An Introduction to Systems Biology. Design Principles of Biological Networks

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Chapter 18
18.1 Introduction


Alon, U., 2007. An Introduction to Systems Biology. Design Principles of Biological Networks. Chapman and Hall.

Sauro, H. M., and Kholodenko, B. N., 2004. Quantitative analysis of signaling networks. Prog. Biophys. Mol. Biol. v. 86 p. 5–43.


Milo, R., Shen-Orr, S., Itzkovitz, S., Kashtan, N., Chklovskii, D., and Alon, U., 2002. Network motifs: simple building blocks of complex networks. Science v. 298 p. 824–827.

18.2 Cellular signaling is primarily chemical


Arshavsky, V. Y., Lamb, T. D., and Pugh, E. N., Jr., 2002. G proteins and phototransduction. Annu. Rev. Physiol. v. 64 p. 153–187.

Caterina, M. J., and Julius, D., 2001. The vanilloid receptor: a molecular gateway to the pain pathway. Annu. Rev. Neurosci. v. 24 p. 487–517.

Gillespie, P. G., and Cyr, J. L., 2004. Myosin-1c, the hair cell’s adaptation motor. Annu. Rev. Physiol. v. 66 p. 521–545.

Lin, C., and Shalitin, D., 2003. Cryptochrome structure and signal transduction. Annu. Rev. Plant Biol. v. 54 p. 469–496.

Rockwell, N. C., Su, Y.-S., and Lagarias, J.C., 2006. Phytochrome structure and signaling mechanisms. Annu. Rev. Plant Biology, v. 57 p. 837–858.

18.3 Receptors sense diverse stimuli but initiate a limited repertoire of cellular signals


Klein, C., Paul, J. I., Sauvé, K., Schmidt, M. M., Arcangeli, L., Ransom, J., Trueheart, J.,

Manfredi, J. P., Broach, J. R., and Murphy, A. J., 1998. Identification of surrogate agonists for the human FPRL-1 receptor by autocrine selection in yeast. Nat. Biotechnol. v. 16 p. 1334–1337.

18.5 Ligand binding changes receptor conformation


Ross, E. M., and Kenakin, T. P., 2001. Pharmacodynamics: Mechanisms of drug action and the relationship between drug concentration and effects. In Goodman and Gilmans’s The Pharmacological Basis of Therapeutics, 10th Ed., J. G. Hardman and L. E. Limbird, eds., New York: McGraw-Hill, p. 31–43.

18.6 Signals are sorted and integrated in signaling pathways and networks


Itzkovitz, S., Milo, R., Kashtan, N., Ziv, G., and Alon, U., 2003. Subgraphs in random networks. Phys. Rev. E. v. 68 p. 126–127.

18.7 Cellular signaling pathways can be thought of as biochemical logic circuits


Milo, R., Shen-Orr, S., Itzkovitz, S., Kashtan, N., Chklovskii, D., and Alon, U., 2002. Network motifs: Simple building blocks of complex networks. Science v. 298 p. 824–827.


Torres, E., and Rosen, M. K., 2003. Contingent phosphorylation/dephosphorylation provides a mechanism of molecular memory in WASP. Mol. Cell v. 11 p. 1215–1227.

18.8 Scaffolds increase signaling efficiency and enhance spatial organization of signaling


Elion, E. A., 2001. The Ste5p scaffold. J. Cell Sci. v. 114 p. 3967–3978.

O’Rourke, S. M., Herskowitz, I., and O’Shea, E. K., 2002. Yeast go the whole HOG for the hyperosmotic response. Trends Genet. v. 18 p. 405–412.

Pawson, T. and Nash, P., 2003. Assembly of cell regulatory systems through protein interaction domains. Science v. 300 p. 445–452.

Tsunoda, S., and Zuker, C. S., 1999. The organization of INAD-signaling complexes by a multivalent PDZ domain protein in Drosophila photoreceptor cells ensures sensitivity and speed of signaling. Cell Calcium v. 26 p. 165–171.


Levchenko, A., Bruck, J., and Sternberg, P. W., 2000. Scaffold proteins may biphasically affect the levels of mitogen-activated protein kinase signaling and reduce its threshold properties. Proc. Natl. Acad. Sci. USA v. 97 p. 5818–5823.

18.9 Independent, modular domains specify protein-protein interactions


Pawson, T., and Nash, P., 2003. Assembly of cell regulatory systems through protein interaction domains. Science v. 300 p. 445–452.


