Spatially interacting phosphorylation sites and mutations in cancer.
Spatially interacting phosphorylation sites and mutations in cancer.
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DOI：
10.1038/s41467-021-22481-w
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发表时间：
2021-04-19
影响因子：
16.6
通讯作者：
Ding L
中科院分区：
文献类型：
--
作者：
Huang KL;Scott AD;Zhou DC;Wang LB;Weerasinghe A;Elmas A;Liu R;Wu Y;Wendl MC;Wyczalkowski MA;Baral J;Sengupta S;Lai CW;Ruggles K;Payne SH;Raphael B;Fenyö D;Chen K;Mills G;Ding L
质谱技术的进步已经产生了越来越大规模的蛋白质组学数据集，其中包含数万个需要优先排序的磷酸化位点（磷酸化位点）。我们开发了一个名为HotPho的生物信息学工具，系统地发现了蛋白质结构上磷酸化位点和癌症突变的3D共聚类。HotPho鉴定了474个含有1255个共聚磷酸化位点的杂交簇，包括RET p.S904/Y 928、保守的HRAS/KRAS p.Y96和IDH 1 p.Y139/IDH 2 p.Y179，它们与线性邻近方法未发现的蛋白质结构上的复发突变相邻。富含组蛋白和激酶结构域的杂交簇通常包括实验上显示为激活和赋予遗传依赖性的表达相关突变。在5种癌症类型或先前与癌症有关的患者样品中验证了约300个共聚磷酸化位点，包括CTNNB 1 p.S29/Y30、EGFR p.S720、MAPK 1 p.S142和PTPN 12 p.S275。总之，系统性3D聚类分析突出了近3,000个可能的功能突变和超过1000个癌症磷酸化位点，用于下游研究和潜在临床相关性的评价。磷酸化失调在癌症中是众所周知的，但它在很大程度上是从突变中分离出来研究的。在这里，作者介绍了HotPho，这是一种可以发现磷酸化位点和突变之间空间相互作用的工具，与癌症中的激活突变和遗传依赖性有关。
Advances in mass-spectrometry have generated increasingly large-scale proteomics datasets containing tens of thousands of phosphorylation sites (phosphosites) that require prioritization. We develop a bioinformatics tool called HotPho and systematically discover 3D co-clustering of phosphosites and cancer mutations on protein structures. HotPho identifies 474 such hybrid clusters containing 1255 co-clustering phosphosites, including RET p.S904/Y928, the conserved HRAS/KRAS p.Y96, and IDH1 p.Y139/IDH2 p.Y179 that are adjacent to recurrent mutations on protein structures not found by linear proximity approaches. Hybrid clusters, enriched in histone and kinase domains, frequently include expression-associated mutations experimentally shown as activating and conferring genetic dependency. Approximately 300 co-clustering phosphosites are verified in patient samples of 5 cancer types or previously implicated in cancer, including CTNNB1 p.S29/Y30, EGFR p.S720, MAPK1 p.S142, and PTPN12 p.S275. In summary, systematic 3D clustering analysis highlights nearly 3,000 likely functional mutations and over 1000 cancer phosphosites for downstream investigation and evaluation of potential clinical relevance. Dysregulated phosphorylation is well-known in cancers, but it has largely been studied in isolation from mutations. Here the authors introduce HotPho, a tool that can discover spatial interactions between phosphosites and mutations, which are associated with activating mutation and genetic dependencies in cancer.
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影响因子：
5.8
作者：
Porta-Pardo, Eduard;Godzik, Adam
通讯作者：
Godzik, Adam
DOI：
10.1073/pnas.88.11.5006
发表时间：
1991-06-01
影响因子：
11.1
作者：
DAVIDOFF, AM;HUMPHREY, PA;MARKS, JR
通讯作者：
MARKS, JR
影响因子：
7
作者：
Huang, Kuan-lin;Wu, Yige;Ding, Li
通讯作者：
Ding, Li
影响因子：
4.4
作者：
Carter H;Douville C;Stenson PD;Cooper DN;Karchin R
通讯作者：
Karchin R
影响因子：
8.8
作者：
Brenan L;Andreev A;Cohen O;Pantel S;Kamburov A;Cacchiarelli D;Persky NS;Zhu C;Bagul M;Goetz EM;Burgin AB;Garraway LA;Getz G;Mikkelsen TS;Piccioni F;Root DE;Johannessen CM
通讯作者：
Johannessen CM