Stephan M Feller

S de Chadarevian

TJ Gibson

BJ Mayer

CE Holt

JD Scott

C Jørgensen

V Csizmok

AK Dunker

M Fuxreiter

U Midic

AH Bild

M Emaduddin

T Aleksic

JT Chang

Cell Communication and Signaling

PubMed

Crossref

The dawn of a new era in cell signalling research

Feller, SM

Oxford University Research Archive (ORA)

The dawn of a new era in cell signalling research.

ORA - Oxford University Research Archive

Oxford University Research Archive

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Feller Cell Communication and Signaling 2010, 8:7
http://www.biosignaling.com/content/8/1/7
Open AccessE D I T O R I A LEditorialThe dawn of a new era in cell signalling research
Stephan M Feller
Dramatic changes in our thinking of how cells organise
and utilise their signal transduction networks are cur-
rently arising. These changes have by and large not yet
reached the majority of the scientific community and uni-
versity teaching. Even in the latest editions of top cell
biology books the cell signalling machinery is typically
depicted as an assembly of fairly unorganised protein
molecules, for example diffusing more or less freely in the
cytosol. According to current textbook wisdom, upon
activation of a signalling pathway its components sto-
chastically meet to generate transient assemblies in the
form of signalling 'cascades' or protein complexes with up
to 10 or so components. These in turn appear to be linked
together into a giant 'floating signalling network' of sev-
eral thousand proteins which nobody really understands.
We are now beginning to appreciate that this image is
far from the truth. It is in fact hindering us in designing
more appropriate experiments to understand cell signal-
ling in general and the role of specific components in par-
ticular.
Similarly, attempts to describe cellular signalling events
with mathematical equations that are based on solution
phase diffusion chemistry by self-declared 'systems biolo-
gists' [1] are commonly doomed to failure.
A number of recent publications [2-6] and conferences
(e.g. the 2009 Seefeld Meeting of the Protein Modules
Consortium; http://www.proteinmodules.org/) provide
some insight into how we can advance our research field
in the future. To give but a few examples:
We must take into serious consideration that signalling
mostly occurs in protein assemblies that may be highly
organised but are at least specifically localised to distinct,
functionally defined subcellular compartments. These
complexes are often of considerable size and probably
contain vast numbers of components in some cases.
We must take into account that many of the utilised
proteins are being produced (translated) in restricted
subcellular locations and that they may not diffuse much
before they meet most of their interaction partners.
We need to investigate more carefully in which cases
signalling enzyme - substrate interactions are primarily
driven by highly specific recognition motifs and in which
by close proximity of the interacting components [or by a
combination of both].
Some signalling proteins appear to be quite scarce, with
only a few molecules present per cell, while others can be
found in several distinct pools with many thousand cop-
ies in each pool. Local signal transduction component
ratios within distinct cellular sites therefore deserve
much more detailed investigation than is currently
undertaken. In this context it should be pointed out that
many standard over-expression experiments are rather
likely to produce substantial artefacts: the resulting inap-
propriate amounts and localisations of signalling compo-
nents will often lead to signal spill-over and/or disrupt
the functionality of native complexes.
The distinct signals elicited by different concentrations
within the sometimes 3-log-wide physiological concen-
tration range of cytokines and other regulatory factors
remains largely unexplored. Too many signalling experi-
ments still rely for convenience on 'super-natural' con-
centrations of stimuli.
Our knowledge on the temporal features of many sig-
nalling events, including oscillations of signals in subcel-
lular compartments of individual cells and waves of
signals migrating through tissues is still minimal, espe-
cially when physiological concentrations of stimuli are
being considered.
We need to explore whether multi-component signal-
ling 'machines' like transmembrane-receptor kinases are
indeed pleiomorphic entities [3] which generate 'fuzzy
signals' or whether we simply do not understand yet their
more sophisticated ways of generating reasonably dis-
crete signalling outputs.
Molecular highways for the directional transport of sig-
nalling proteins, as well as meeting points for some
molecular signalling components that have not yet been
integrated into their destination complexes, are only
barely known.
* Correspondence: stephan.feller@imm.ox.ac.uk
1 Cell Signalling Group, Department of Molecular Oncology, Weatherall 
Institute of Molecular Medicine, John Radcliffe Hospital, Headley Way, Oxford 
OX3 9DS, UK
Full list of author information is available at the end of the articleBioMed Central
© 2010 Feller; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attri-
bution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.
Feller Cell Communication and Signaling 2010, 8:7
http://www.biosignaling.com/content/8/1/7
Page 2 of 2We still have a very limited understanding of how the
rather substantial unstructured portion of the proteome,
which is often linked to disease development, i.e. not a
'dirty dozen' but the 'dirty thousand', contribute to the
organisation and function of cell signalling networks and
pathologies [7-10].
I firmly believe that the best is yet to come for the field
of biological signal transduction research, but despite
impressive technical advances, e.g. HTP-proteomics, -
transcriptomics and -genomics, one must still tread care-
fully when devising conceptual frameworks in which
these vast amounts of data are funnelled. If we get these
wrong, all those HTP-data will not amount to much in
terms of generating robust and realistic information.
Moreover, we will require not only fundamental shifts in
our currently prevailing concepts but also an arsenal of
novel tools in bioinformatics and the 'wet lab'.
Equally important, changing our ways of investigating
cellular signalling components, pathways and networks
will require abandoning some of the much used current
methods, though they may have served us seemingly well
in the past. The already mentioned over-expression stud-
ies are one example.
On the ultrastructural level, protein crystallography
studies will need to be combined more often with analy-
ses by NMR and other solution phase methods to prevent
misconceptions from arising. Global folding effects and
site-specific long-range effects of introduced point muta-
tions will need to receive more attention. The same is
true for the common terminal tagging of proteins, which
can lead to mislocalisation or partial unfolding of pro-
teins. In cases where both termini have functional roles,
careful tagging in internal loops may be the only option.
On the cellular level, monitoring individual cells within a
population in real time will become increasingly impor-
tant.
Eventually, we will even need to think about how differ-
ent individuals may vary in their signalling components
and networks due to their unique genetic compositions.
Possibly the most obvious example for this 'personalised'
signalling heterogeneity is the tremendous diversity of
molecular defects in signalling proteins and networks of
human cancers [11-16], but this also applies for some
physiological signals transmitted in genetically different
individuals.
These are exciting times for young signalling research-
ers. They will be able to make rapid progress by building
on more than three decades of pioneering signal trans-
duction research - if they dare to leave some of the old
misconceptions and false dogmas behind. These have
often arisen from the 'primitive' tools available at that
time and the apparent urge of the human brain to build
simple linear models with a small number of components
to explain functional relationships.
Author Details
Cell Signalling Group, Department of Molecular Oncology, Weatherall Institute 
of Molecular Medicine, John Radcliffe Hospital, Headley Way, Oxford OX3 9DS, 
UK
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doi: 10.1186/1478-811X-8-7
Cite this article as: Feller, The dawn of a new era in cell signalling research 
Cell Communication and Signaling 2010, 8:7
Received: 22 April 2010 Accepted: 24 May 2010 
Published: 24 May 2010
This article is available from: http://www.biosignaling.com/content/8/1/7© 2010 Feller; license Bi Med Central Ltd. is an Open Access articl  istributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Cell Communication and S gnaling 2010, 8:7


