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The JAK-STAT Signaling Network in the Human B-Cell: An Extreme Signaling Pathway Analysis

Department of Bioengineering, University of California, San Diego, La Jolla, California

Correspondence: Address correspondence to Bernhard O. Palsson, Dept. of Bioengineering, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0412. Tel.: 858-534-5668; E-mail: palsson{at}ucsd.edu.

Large-scale models of signaling networks are beginning to be reconstructed and corresponding analysis frameworks are being developed. Herein, a reconstruction of the JAK-STAT signaling system in the human B-cell is described and a scalable framework for its network analysis is presented. This approach is called extreme signaling pathway analysis and involves the description of network properties with systemically independent basis vectors called extreme pathways. From the extreme signaling pathways, emergent systems properties of the JAK-STAT signaling network have been characterized, including 1), a mathematical definition of network crosstalk; 2), an analysis of redundancy in signaling inputs and outputs; 3), a study of reaction participation in the network; and 4), a delineation of 85 correlated reaction sets, or systemic signaling modules. This study is the first such analysis of an actual biological signaling system. Extreme signaling pathway analysis is a topologically based approach and assumes a balanced use of the signaling network. As large-scale reconstructions of signaling networks emerge, such scalable analyses will lead to a description of the fundamental systems properties of signal transduction networks.

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