Demo-2
TNF Signaling Through TNFR1
A Guided Tour

Tumor Necrosis Factor-α (TNF-α) is a ligand for TNF Receptor-I (TNFR1).  Binding of TNF-α to the receptor can promote either cell survival or death, depending on the context.  TNF-α can promote cell survival by activating the transcription factor NF-kB and the JNK pathway, which together activate anti-apoptotic genes.  In general, if expression of these genes is suppressed (e.g., by the protein synthesis inhibitor cycloheximide) apoptosis becomes the default response of the cell.

Micheau and Tschopp have proposed a mechanism of TNFR1-induced apoptosis involving the sequential assembly of two multiprotein signaling complexes.  First, following TNF-α binding, a complex is formed at the cell membrane that consists of TNFR1, the adaptor protein TRADD, the protein kinase RIP1, and the TRAF2 protein (complex I).  Complex I rapidly signals activation of NF-kB as a pro-survival response.  Subsequently, a second complex (complex II) is formed in the cytoplasm in which TRADD and RIP1 associate with FADD and the inactive form of the apoptotic protease caspase-8.  If the activation of pro-survival pathways is unsuccessful, caspase-8 will homodimerize and undergo self-cleavage to become fully activated as an apoptotic protease.  However, in this model if NF-kB is able to induce the expression of the anti-apoptotic protein c-FLIP (FLIP), activation of caspase-8 to its pro-apoptotic form will be directly inhibited and survival will be likely.  Kataoka and Tschopp have demonstrated that FLIP is able to dimerize with caspase-8 and itself become activated by proteolysis, preventing the homodimerization of caspase-8.  (Micheau O, Tschopp J; Cell 114:181 2003;  Kataoka T, Tscopp, J Mol Cell Biol 24:2627 2004).

This current model of early events in TNF-α and TNFR1 signaling provides a detailed example of a biochemical mechanism having a profound biological effect, the determination of cell fate.  The purpose of Demo-2, which builds on the principles discussed in Demo-1, is to illustrate how the Pathway Logic viewer can be used to explore and understand this mechanism within a large model that includes JNK signaling (here JNK1).

References specific for each rule can be found in rules2.maude.

(1) Compare the Activation of NF-kB and Jnk1

    First step (Viewer Screen #1):  Show all the ways that JNK1 can be activated by TNF-α.     Second step (Viewer Screen #2):  Show all the ways that NF-kB can be activated by TNF-α.     Third step (Viewer Screen #3):  Compare the last two subnets.

(2) Compare the Activation of NF-kB, JNK1, and Caspase-8

    First step (Viewer Screen #1):  Show all the ways that JNK1 and NF-kB can be activated by TNF-α.     Second step (Viewer Screen #2):  Show all the ways that Caspase-8 can be activated by TNF-α     Third step (Screen #3):  Compare subnets

(3) Can NF-kb be activated in the presence of cycloheximide?

(4) Is cycloheximide required for the activation of caspase-8?

(5) Is unactivated caspase-8 required for NF-kB activation by TNF-α?

    Or:

(6) Is unactivated Caspase-8 required for JNK1 activation?

    Or:

The Maude model is available in Demo2Model

To try Demo 2, click on the appropriate link:  [light]  [heavy]

Back to the main Pathway Logic Demo page.