PPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEK.
PPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEK.
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DOI：
10.1016/j.celrep.2021.108928
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发表时间：
2021-03-30
期刊：
影响因子：
8.8
通讯作者：
Turk BE
中科院分区：
文献类型：
--
作者：
Cho E;Lou HJ;Kuruvilla L;Calderwood DA;Turk BE
RAF-MEK-ERK 蛋白激酶级联的通量由作用于该途径核心成分的磷酸酶决定。尽管 MEK 是一个既定的药物靶点和串扰调节中心，但人们对级联中的中心激酶 MEK 的去磷酸化知之甚少。在这里，我们将 PPP6C（一种在黑色素瘤中经常突变或下调的磷酸酶）确定为具有致癌 ERK 通路激活的细胞中的主要 MEK 磷酸酶。 MEK 向 PPP6C 的招募是通过与其相关的调节亚基相互作用而发生的。 PPP6C 的缺失会导致 MEK 在激活和串扰磷酸化位点处过度磷酸化，从而促进通过 ERK 途径的信号传导并降低对 MEK 抑制剂的敏感性。与黑色素瘤相关的反复出现的 PPP6C 突变会导致 MEK 过度磷酸化，这表明它们至少部分通过激活驱动黑色素瘤的核心致癌途径来促进疾病。总的来说，我们的研究确定了 ERK 信号传导的关键负调节因子，可能会影响对靶向癌症治疗的敏感性。 Cho 等人通过 shRNA 筛选。确定 PPP6C 是一种磷酸酶，可使激酶 MEK 失活，使肿瘤细胞对临床 MEK 抑制剂敏感。这项研究表明，黑色素瘤中普遍存在的与癌症相关的功能丧失 PPP6C 突变可激活驱动该疾病的核心致癌 RAF-MEK-ERK 通路。
Flux through the RAF-MEK-ERK protein kinase cascade is shaped by phosphatases acting on the core components of the pathway. Despite being an established drug target and a hub for crosstalk regulation, little is known about dephosphorylation of MEK, the central kinase within the cascade. Here, we identify PPP6C, a phosphatase frequently mutated or downregulated in melanoma, as a major MEK phosphatase in cells exhibiting oncogenic ERK pathway activation. Recruitment of MEK to PPP6C occurs through an interaction with its associated regulatory subunits. Loss of PPP6C causes hyperphosphorylation of MEK at activating and crosstalk phosphorylation sites, promoting signaling through the ERK pathway and decreasing sensitivity to MEK inhibitors. Recurrent melanoma-associated PPP6C mutations cause MEK hyperphosphorylation, suggesting that they promote disease at least in part by activating the core oncogenic pathway driving melanoma. Collectively, our studies identify a key negative regulator of ERK signaling that may influence susceptibility to targeted cancer therapies. Through an shRNA screen, Cho et al. identify PPP6C as a phosphatase that inactivates the kinase MEK, sensitizing tumor cells to clinical MEK inhibitors. This study suggests that cancer-associated loss-of-function PPP6C mutations prevalent in melanoma serve to activate the core oncogenic RAF-MEK-ERK pathway that drives the disease.
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