To delineate the mechanisms by which the ERK1 and ERK2 mitogen-activated protein kinases support mutant KRAS–driven cancer growth, we determined the ERK-dependent phosphoproteome in KRAS-mutant pancreatic cancer. We determined that ERK1 and ERK2 share near-identical signaling and transforming outputs and that the KRAS-regulated phosphoproteome is driven nearly completely by ERK. We identified 4666 ERK-dependent phosphosites on 2123 proteins, of which 79 and 66%, respectively, were not previously associated with ERK, substantially expanding the depth and breadth of ERK-dependent phosphorylation events and revealing a considerably more complex function for ERK in cancer. We established that ERK controls a highly dynamic and complex phosphoproteome that converges on cyclin-dependent kinase regulation and RAS homolog guanosine triphosphatase function (RHO GTPase). Our findings establish the most comprehensive molecular portrait and mechanisms by which ERK drives KRAS-dependent pancreatic cancer growth.

中文翻译：

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确定驱动 KRAS 突变癌症的 ERK 调节磷酸化蛋白质组


为了描述 ERK1 和 ERK2 丝裂原激活蛋白激酶支持突变型 KRAS 驱动的癌症生长的机制，我们确定了 KRAS 突变型胰腺癌中 ERK 依赖性磷酸化蛋白质组。我们确定 ERK1 和 ERK2 具有几乎相同的信号传导和转化输出，并且 KRAS 调节的磷酸化蛋白质组几乎完全由 ERK 驱动。我们在 2123 个蛋白质上鉴定了 4666 个 ERK 依赖性磷酸位点，其中分别有 79% 和 66% 以前与 ERK 不相关，大大扩展了 ERK 依赖性磷酸化事件的深度和广度，并揭示了 ERK 在癌症中更为复杂的功能。我们确定 ERK 控制高度动态且复杂的磷酸蛋白质组，该蛋白质组集中在细胞周期蛋白依赖性激酶调节和 RAS 同源鸟苷三磷酸酶功能 (RHO GTPase) 上。我们的研究结果建立了 ERK 驱动 KRAS 依赖性胰腺癌生长的最全面的分子肖像和机制。