Human phosphatase CDC14A regulates actin organization through dephosphorylation of epithelial protein lost in neoplasm
Human phosphatase CDC14A regulates actin organization through dephosphorylation of epithelial protein lost in neoplasm
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DOI：
10.1073/pnas.1619356114
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发表时间：
2017-05-16
影响因子：
11.1
通讯作者：
Schiebel, Elmar
中科院分区：
文献类型：
--
作者：
Chen, Nan-Peng;Uddin, Borhan;Schiebel, Elmar
在酿酒酵母中，CDC14是一种重要的双特异性磷酸酶，它在酿酒酵母的有丝分裂后期抑制CDK1的活性，促进有丝分裂的退出。令人惊讶的是，人类CDC14A对细胞周期进程并不是必需的。相反，它调节细胞迁移和细胞黏附。人们对hCDC14A的底物和相互作用的激酶知之甚少。在这里，我们结合了磷酸蛋白质组图谱和邻近生物素鉴定来鉴定hCDC14A底物。这些靶点包括肌动蛋白调节因子，包括肿瘤抑制因子eplin。HCDC14A通过使eplin在两个已知的细胞外信号调节的激酶位点丝氨酸362和604去磷酸化来对抗EGF诱导的肌动蛋白细胞骨架的重排。HCDC14A(PD)和eplin基因敲除细胞株在细胞间黏附时E-钙粘附素表达下调，α/β-连环蛋白表达减少。HCDC14A和eplin mRNA水平降低常与结直肠癌相关，并与预后不良相关。因此，我们认为hCDC14A对eplin的去磷酸化降低了肌动蛋白的动力学，从而限制了肿瘤的恶性。
CDC14 is an essential dual-specificity phosphatase that counteracts CDK1 activity during anaphase to promote mitotic exit in Saccharomyces cerevisiae. Surprisingly, human CDC14A is not essential for cell cycle progression. Instead, it regulates cell migration and cell adhesion. Little is known about the substrates of hCDC14A and the counteracting kinases. Here, we combine phospho-proteome profiling and proximity-dependent biotin identification to identify hCDC14A substrates. Among these targets were actin regulators, including the tumor suppressor eplin. hCDC14A counteracts EGF-induced rearrangements of actin cytoskeleton by dephosphorylating eplin at two known extracellular signal-regulated kinase sites, serine 362 and 604. hCDC14A(PD) and eplin knockout cell lines exhibited down-regulation of E-cadherin and a reduction in alpha/beta-catenin at cell-cell adhesions. Reduction in the levels of hCDC14A and eplin mRNA is frequently associated with colorectal carcinoma and is correlated with poor prognosis. We therefore propose that eplin dephosphorylation by hCDC14A reduces actin dynamics to restrict tumor malignancy.