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Abstract：
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.
摘要：
为了描述ERK1和ERK2丝裂原活化蛋白激酶支持突变KRAS驱动的癌症生长的机制，我们测定了KRAS突变型胰腺癌的ERK依赖性磷酸化蛋白质组.我们确定ERK1和ERK2共享几乎相同的信号和转化输出，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依赖性磷酸化位点，其中79％和66％，分别,以前与ERK无关，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在癌症中的更复杂的功能。我们确定ERK控制着高度动态和复杂的磷酸蛋白质组，该蛋白质组集中于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（RHOGTPase）。我们的发现建立了ERK驱动KRAS依赖性胰腺癌生长的最全面的分子图谱和机制。
