Regulated Phosphosignaling Associated with Breast Cancer Subtypes and Druggability
Regulated Phosphosignaling Associated with Breast Cancer Subtypes and Druggability
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DOI：
10.1074/mcp.ra118.001243
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发表时间：
2019-08-01
影响因子：
7
通讯作者：
Ding, Li
中科院分区：
文献类型：
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作者：
Huang, Kuan-lin;Wu, Yige;Ding, Li
激酶对底物蛋白的磷酸化调节信号通路和细胞机制。异常信号是癌症的标志。我们研究了乳腺肿瘤和异种移植物中超过3万个磷酸化位点的激酶-底物对之间的定量相关性，发现了与特定癌症亚型、可药物靶点以及显示临床相关或免疫特征相关的自磷酸化激酶和激酶-底物对。我们的研究将驱动激酶与它们的信号作用联系起来，为个体乳腺肿瘤的合理靶向治疗提供信息。异常磷酸信号传导是癌症的标志。我们研究了77个乳腺肿瘤和24个乳腺癌异种移植物中33，239个磷酸化位点（磷酸化位点）的激酶底物调节。我们的搜索发现了2134定量相关的激酶磷酸化位点对，丰富和扩展实验或结合基序的预测。在具有自身磷酸化的91种激酶中，EGFR、ERBB 2、PRKG 1和WNK 1磷酸化信号升高分别在基底、HER 2-E、Luminal A和Luminal B乳腺癌中富集，揭示了亚型特异性调节。CDK、MAPKs和共济失调-毛细血管扩张蛋白是底物磷酸化的主要调节因子，其活性尚未被基因组证据所捕获。我们从113个激酶-底物对和激酶下游级联中揭示了磷酸化信号传导和可药用靶点，包括AKT 1，BRAF和EGFR。我们进一步鉴定了与临床或免疫特征相关的激酶底物对，并通过实验验证了ERBB 2、EIF 4 EBP 1和EGFR的活化磷酸化位点。总体而言，迄今为止最大的无偏全球磷酸化数据揭示的激酶底物调节将驱动事件与其信号传导效应联系起来。
Phosphorylation of substrate proteins by kinases regulates signaling pathways and cellular mechanisms. Aberrant signaling is a hallmark of cancer. We investigated quantitative associations between kinase-substrate pairs of more than 30 thousand phosphorylation sites in breast tumors and xenografts, finding auto-phosphorylating kinases and kinase-substrate pairs associated with specific cancer subtypes, druggable targets, and ones that show clinically-related or immune signatures. Our study connects driver kinases to their signaling effects toward informing rational targeted treatments of individual breast tumors. Aberrant phospho-signaling is a hallmark of cancer. We investigated kinase-substrate regulation of 33,239 phosphorylation sites (phosphosites) in 77 breast tumors and 24 breast cancer xenografts. Our search discovered 2134 quantitatively correlated kinase-phosphosite pairs, enriching for and extending experimental or binding-motif predictions. Among the 91 kinases with auto-phosphorylation, elevated EGFR, ERBB2, PRKG1, and WNK1 phosphosignaling were enriched in basal, HER2-E, Luminal A, and Luminal B breast cancers, respectively, revealing subtype-specific regulation. CDKs, MAPKs, and ataxia-telangiectasia proteins were dominant, master regulators of substrate-phosphorylation, whose activities are not captured by genomic evidence. We unveiled phospho-signaling and druggable targets from 113 kinase-substrate pairs and cascades downstream of kinases, including AKT1, BRAF and EGFR. We further identified kinase-substrate-pairs associated with clinical or immune signatures and experimentally validated activated phosphosites of ERBB2, EIF4EBP1, and EGFR. Overall, kinase-substrate regulation revealed by the largest unbiased global phosphorylation data to date connects driver events to their signaling effects.