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PLoS Comput Biol. 2017 Mar 17;13(3):e1005432. doi: 10.1371/journal.pcbi.1005432. eCollection 2017 Mar.

Reconstruction and signal propagation analysis of the Syk signaling network in breast cancer cells.

Naldi A1,2, Larive RM2,3,4,5, Czerwinska U1,2, Urbach S2,6,7,8, Montcourrier P2,3,4,5, Roy C1,2, Solassol J2,3,4,9, Freiss G2,3,4,5, Coopman PJ2,3,4,5, Radulescu O1,2.

Author information

1
DIMNP, Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS, UMR5235, Montpellier, France.
2
Université de Montpellier, Montpellier, France.
3
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.
4
INSERM, U1194, Montpellier, France.
5
Institut régional du Cancer de Montpellier, Montpellier, France.
6
Plateforme de Protéomique Fonctionnelle (FPP), Institut de Génomique Fonctionnelle, Montpellier, France.
7
Institut de Génomique Fonctionnelle (IGF), CNRS UMR5203, Centre National de la Recherche Scientifique (CNRS), Montpellier, France.
8
Inserm, U1191, Montpellier, France.
9
CHU Montpellier, Arnaud de Villeneuve Hospital, Department of Pathology, Montpellier, France.

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.

PMID:
28306714
PMCID:
PMC5376343
DOI:
10.1371/journal.pcbi.1005432
[Indexed for MEDLINE]
Free PMC Article

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