BannMI deciphers potential n-to-1 information transduction in signaling pathways to unravel message of intrinsic apoptosis

Abstract

Motivation: Cell fate decisions, such as apoptosis or proliferation, are communicated via signaling pathways. The pathways are heavily intertwined and often consist of sequential interaction of proteins (kinases). Information integration takes place on the protein level via n-to-1 interactions. A state-of-the-art procedure to quantify information flow (edges) between signaling proteins (nodes) is network inference. However, edge weight calculation typically refers to 1-to-1 interactions only and relies on mean protein phosphorylation levels instead of single cell distributions. Information theoretic measures such as the mutual information (MI) have the potential to overcome these shortcomings but are still rarely used. Results: This work proposes a Bayesian nearest neighbor-based MI estimator (BannMI) to quantify n-to-1 kinase dependency in signaling pathways. BannMI outperforms the state-of-the-art MI estimator on protein-like data in terms of mean squared error and Pearson correlation. Using BannMI, we analyze apoptotic signaling in phosphoproteomic cancerous and noncancerous breast cell line data. Our work provides evidence for cooperative signaling of several kinases in programmed cell death and identifies a potential key role of the mitogen-activated protein kinase p38.