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

Lei Li; Chabane Tibiche; Cong Fu; Tomonori Kaneko; Michael F. Moran; Martin R. Schiller; Shawn Shun-Cheng Li; Edwin Wang

doi:10.1101/gr.128819.111

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

¹Department of Biochemistry and the Siebens-Drake Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada;
²Molecular Structure and Function Program, Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1X8, Canada;
³Computational Chemistry and Bioinformatics Group, Biotechnology Research Institute, National Research Council Canada, Montreal, Quebec H4P 2R2, Canada;
⁴Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
⁵McLaughlin Centre for Molecular Medicine and Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario M5G 1L7, Canada;
⁶School of Life Sciences, University of Nevada, Las Vegas, Nevada 89154-4004, USA;
⁷Children's Health Research Institute, London, Ontario N6C 2V5, Canada;
⁸Center for Bioinformatics, McGill University, Montreal, Quebec H3G 0B1, Canada

↵9 These authors contributed equally to this work.

↵10 Present address: State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun 130023, P. R. China.

Abstract

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.

Footnotes

↵11 Corresponding authors

E-mail sli{at}uwo.ca

E-mail edwin.wang{at}cnrc-nrc.gc.ca
[Supplemental material is available for this article.]
Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.128819.111.

Received July 10, 2011.
Accepted December 2, 2011.

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