAD kinase family(6-10). This inhibition may be direct, because in vivo and in vitro evidence suggest that Pom1 phosphorylates Cdr2. Whereas Cdr1 and Cdr2 localize to a medial cortical region, Pom1 forms concentration gradients from cell tips that overlap with Cdr1 and Cdr2 in short cells, but not in long cells. Disturbing these Pom1 gradients leads to Cdr2 phosphorylation and imposes a G2 delay. In short cells, Pom1 prevents precocious M-phase entry, suggesting that the higher medial Pom1 levels inhibit Cdr2 and promote a G2 delay. Thus, gradients of Pom1 from cell ends provide a measure of cell length to regulate M-phase entry.