Biology Reference
In-Depth Information
(Ku-0063794, an ATP-competitive mTor inhibitor) leading
to the identification of rapamycin-insensitive substrates of
mTORC1 and mTORC2.
[3] Hou SX, Zheng Z, Chen X, Perrimon N. The Jak/STAT pathway
in model organisms: emerging roles in cell movement. Dev Cell
2002;3:765 e 78.
[4] Thomas JH. Thinking about genetic redundancy. Trends Genet
1993;9:395 e 9.
[5] Perrimon N, Pitsouli C, Shilo B-Z. Signaling mechanisms
controlling cell fate and patterning. Cold Spring Harb Perspect
Biol 2012;4(8):pii: a005975.
[6] Noselli S, Agnes F. Roles of the JNK signaling pathway in
Drosophila
CONCLUDING REMARKS
Building on several decades of targeted classic genetics
approaches, unbiased high-throughput technologies are
beginning to generate a systems-level view of cellular
signaling networks. In this chapter we have reviewed
a number of experimental methods available to generate
a comprehensive 'parts list' of cellular signaling networks.
Further, we have described various approaches that can be
used to construct network models based on the phenotypic
signatures of each component. These techniques give us the
unprecedented opportunity to evaluate globally and
systematically the contribution of all genes to a specific
biological process. However, the implementation of these
methods is technically challenging and in some cases they
are best used in combination, as integration of data sets
increases the quality of the networks. Although the false
positive and false negative rates for networks generated
from high-throughput methods are currently relatively
high, new experimental techniques and new methods for
integrating multiple interacting data types will allow these
networks to become powerful predictive tools.
A global view of cellular networks holds great promise
in advancing our mechanistic understanding of how indi-
vidual genetic alterations, as well as combinations of gene
mutations, lead to a disease phenotype. For example,
sequencing of cancer genomes [271] and genome-wide
association studies [272] have identified hundreds of
genetic aberrations that are linked to different cancers and
complex diseases such as diabetes, obesity, hypertension
and Crohn's disease. Comprehensive structure/function
analysis of networks should help to understand the bio-
logical functions of many of the affected genes. Impor-
tantly, network analyses will facilitate the selection of
protein targets for therapeutic intervention based on the
underlying mechanisms of action. Furthermore, network
maps will shed light on how certain drug
morphogenesis.
Curr
Opin
Genet
Dev
1999;9:466 e 72.
[7] Lum L, Yao S, Mozer B, Rovescalli A, Von Kessler D,
Nirenberg M, et al. Identification of Hedgehog pathway compo-
nents
by RNAi
in Drosophila
cultured
cells. Science
2003;299:2039 e 45.
[8] Varelas X, Miller BW, Sopko R, Song S, Gregorieff A,
Fellouse FA, et al. The Hippo pathway regulates Wnt/beta-catenin
signaling. Dev Cell 2010;18:579 e 91.
[9] Xia L, Jia S, Huang S, Wang H, Zhu Y, Mu Y, et al. The Fused/
Smurf complex controls the fate of Drosophila germline stem
cells
by
generating
a
gradient BMP
response. Cell
2010;143:978 e 90.
[10] Nusslein-Volhard C, Wieschaus E. Mutations affecting segment
number and polarity in Drosophila Nature 1980;287:795 e 801.
[11] Nusse R. Wnts and Hedgehogs: lipid-modified proteins and
similarities in signaling mechanisms at the cell surface. Devel-
opment 2003;130:5297
305.
[12] Friedman A, Perrimon N. Genetic screening for signal trans-
duction in the era of network biology. Cell 2007;128:225 e 31.
[13] Barabasi AL, Oltvai ZN. Network biology: understanding the
cell's functional organization. Nat Rev Genet 2004;5:101 e 13.
[14] Forster J, Famili I, Fu P, Palsson BO, Nielsen J. Genome-scale
reconstruction of
e
the Saccharomyces
cerevisiae metabolic
network. Genome Res 2003;13:244 e 53.
[15] Han JD, Bertin N, Hao T, Goldberg DS, Berriz GF, Zhang LV,
et al. Evidence for dynamically organized modularity in the yeast
protein e protein interaction network. Nature 2004;430:88 e 93.
[16] Deplancke B, Mukhopadhyay A, Ao W, Elewa AM, Grove CA,
Martinez NJ, et al. A gene-centered C. elegans protein e DNA
interaction network. Cell 2006;125:1193 e 205.
[17] Watts DJ, Strogatz SH. Collective dynamics of 'small-world'
networks. Nature 1998;393:440 e 2.
[18] Barabasi AL, Albert R. Emergence of scaling in random
networks. Science 1999;286:509 e 12.
[19] Hahn MW, Kern AD. Comparative genomics of centrality and
essentiality in three eukaryotic protein-interaction networks. Mol
Biol Evol 2005;22:803 e 6.
target interac-
tions may lead to toxic effects. Such a mechanistic under-
standing is critical to the development of effective and safe
treatments. Eventually, generation of comprehensive
dynamic models of protein networks in response to signals
over time will allow scientists to quantitatively predict the
outcome of various perturbations.
e
[20]
Jeong H, Mason SP, Barabasi AL, Oltvai ZN. Lethality and
centrality in protein networks. Nature 2001;411:41
2.
[21] Li S, Armstrong CM, Bertin N, Ge H, Milstein S, Boxem M, et al.
A map of the interactome network of the metazoan C. elegans.
Science 2004;303:540 e 3.
[22] Albert R, Jeong H, Barabasi AL. Error and attack tolerance of
complex networks. Nature 2000;406:378 e 82.
[23] Toroczkai Z, Bassler KE. Network dynamics: jamming is limited
in scale-free systems. Nature 2004;428:716.
[24] Aldana M, Cluzel P. A natural class of robust networks. Proc Natl
Acad Sci U S A 2003;100:8710 e 4.
e
REFERENCES
[1] Pawson T. Protein modules and signaling networks. Nature
1995;373:573 e 80.
[2] Noselli S, Perrimon N. Signal transduction. Are there close
encounters between signaling pathways? Science 2000;290:68 e 9.
Search WWH ::




Custom Search