Gnad Florian, Doll Sophia, Song Kyung, Stokes Matthew P, Moffat John, Liu Bonnie, Arnott David, Wallin Jeffrey, Friedman Lori S, Hatzivassiliou Georgia, Belvin Marcia
Department of Bioinformatics and Computational Biology, Genentech Inc, South San Francisco, CA, USA.
Department of Protein Chemistry, Genentech Inc, South San Francisco, CA, USA.
Proteomics. 2016 Jul;16(14):1998-2004. doi: 10.1002/pmic.201600119.
The RAS-RAF-MEK-ERK (MAPK) pathway is prevalently perturbed in cancer. Recent large-scale sequencing initiatives profiled thousands of tumors providing insight into alterations at the DNA and RNA levels. These efforts confirmed that key nodes of the MAPK pathway, in particular KRAS and BRAF, are among the most frequently altered proteins in cancer. The establishment of targeted therapies, however, has proven difficult. To decipher the underlying challenges, it is essential to decrypt the phosphorylation network spanned by the MAPK core axis. Using mass spectrometry we identified 2241 phosphorylation sites on 1020 proteins, and measured their responses to inhibition of MEK or ERK. Multiple phosphorylation patterns revealed previously undetected feedback, as upstream signaling nodes, including receptor kinases, showed changes at the phosphorylation level. We provide a dataset rich in potential therapeutic targets downstream of the MAPK cascade. By integrating TCGA (The Cancer Genome Atlas) data, we highlight some downstream phosphoproteins that are frequently altered in cancer. All MS data have been deposited in the ProteomeXchange with identifier PXD003908 (http://proteomecentral.proteomexchange.org/dataset/PXD003908).
RAS-RAF-MEK-ERK（丝裂原活化蛋白激酶）信号通路在癌症中普遍受到干扰。最近的大规模测序计划对数千个肿瘤进行了分析，从而深入了解了DNA和RNA水平的改变。这些研究证实，丝裂原活化蛋白激酶信号通路的关键节点，尤其是KRAS和BRAF，是癌症中最常发生改变的蛋白质之一。然而，靶向治疗的建立已被证明是困难的。为了解释潜在的挑战，解密丝裂原活化蛋白激酶核心轴所跨越的磷酸化网络至关重要。我们使用质谱法鉴定了1020种蛋白质上的2241个磷酸化位点，并测量了它们对MEK或ERK抑制的反应。多种磷酸化模式揭示了以前未检测到的反馈，因为包括受体激酶在内的上游信号节点在磷酸化水平上发生了变化。我们提供了一个富含丝裂原活化蛋白激酶级联下游潜在治疗靶点的数据集。通过整合癌症基因组图谱（TCGA）数据，我们突出了一些在癌症中经常发生改变的下游磷酸化蛋白。所有质谱数据已存入蛋白质组交换库，标识符为PXD003908（http://proteomecentral.proteomexchange.org/dataset/PXD003908）。