Ginty, D. D., Kornhauser, J. M., Thompson, M. A., Bading, H., Mayo, K. E., Takahashi, J. S., and Greenberg, M. E., 1993. Regulation of CREB phosphorylation in the suprachiasmatic nucleus by light and a circadian clock. Science v. 260 p. 238–241.

18.10 Cellular signaling is remarkably adaptive


Perkins, J. P., Hausdorff, W. P., and Lefkowitz, R. J., 1990. Mechanisms of ligand-induced desensitization of -adrenergic receptors. In The Beta-Adrenergic Receptors, J. P. Perkins, ed., Clifton, NJ: Humana Press, p. 73–124.

18.11 Signaling proteins are frequently expressed as multiple species


Barnes, N. M., and Sharp, T., 1999. A review of central 5-HT receptors and their function. Neuropharmacology v. 38 p. 1083–1152.

Gilman, A. G., 1987. G proteins: Transducers of receptor-generated signals Annu. Rev. Biochem. v. 56 p. 615–649.

Rebecchi, M. J., and Pentyala, S. N., 2000. Structure, function, and control of phosphoinositide-specific phospholipase C. Physiol. Rev. v. 80 p. 1291–1335.

Sunahara, R. K., and Taussig, R., 2002. Isoforms of mammalian adenylyl cyclase: Multiplicities of signaling. Mol. Interventions v. 2 p. 168–184.

18.14 Second messengers provide readily diffusible pathways for information transfer


Beavo, J. A., Bechtel, P. J., and Krebs, E. G., 1975. Mechanisms of control for cAMP-dependent

protein kinase from skeletal muscle. Adv. Cyclic Nucleotide Res. v. 5 p. 241–251.

Wong, W., and Scott, J. D., 2004. AKAP signalling complexes: focal points in space and time. Nat. Rev. Mol. Cell Biol. v. 5 p. 959–970.


Rall, T. W, and Sutherland, E. W., 1958. Formation of a cyclic adenine ribonucleotide by tissue particles. J. Biol. Chem. v. 232 p. 1065–1076.

18.15 Ca2+ signaling serves diverse purposes in all eukaryotic cells


Clapperton, J. A., Martin, S. R., Smerdon, S. J., Gamblin, S. J., and Bayley, P. M., 2002. Structure of the complex of calmodulin with the target sequence of calmodulin dependent protein kinase I: Studies of the kinase activation mechanism. Biochemistry. v. 41 p. 14669–14679.

Kuboniwa, H., Tjandra, N., Grzesiek, S., Ren, H., Klee, C. B., Bax, A., 1995. Solution structure

of calcium-free calmodulin. Nat. Struct. Biol. v. 2 p. 768–776.

18.16 Lipids and lipid-derived compounds are signaling molecules


Rebecchi, M. J., and Pentyala, S. N., 2000. Structure, function, and control of phosphoinositide-specific phospholipase C. Physiol. Rev. v. 80 p. 1291–1335.

Yang, C., and Kazanietz, M. G., 2003. Divergence and complexities in DAG signaling: Looking beyond PKC. Trends Pharmacol. Sci. v. 24 p. 602–608.

18.17 PI 3-kinase regulates both cell shape and the activation of essential growth and metabolic functions


Downward, J., 2004. PI 3-kinase, Akt and cell survival. Semin. Cell Dev. Biol. v. 15

p. 177–182.

1Mora, A., Komander, D., van Aalten, D. M., Alessi, D. R 2004. PDK1, the master regulator of AGC kinase signal transduction.Semin Cell Dev Biol. Apr;15(2):161-70.

Van Haastert, P. J. and Devreotes, P. N. 2004. Chemotaxis: Signaling the way forward. Nat. Rev. Mol. Cell Biol. v. 5. p. 626–634.

18.18 Signaling through ion channel receptors is very fast


Clapham, D. E., 2003. TRP channels as cellular sensors. Nature v. 426 p. 517–524.

Corey, D. P., 2003. New TRP channels in hearing and mechanosensation. Neuron v. 39 p. 585–588.

Hille, B., 1992. Ionic channels of excitable membranes. Sunderland, MA: Sinauer Associates.

Siegelbaum, S. A., and Koester, J., 2000. Ion channels and Membrane potential. In Principles of Neural Science, 4th Ed., E. R. Kandel, J. H. Schwartz, and T. M. Jessell, eds., New York: McGraw-Hill. p. 105–139.


