Modeling human phosphorylation networks through kinome-wide profiling

描述（由申请人提供）：蛋白质磷酸化是真核生物中最常见的可逆翻译后修饰，然而由蛋白激酶、它们的调节剂和它们的底物组成的信号网络只被部分阐明。该计划的总体目标是利用排列位置扫描肽库，为人类基因组中编码的所有蛋白激酶建立一个全面的磷酸化基序，并将这些数据整合到整个生物医学界目前可用的网络可访问工具中。由此产生的蛋白激酶特异性基元和信息学工具数据集将：(1)允许对大量磷酸化位点已经或目前正在高通量磷酸蛋白组质谱实验和数据集进行功能注释，这些实验和数据集先前已由NIH资助，现在确定了负责这些修饰的相关激酶和信号通路；(2)允许鉴定新的蛋白质

DESCRIPTION (provided by applicant): Protein phosphorylation is the most common reversible post-translational modification in eukaryotes, yet signaling networks comprising protein kinases, their regulators, and their substrates are only partially elucidated. The overall goals of the proposed project are to build a comprehensive collection of consensus phosphorylation motifs for the entire collection of protein kinases encoded in the human genome using arrayed positional scanning peptide libraries, and integrate this data into web-accessible tools that are currently available to the entire biomedical community. The resulting dataset of protein kinase specificity motifs and informatics tools will: (1) allow functional annotation of a large number of proteins whose phosphorylation sites already have been, or currently are, being mapped in high-throughput phosphoproteomic mass- spectrometry experiments and datasets that have been previously funded by the NIH by now identifying the relevant kinase and signaling pathways responsible for these modifications; (2) allow the identification of new protein kinase substrates relevant to human health and disease and place them within the context of specific signal transduction pathways; and (3) provide a general set of kinase tools useful for structural and drug inhibitor studies and for the therapeutic targeting of specific signaling pathways implicated in human disease. To illustrate the utility of our approach, we will investigate predicted substrates of protein kinases in the Hippo signaling pathway, a conserved tumor suppressor pathway important in regulating cell proliferation, differentiation and survival. This project will serve to increase our fundamental understanding of how specificity is achieved by protein kinases, will identify critical connections in signaling networks, and will provide a general resource for researchers studying signal transduction and protein phosphorylation.