The human phosphotyrosine signaling network: Evolution and hotspots of hijacking in cancer

被引:61
作者
Li, Lei [1 ,2 ,9 ]
Tibiche, Chabane [3 ]
Fu, Cong [3 ]
Kaneko, Tomonori [1 ,2 ]
Moran, Michael F. [4 ,5 ,9 ]
Schiller, Martin R. [6 ]
Li, Shawn Shun-Cheng [1 ,2 ,7 ]
Wang, Edwin [3 ,8 ]
机构
[1] Univ Western Ontario, Schulich Sch Med & Dent, Dept Biochem, London, ON N6A 5C1, Canada
[2] Univ Western Ontario, Schulich Sch Med & Dent, Siebens Drake Res Inst, London, ON N6A 5C1, Canada
[3] Natl Res Council Canada, Biotechnol Res Inst, Computat Chem & Bioinformat Grp, Montreal, PQ H4P 2R2, Canada
[4] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada
[5] Univ Toronto, Banting & Best Dept Med Res, McLaughlin Ctr Mol Med, Toronto, ON M5G 1L7, Canada
[6] Univ Nevada, Sch Life Sci, Las Vegas, NV 89154 USA
[7] Childrens Hlth Res Inst, London, ON N6C 2V5, Canada
[8] McGill Univ, Ctr Bioinformat, Montreal, PQ H3G 0B1, Canada
[9] Univ Toronto, Hosp Sick Children, Mol Struct & Funct Program, Toronto, ON M5G 1X8, Canada
基金
美国国家卫生研究院;
关键词
QUANTITATIVE PHOSPHOPROTEOMICS; PHOSPHORYLATION SITES; MONOSIGA-BREVICOLLIS; IN-VIVO; PROTEINS; KINASES; GENOME;
D O I
10.1101/gr.128819.111
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Phosphotyrosine (pTyr) signaling, which plays a central role in cell-cell and cell-environment interactions, has been considered to be an evolutionary innovation in multicellular metazoans. However, neither the emergence nor the evolution of the human pTyr signaling system is currently understood. Tyrosine kinase (TK) circuits, each of which consists of a TK writer, a kinase substrate, and a related reader, such as Src homology (SH) 2 domains and pTyr-binding (PTB) domains, comprise the core machinery of the pTyr signaling network. In this study, we analyzed the evolutionary trajectories of 583 literature-derived and 50,000 computationally predicted human TK circuits in 19 representative eukaryotic species and assigned their evolutionary origins. We found that human TK circuits for intracellular pTyr signaling originated largely from primitive organisms, whereas the inter- or extracellular signaling circuits experienced significant expansion in the bilaterian lineage through the "back-wiring" of newly evolved kinases to primitive substrates and SH2/PTB domains. Conversely, the TK circuits that are involved in tissue-specific signaling evolved mainly in vertebrates by the back-wiring of vertebrate substrates to primitive kinases and SH2/PTB domains. Importantly, we found that cancer signaling preferentially employs the pTyr sites, which are linked to more TK circuits. Our work provides insights into the evolutionary paths of the human pTyr signaling circuits and suggests the use of a network approach for cancer intervention through the targeting of key pTyr sites and their associated signaling hubs in the network.
引用
收藏
页码:1222 / 1230
页数:9
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