Network Reconstruction and Significant Pathway Extraction Using Phosphoproteomic Data from Cancer Cells

Abstract

Protein phosphorylation acts as an efficient switch controlling deregulated key signaling pathway in cancer. Computational biology aims to address the complexity of reconstructed networks but overrepresents well-known proteins and lacks information on less-studied proteins. A bioinformatic tool to reconstruct and select relatively small networks that connect signaling proteins to their targets in specific contexts is developed. It enables to propose and validate new signaling axes of the Syk kinase. To validate the potency of the tool, it is applied to two phosphoproteomic studies on oncogenic mutants of the well-known phosphatidyl-inositol 3-kinase (PIK3CA) and the unfamiliar Src-related tyrosine kinase lacking C-terminal regulatory tyrosine and N-terminal myristoylation sites (SRMS) kinase. By combining network reconstruction and signal propagation, comprehensive signaling networks from large-scale experimental data are built and multiple molecular paths from these kinases to their targets are extracted. Specific paths from two distinct PIK3CA mutants are retrieved, and their differential impact on the HER3 receptor kinase is explained. In addition, to address the missing connectivities of the SRMS kinase to its targets in interaction pathway databases, phospho-tyrosine and phospho-serine/threonine proteomic data are integrated. The resulting SRMS-signaling network comprises casein kinase 2, thereby validating its currently suggested role downstream of SRMS. The computational pipeline is publicly available, and contains a user-friendly graphical interface (http://doi.org/10.5281/zenodo.3333687).

Keywords: Src-related tyrosine kinase lacking C-terminal regulatory tyrosine and N-terminal myristoylation sites; data processing and analysis; oncogenic signaling; phosphatidyl-inositol 3-kinase enzyme; phosphoproteomics.