System Biology of Cell Signaling - Systems Biology Concepts and Insights

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(A)

(B)

Prolonged

Transient

MAPK

activity

c-Fos

levels

Positive

Feedback

Loop

Negative

Feedback

Loop

MAPK*

Rsk

c-Fos

c-Fos-P

c-Fos-Ub

c-Fos-P

c-Fos-Ub

Incoherent

Feedback

Motif

Coherent

Feedback

Motif

Fos-dependent

gene expression

Proteasomal

degradation

Fos-dependent

gene expression

Proteasomal

degradation

(C)

(D)

Extracelluar

ligands (33)

Extracellular Ligands

Membrane Proteins and receptors

Central Signalling Network

Receptors

and other

membrane

proteins (63)

Central

signalling

network (311)

Transcription

machinery (37)

Ion channels

(16)

Electrical

Response

(Ion Channels)

Translation

machinery (33)

Secretory

apparatus (27)

Motility

machinery (25)

Transcription

Machinery

Translation

Machinery

Secretion

Apparatus

Motility

Machinery

FIGURE 16.4 Topology of cell signaling networks. (A) The structure of regulatory motifs: positive and negative feedback loops (upper panel) and

coherent and incoherent feedforward motifs (lower panel). Individual components are depicted as circles. Diagonal arrows depict signal flow into and out

of the motif. Arrows indicate activation and plungers indicate inhibition. (B) A coherent feedforward motif can help filter short from long duration signals.

The response of MAPK-1,2 activation involves the induction of immediate-early genes (IEGs), e.g., c-Fos. The presence of a feedforward motif within the

network allows MAPK signals with longer duration to phosphorylate c-FOS and protect it against ubiquitin-mediated degradation, enabling bridging

across timescales of minutes for MAPK activation and hours for c-Fos-regulated gene expression (reprinted with permission from [59] , based on

experiments from [55] ). (C) The organization of a functional cell is shown as an interconnected network of a central signaling network and cellular

machines. The block diagram shows how information generated from extracellular ligands is transmitted to different cellular machines and functional

compartments. Numbers in parentheses represent the number of nodes. (D) Directed sign-specified network representation of signal flow: triangles

represent nodes and their size is proportional to their level of connectivity (i.e., number of edges). Interactions that lead to activation are visualized as

green arrows, while inhibitory ones are visualized as red ones and blue arrows represent neutral interactions (figures (C) and (D) reprinted with permission

from [60] ).

difference in the timescale activation for MAPK (minutes)

and c-Fos-stimulated gene expression (hours).

signal processing may help control cellular decisions. The

CA1 neuron was represented as a set of interacting

components that make up a network of signaling pathways

that connects to various cellular machines ( Figure 16.4 C).

The fully connected network was built from known direct

interactions, with functional effects documented in the

experimental literature ( Figure 16.4 D).

To understand how signaling in the hippocampal neuron

may lead to synaptic plasticity, the authors analyzed signal