The ERK1/2 pathway is one of the most commonly dysregulated pathways in human cancers and controls many vital cellular processes. Although many ERK1/2 kinase substrates have been identified, the diversity of ERK1/2 mediated processes suggests the existence of additional targets. Here, we identified Deoxyhypusine synthase (DHPS), an essential hypusination enzyme regulating protein translation, as a major and direct-binding protein of ERK1/2. Further experiments showed that ERK1/2 phosphorylate DHPS at Ser-233 site. The Ser-233 phosphorylation of DHPS by ERK1/2 is important for its function in cell proliferation. Moreover, we found that higher DHPS expression correlated with poor prognosis in lung adenocarcinoma and increased resistance to inhibitors of the ERK1/2 pathway. In summary, our results suggest that ERK1/2-mediated DHPS phosphorylation is an important mechanism that underlies protein translation and that DHPS expression is a potent biomarker of response to therapies targeting ERK1/2-pathway.

ERK1/2 通路是人类癌症中最常见的失调通路之一，控制着许多重要的细胞过程。尽管已经鉴定了许多 ERK1/2 激酶底物，但 ERK1/2 介导过程的多样性表明存在其他目标。在这里，我们确定了脱氧hypusine 合酶（DHPS），一种调节蛋白质翻译的必需hypusination 酶，是ERK1/2 的主要和直接结合蛋白。进一步的实验表明 ERK1/2 在 Ser-233 位点磷酸化 DHPS。ERK1/2 对 DHPS 的 Ser-233 磷酸化对其在细胞增殖中的功能很重要。此外，我们发现较高的 DHPS 表达与肺腺癌的不良预后和对 ERK1/2 通路抑制剂的抵抗力增加相关。总之，