Unwin, N., 2005. Refined structure of the nicotinic acetylcholine receptor at 4Å resolution. J. Mol. Biol. v. 346 p. 967.

18.19 Nuclear receptors regulate transcription


Mangelsdorf, D. J., et al., 1995. The nuclear receptor superfamily: The second decade. Cell v. 83 p. 835–839.

Smith, C. L. and O’Malley, B. W., 2004. Coregulator function: A key to understanding tissue specificity of selective receptor modulators. Endocr. Rev. v. 25 p. 45–71.


Brzozowski A. M., Pike, A. C., Dauter, Z., Hubbard, R. E., Bonn, T., Engstrom, O., Ohman, L., Green, G. L., Gustafsson, J. A., and Carlquist, M., 1997. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature v. 389 p. 753–758.

18.20 G protein signaling modules are widely used and highly adaptable


Clapham, D. E., and Neer, E. J., 1997. G protein βγ subunits. Annu. Rev. Pharmacol. Toxicol. v. 37 p. 167–203.

Ross, E. M., and Wilkie, T. M., 2000. GTPase-activating proteins for heterotrimeric G proteins:

Regulators of G protein signaling (RGS) and RGS-like proteins. Annu. Rev. Biochem. v. 69 p. 795–827.

Sprang, S. R., 1997. G proteins, effectors and GAPs: Structure and mechanism. Curr. Opin. Struct. Biol. v. 7 p. 849–856.

Sprang, S. R., 1997. G protein mechanisms: Insights from structural analysis. Annu. Rev. Biochem. v. 66 p. 639–678.


Chen, C.-K., Burns, M. E., He, W., Wensel, T. G., Baylor, D. A., and Simon, M. I., 2000. Slowed recovery of rod photoresponse in mice lacking the GTPase acceleration protein RGS9-1. Nature, v. 403 p. 557–560.

Wall, M. A., Coleman, D. E., Lee, E., Iniguez-Lluhi, J. A., Posner, B. A., Gilman, A. G., and Sprang, S. R., 1995. The structure of the G protein heterotrimer Gia1β1γ2. Cell v. 83 p. 1047–1058.

1Warne T, Serrano-Vega MJ, Baker JG, Moukhametzianov R, Edwards PC, Henderson R, Leslie AGW, Tate CG, and Schertler GFX 2008. 1Structure of a 1-adrenergic G-protein-coupled receptor. Nature, v. p. 1454 486-491.

18.23 Small, monomeric GTP-binding proteins are multiuse switches


1Heasman, S. J., Ridley, A. J. 2008 Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol. v. 9 p. 690-701.

Kuersten, S., Ohno, M., and Mattaj, I. W., 2001. Nucleocytoplasmic transport: Ran, beta and beyond. Trends Cell Biol. v. 11 p. 497–503.

Takai, Y., Sasaki, T., and Matozaki, T., 2001. Small GTP-binding proteins. Physiol. Rev. v. 81 p. 153–208.

18.24 Protein phosphorylation/dephosphorylation is a major regulatory mechanism in the cell


Cohen, S., 1983. The epidermal growth factor (EGF). Cancer v. 51 p. 1787–1791.

Fischer, E. H., 1997. “Protein phosphorylation and cellular regulation, II,” in Nobel Lectures, Physiology or Medicine 1991–1995, N., Ringertz, Ed., Singapore: World Scientific Publishing Co.

Krebs, E. G., 1993. Protein phosphorylation and cellular regulation. Bioscience Reports v. 13 p. 127–142.

Manning, G., Whyte, D. B., Martinez, R., Hunter, T., and Sudarsanam, S., 2002. The protein kinase complement of the human genome. Science v. 298 p. 1912–1934.

Miller ML, Jensen LJ, Diella F, Jørgensen C, Tinti M, Li L, Hsiung M, Parker SA, Bordeaux J,

Sicheritz-Ponten T, Olhovsky M, Pasculescu A, Alexander J, Knapp S, Blom N, Bork P, Li S, Cesareni G, Pawson T, Turk BE, Yaffe MB, Brunak S, Linding R. 2008. Linear motif atlas for phosphorylation-dependent signaling. Sci Signal. v. 1 p. ra2.

Nolen, B., Taylor, S., and Ghosh, G., 2004. Regulation of protein kinases; controlling activity through activation segment conformation. Mol. Cell v. 15 p. 661–675.

