Multi-label multi-instance transfer learning for simultaneous reconstruction and cross-talk modeling of multiple human signaling pathways

Suyu Mei, Hao Zhu

Signaling pathways play important roles in the life processes of cell growth, cell apoptosis and organism development. At present the signal transduction networks are far from complete. As an effective complement to experimental methods, computational modeling is suited to rapidly reconstruct the signaling pathways at low cost. To our knowledge, the existing computational methods seldom simultaneously exploit more than three signaling pathways into one predictive model for the discovery of novel signaling components and the cross-talk modeling between signaling pathways. In this work, we propose a multi-label multi-instance transfer learning method to simultaneously reconstruct 27 human signaling pathways and model their cross-talks. Computational results show that the proposed method demonstrates satisfactory multi-label learning performance and rational proteome-wide predictions. Some predicted signaling components or pathway targeted proteins have been validated by recent literature. The predicted signaling components are further linked to pathways using the experimentally derived PPIs (protein-protein interactions) to reconstruct the human signaling pathways. Thus the map of the cross-talks via common signaling components and common signaling PPIs is conveniently inferred to provide valuable insights into the regulatory and cooperative relationships between signaling pathways. Lastly, gene ontology enrichment analysis is conducted to gain statistical knowledge about the reconstructed human signaling pathways. Multi-label learning framework has been demonstrated effective in this work to model the phenomena that a signaling protein belongs to more than one signaling pathway. As results, novel signaling components and pathways targeted proteins are predicted to simultaneously reconstruct multiple human signaling pathways and the static map of their cross-talks for further biomedical research.