Feller Stephan M

Directory of Open Access Journals

Bullock SL: Subcellular mRNA localization in animal cells and why it matters. Science

Cell regulation: determined to signal discrete cooperation. Trends Biochem Sci

FJ: Malleable machines take shape in eukaryotic transcriptional regulation. Nat Chem Biol

Function and structure of inherently disordered proteins. Curr Opin Struct Biol

JR: A genomic strategy to elucidate modules of oncogenic pathway signaling networks. Mol Cell

Linding R: Simplistic pathways or complex networks? Curr Opin Genet Dev

Linking oncogenic pathways with therapeutic opportunities. Nat Rev Cancer

LM: Molecular machines or pleiomorphic ensembles: signaling complexes revisited.

Oncogenic pathway signatures in human cancers as a guide to targeted therapie. Nature

Pawson T: Cell signaling in space and time: where proteins come together and when they're apart. Science

S: Interview with Sydney Brenner. Stud Hist Philos Biol Biomed Sci

SM: Cell growth, global phosphotyrosine elevation, and c-Met phosphorylation through Src family kinases in colorectal cancer cells. Proc Natl Acad Sci USA

SM: Gamma-secretase inhibition combined with platinum compounds enhances cell death in a large subset of colorectal cancer cells. Cell Commun Signal

Towards proteomic approaches for the identification of structural disorder. Curr Protein Pept Sci

Uversky VN: Unfoldomics of human genetic diseases: illustrative examples of ordered and intrinsically disordered members of the human diseasome. Protein Pept Lett

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