Abstract
The ability to build in-depth cell signaling networks from vast experimental data is a key objective of computational biology. The spleen tyrosine kinase (Syk) protein, a well-characterized key player in immune cell signaling, was surprisingly first shown by our group to exhibit an onco-suppressive function in mammary epithelial cells and corroborated by many other studies, but the molecular mechanisms of this function remain largely unsolved. Based on existing proteomic data, we report here the generation of an interaction-based network of signaling pathways controlled by Syk in breast cancer cells. Pathway enrichment of the Syk targets previously identified by quantitative phospho-proteomics indicated that Syk is engaged in cell adhesion, motility, growth and death. Using the components and interactions of these pathways, we bootstrapped the reconstruction of a comprehensive network covering Syk signaling in breast cancer cells. To generate in silico hypotheses on Syk signaling propagation, we developed a method allowing to rank paths between Syk and its targets. We first annotated the network according to experimental datasets. We then combined shortest path computation with random walk processes to estimate the importance of individual interactions and selected biologically relevant pathways in the network. Molecular and cell biology experiments allowed to distinguish candidate mechanisms that underlie the impact of Syk on the regulation of cortactin and ezrin, both involved in actin-mediated cell adhesion and motility. The Syk network was further completed with the results of our biological validation experiments. The resulting Syk signaling sub-networks can be explored via an online visualization platform.
Highlights
Tyrosine phosphorylation of proteins acts as an efficient switch allowing to control key signaling pathways involved in cell proliferation, apoptosis, migration, and invasion, and is involved in oncogenesis
Our main goal was to pinpoint a limited number of biologically realistic molecular “paths” from spleen tyrosine kinase (Syk) to its effectors
Starting with the set of Syk-dependent targets identified by phosphoproteomics, we identified a network explaining the propagation of the signal from Syk to its targets
Summary
Tyrosine phosphorylation of proteins acts as an efficient switch allowing to control key signaling pathways involved in cell proliferation, apoptosis, migration, and invasion, and is involved in oncogenesis. The non-receptor spleen tyrosine kinase Syk has for a long time been considered as a hematopoietic cell-specific signaling molecule. In these cells, Syk is involved in coupling activated immunoreceptors to downstream signaling events affecting cell proliferation, differentiation and survival [8]. Syk functions as an essential component of the signaling machinery of multiple immune receptors and adapter proteins that are, not expressed in non-hematopoietic cells. Unveiling the Syk signaling pathways and tumor suppressor mechanisms is a public health issue as pharmacological Syk inhibitors are being used in clinical trials for treating auto-immune diseases [15,16]
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