1Gallegos L. L., Newton A. C., 2008. Spatiotemporal dynamics of lipid signaling: Protein kinase C as a paradigm. IUBMB Life. 2008 Aug 20. in press


Canagarajah, B. J., Khokhlatchev, A., Cobb, M. H., and Goldsmith, E. J., 1997. Activation mechanism of the MAP kinase ERK2 by dual phosphorylation. Cell v. 90 p. 859–869.

Ginty, D. D., Kornhauser, J. M., Thompson, M. A., Bading, H., Mayo, K. E., Takahashi, J. S., and Greenberg, M. E., 1993. Regulation of CREB phosphorylation in the suprachiasmatic nucleus by light and a circadian clock. Science v. 260 p. 238–241.

Knighton, D. R., Zheng, J. H., Ten Eyck, L. F., Ashford, V. A., Xuong, N. H., Taylor, S. S., and Sowadski, J. M., 1991. Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science v. 253 p. 407–414.

Zhang, F., Strand, A., Robbins, D., Cobb, M. H., and Goldsmith, E. J., 1994. Atomic structure of the MAP kinase ERK2 at 2.3 Å resolution. Nature v. 367 p. 704–711.

18.25 Two-component protein phosphorylation systems are signaling relays


Hoch, J. A., and Silhavy, T. J., eds., 1995. Two-component signal transduction. Washington, D.C.: American Society for Microbiology.

Stock, A. M., Robinson, V. L., and Goudreau, P. N., 2000. Two-component signal transduction. Annu. Rev. Biochem. v. 69 p. 183–215.

18.26 Pharmacological inhibitors of protein kinases may be used to understand and treat disease


1Sebolt-Leopold, J. S., English, J., M. 2006. .Mechanisms of drug inhibition of signalling molecules. Nature. May 25;441 (7092):457-62.

Davies, S. P., Reddy, H., Caivano, M., and Cohen, P., 2000. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J. v. 351 p. 95–105.

18.27 Phosphoprotein phosphatases reverse the actions of kinases and are independently regulated


1Alonso, A., Sasin, J., Bottini, N., Friedberg, I., Friedberg, I., Osterman, A., Godzik, A., Hunter, T., Dixon, J., Mustelin, T. 2004. Protein tyrosine phosphatases in the human genome. Cell. v. 117 p. 699-711.

Aramburu, J., Heitman, J., and Crabtree, G. R., 2004. Calcineurin: A central controller of signalling in eukaryotes. EMBO Rep. v. 5 p. 343–348.

Dounay, A. B., and Forsyth, C. J., 2002. Okadaic acid: The archetypal serine/threonine protein phosphatase inhibitor. Curr. Med. Chem. v. 9 p. 1939–1980.

Neel, B. G., Gu, H., and Pao, L., 2003. The ‘Shp’ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem. Sci. v. 28 p. 284–293.

Virshup, D. M., 2000. Protein phosphatase 2A: A panoply of enzymes. Curr. Opin. Cell Biol. v. 12 p. 180–185.


Sun, H., et al. 1993. MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo Cell v. 75 p. 487–493.

Terrak, M., Kerff, F., Langsetmo, K., Tao, T., and Dominguez, R., 2004. Structural basis of protein phosphatase 1 regulation. Nature v. 429 p. 780–784.

18.28 Covalent modification by ubiquitin and ubiquitin-like proteins is another way of

regulating protein function


Gill, G., 2004. SUMO and ubiquitin in the nucleus: different functions, similar mechanisms? Genes Dev. v. 18 p. 2046–2059.

Pickart, C. M. and Eddins, M. J., 2004. Ubiquitin: Structures, functions, mechanisms. Biochim. Biophys. Acta v. 1695 p. 55–72.


Dharmasiri, N., Dharmasiri, S., and Estelle, M., 2005. The F-box protein TIR1 is an auxin receptor. Nature v. 435 p. 441–445.

Kanayama, A. et al. 2004. TAB2 and TAB3 activate the NF-kB pathway through binding to polyubiquitin chains. Mol. Cell v. 15 p. 535–548

Kepinski, S., and Leyser, O., 2005. The Arabidopsis F-box protein TIR1 is an auxin receptor. Nature v. 435 p. 446–451.

18.29 The Wnt pathway regulates cell fate during development and other processes in the adult


Logan, C. Y., and Nusse, R., 2004. The WNT signaling pathway in development and disease. Annu. Rev. Cell. Dev. Biol. v. 20, p. 781–810.

