Reconstruction and signal propagation analysis of the Syk signaling network in breast cancer cells.
PLoS Comput Biol
; 13(3): e1005432, 2017 03.
Article
en En
| MEDLINE
| ID: mdl-28306714
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama
/
Transducción de Señal
/
Regulación Neoplásica de la Expresión Génica
/
Quinasa Syk
/
Modelos Biológicos
/
Proteínas de Neoplasias
Límite:
Female
/
Humans
Idioma:
En
Revista:
PLoS Comput Biol
Asunto de la revista:
BIOLOGIA
/
INFORMATICA MEDICA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Francia