Core Network Identification Using Parametric Sensitivity and Multi-way Principal Component Analysis

Biochemical networks are complex in nature. It is desirable that the key features be captured and analyzed using a core-network. In this work, a hierarchical core-network identification procedure was developed using parametric sensitivity and multi-way principal component analysis. The procedure was applied to the intracellular IKK to NFkBn (NFkB in nucleus) signaling transduction network to identify the key reactions in the network. We found that the key internal feedback control of IKK to NFkBnsigaling transduction is through IkBa. The key reactions governing initial signal transduction are the phosphorylation of IkBaNFkB by IKK outside the nucleus, subsequent dissociation to release NFkB, and the transport of NFkB into the nucleus. Similar reactions involving IkBe and IkBb are only important when the IKK stimuli are relatively large. Moreover, this signal transduction network is able to damp the initial NFkBn response to IKK stimulus and transform large stimulus into delayed and sustained response. Such damping effect is present with only IkBa feedback loop is included, but IkBe and IkBb are responsible for transforming large stimulus into sustained response. Furthermore, the alternative pathway of formation IKK-IkBa and trimerization of NFkB is responsible for a secondary buildup of IKK at large stimulus.