Research Article: Hierarchical Feedback Modules and Reaction Hubs in Cell Signaling Networks

Date Published: May 7, 2015

Publisher: Public Library of Science

Author(s): Jianfeng Xu, Yueheng Lan, Ying Xu.


Despite much effort, identification of modular structures and study of their organizing and functional roles remain a formidable challenge in molecular systems biology, which, however, is essential in reaching a systematic understanding of large-scale cell regulation networks and hence gaining capacity of exerting effective interference to cell activity. Combining graph theoretic methods with available dynamics information, we successfully retrieved multiple feedback modules of three important signaling networks. These feedbacks are structurally arranged in a hierarchical way and dynamically produce layered temporal profiles of output signals. We found that global and local feedbacks act in very different ways and on distinct features of the information flow conveyed by signal transduction but work highly coordinately to implement specific biological functions. The redundancy embodied with multiple signal-relaying channels and feedback controls bestow great robustness and the reaction hubs seated at junctions of different paths announce their paramount importance through exquisite parameter management. The current investigation reveals intriguing general features of the organization of cell signaling networks and their relevance to biological function, which may find interesting applications in analysis, design and control of bio-networks.

Partial Text

With the arrival of the post-genomic era, high-throughput experiments start to provide enormous amount of data to enable a systematic understanding of cell regulation mechanism with unprecedented accuracy. However, we are still lacking of powerful analytic tools to probe how sets of proteins function as an effective machine orchestrating intracellular responses to disparate external stimuli. Take the cancer therapy as an example. Albeit beneficial response is seen upon treatment with the EGFR Tyr kinase inhibitors, the lung tumor often revives by finding ways around, such as inducing a PI3K mutation or activating alternative cancerous signaling pathways [1]. To cope with this type of complication, apparently we need a comprehensive understanding of the global behavior of cell signaling networks shaped through evolution and determined by the involved molecular species and their interactions [2]. Searching for design principles of these highly correlated reaction chains [3, 4] and for critical reaction hubs in complex signaling pathways is an important problem in biological and medical research.

We apply our decomposition procedure to three typical signaling networks: the GPCR mediated calcium spark network, the EGFR induced MAPK signaling network, and the JAK/STAT signaling network to acquire a quantitative and systematic understanding of the underlying organizing principles. Several common features are recognized that could be ubiquitous in cell signaling since the three signaling networks employ different types of receptors inducing diverse signaling pathways and play distinct yet important roles in living cells. The results show that all three signaling networks are decomposed into one signal forward subgraph and several local or global feedback modules, which brings great convenience and provide new means in analyzing correlation between network structure and their individual function.

In this paper, based on the underlying information flow, we analyzed in great detail three different cell signaling systems: the GPCR, the MAPK and the JAK/STAT network employing a global top-down graph theoretic algorithm coupled with dynamics consideration, which shows its strength in dealing with complex signaling networks. The forward and feedback modules of each network are identified and their detailed functions are tested and explained. Our result exhibits the detailed mechanism of how feedback modules cooperatively maintain the versatility and robustness in signaling [50]. Moreover, hierarchical structure of feedbacks are observed not only in network topology but also in the dynamic regulation as revealed by module perturbation. Global feedbacks wrap the local ones in the three cell signaling networks and our analysis is able to systematically unfold different functions of each modulating unit, producing an onion-like temporal profiles. Moreover, multiple paths in the forward module and the controls exerted by different types of feedback modules give rise to functional redundancy and leads to the emergence of reaction hubs.