Ingeniero Químico

REVIEWS
Critical nodes in signalling pathways:
insights into insulin action
Cullen M. Taniguchi*, Brice Emanuelli* and C. Ronald Kahn

Abstract | Physiologically important cell-signalling networks are complex, and contain
several points of regulation, signal divergence and crosstalk with other signalling cascades.
Here, we use the concept of ‘critical nodes’ to define the importantjunctions in these
pathways and illustrate their unique role using insulin signalling as a model system.

Critical node
A point in a signalling network
that is essential for the
biological function of a ligand–
receptor interaction, but also
allows divergence of the signal
to facilitate crosstalk between
systems and/or to fine-tune the
response to stimuli.

Insulin receptor substrateprotein
(IRS protein). A large protein
scaffold that serves as a
docking platform for other
signalling proteins that contain
Src-homology-2 domains. The
IRS proteins are required for a
complete insulin signal.

Joslin Diabetes Center,
One Joslin Place, Boston,
Massachusetts 02215, USA.
*These authors contributed
equally to this work.
Correspondence to C.R.K.
e-mail: c.ronald.kahn@joslin.harvard.edu
doi:10.1038/nrm1837

Signalling by membrane receptors is essential for
the regulation of several cell functions, but how each
ligand–receptor interaction produces its own specific
pattern of regulated cellular function is a fundamental
question in biology. The identification of specific receptors and second messenger systems, such as cyclic AMP
(cAMP), led to the classicalview of signalling as a linear
cascade (FIG.1a). Over time, this linear cascade evolved
to reflect the divergence that is observed at several steps
in a signalling pathway and the crosstalk between signalling pathways (FIG. 1b,c). However, it is now apparent
that even this model might not be sufficient to explain
the complexity of cellular signalling and the integrated
control of cellularfunctions.
One of the most daunting challenges to understanding
any particular ligand–receptor system is the identification
of components, or nodes, within the network that are essential mediators or modifiers of the ligand’s signal125. Several
groups have taken quantitative approaches that integrate
biochemical and computational data to identify essential
nodes in signalling networks, as well asto describe how
these nodes might interact with other signalling cascades.
We believe that a complementary approach to describing
cell-signalling networks, using data that has been derived
from in vitro and in vivo genetic knockout studies, could
provide a useful framework for integrating the growing
body of knowledge in the field.
Here, we propose that the essential mediators, or‘critical nodes’, of any signalling network (FIG. 1d) can be
identified by three criteria: first, the node must constitute
a group of related proteins (for example, gene isoforms)
that are essential for the receptor-mediated signal, and in
which two or more of these related proteins might have
unique biological roles within a signalling network and
therefore serve as a source of divergence within thesignalling system; second, the node is highly regulated, both
positively and negatively; and third, the node is a junction for potential crosstalk with other signalling systems.

NATURE REVIEWS | M OLECULAR CELL BIOLOGY

We illustrate this concept by analysis of the insulinsignalling network, in which several critical nodes have
been defined and shown to have important roles in
normalphysiology, and disease states such as diabetes,
obesity and the metabolic syndrome.

Complexity of the insulin-signalling network
Insulin signalling is mediated by a complex, highly
integrated network that controls several processes.
In the presence of insulin, the insulin receptor (IR)
phosphorylates insulin receptor substrate proteins (IRS
proteins) that are linked to the activation of...