Tolwinski, N. S., Wieschaus, E., 2004. Rethinking WNT signaling. Trends Genet. v. 20 p. 177–81.

18.30 Diverse signaling mechanisms are regulated by protein tyrosine kinases


Blume-Jensen, P., and Hunter, T., 2001. Oncogenic kinase signalling. Nature v. 411 p. 355–365.

Pawson, T., and Nash, P., 2003. Assembly of cell regulatory systems through protein interaction domains. Science v. 300 p. 445–452.

Tallquist, M., and Kazlauskas, A., 2004. PDGF signaling in cells and mice. Cytokine Growth Factor Rev. v. 15 p. 205–213.

Taniguchi, C. M., Emanuelli, B., and Kahn, C. R., 2006. Critical nodes in signalling pathways: insights into insulin action. Nat. Rev. Mol. Cell Biol. v. 7, p. 85–96.

18.31 Src family protein kinases cooperate with receptor protein tyrosine kinases


Boggon, T. J., and Eck, M. J., 2004. Structure and regulation of Src family kinases. Oncogene v. 23 p. 7918–7927.

Frame, M. C., 2004. Newest findings on the oldest oncogene; how activated src does it. J. Cell Sci. v. 117 p. 989–998.


Xu, W., Harrison, S. C., and Eck, M. J., 1997. Three-dimensional structure of the tyrosine kinase c-Src. Nature v. 385 p. 595–602.

18.32 MAPKs are central to many signaling pathways


1Raman, M., Chen, W., Cobb, M. H.. 2007 Differential regulation and properties of MAPKs. Oncogene. May 14;26(22):3100-12.

Lewis, T. S., Shapiro, P. S., and Ahn, N. G., 1998. Signal transduction through MAP kinase cascades. Adv. Cancer Res. v. 74 p. 49–139.

Sharrocks, A. D., Yang, S. H., and Galanis, A., 2000. Docking domains and substrate-specificity determination for MAP kinases. Trends Biochem. Sci. v. 25 p. 448–453.

Bashor, C. J., Helman, N. C., Yan, S., Lim, W., A. 2008 Using engineered scaffold interactions to reshape MAP kinase pathway signaling dynamics. Science v. 319 p. 1539-43.


Anderson, N. G., Maller, J. L., Tonks, N. K., and Sturgill, T. W., 1990. Requirement for integration of signals from two distinct phosphorylation pathways for activation of MAP kinase. Nature v. 343 p. 651–653.

18.33 Cyclin-dependent protein kinases control the cell cycle


Dorée, M. and Hunt, T., 2002. From Cdc2 to Cdk1: when did the cell cycle kinase join its cyclin partner? J. Cell Sci. v. 115 p. 2461–2464.

Hartwell, L. H., 1991. Twenty-five years of cell cycle genetics. Genetics v. 129 p. 975–980.

Nurse, P., 2000. A long twentieth century of the cell cycle and beyond. Cell v. 100 p. 71–78.


Pavletich, N. P., 1999. Mechanisms of cyclin-dependent kinase regulation: Structures of Cdks, their cyclin activators, and Cip and INK4 inhibitors. J. Mol. Biol. v. 287 p. 821–828.

Russo, A. A., Jeffrey, P. D., and Pavletich, N. P., 1996. Structural basis of cyclin-dependent kinase activation by phosphorylation. Nat. Struct. Biol. v. 3 p. 696–700.

18.34 Diverse receptors recruit protein tyrosine kinases to the plasma membrane


Ernst, M., and Jenkins, B. J., 2004. Acquiring signalling specificity from the cytokine receptor gp130. Trends Genet. v. 20 p. 23–32.

Herrington, J., and Carter-Su, C., 2001. Signaling pathways activated by the growth hormone receptor. Trends Endocrinol. Metab. v. 12 p. 252–257.

Levy, D. E,. and Darnell, J. E., 2002. Stats: transcriptional control and biological impact. Nat. Rev. Mol. Cell Biol. v. 3 p. 651–662.

Miranti, C. K., and Brugge, J. S., 2002. Sensing the environment: A historical perspective on integrin signal transduction. Nat. Cell Biol. v. 4 p. E83–E90.

Palacios, E. H., and Weiss, A., 2004. Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation. Oncogene v. 23 p. 7990–8000.


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1Schindler, T., Bornmann, W., Pellicena, P., Miller, W. T., Clarkson, B., Kuriyan, J. 2000. Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science v. 289 p. 1938-42.
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