Chapter 18
18.1 Introduction
Review
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.
Research
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
Review
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
Research
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
Review
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
Research
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
Review
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.
Research
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
Review
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.
Research
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
Review
Pawson, T., and Nash, P., 2003. Assembly of cell regulatory systems through protein
interaction domains. Science v. 300 p. 445–452.
Research
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
Review
Perkins, J. P., Hausdorff, W. P., and Lefkowitz, R. J., 1990. Mechanisms of ligandin
-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
Review
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
Review
Beavo, J. A., Bechtel, P. J., and Krebs, E. G., 1975. Mechanisms of control for cAMPdependent
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.
Research
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
Research
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
Review
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
Review
Downward, J., 2004. PI 3-kinase, Akt and cell survival. Semin. Cell Dev. Biol. v. 15
p. 177–182.
Mora, 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):16170.
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
Review
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.
Research
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
Review
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.
Research
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
Review
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.
Research
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.
Warne T, Serrano-Vega MJ, Baker JG, Moukhametzianov R, Edwards PC, Henderson R,
Leslie AGW, Tate CG, and Schertler GFX 2008.
1-adrenergic Gprotein-coupled receptor. Nature, v. p. 454 486-491.
18.23 Small, monomeric GTP-binding proteins are multiuse switches
Review
Heasman, 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
Review
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.
Gallegos L. L., Newton A. C., 2008. Spatiotemporal dynamics of lipid signaling: Protein
kinase C as a paradigm. IUBMB Life. 2008 Aug 20. in press
Research
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
Review
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
Review
Sebolt-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
Review
Alonso, 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.
Research
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
Review
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.
Research
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
Review
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
Review
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
Review
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.
Research
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
Review
Raman, 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 substratespecificity 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.
Research
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
Review
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.
Research
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 cyclindependent kinase activation by phosphorylation. Nat. Struct. Biol. v. 3 p. 696–
700.
18.34 Diverse receptors recruit protein tyrosine kinases to the plasma membrane
Review
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.
Research
Clackson, T., and Wells, J. A., 1995. A hot spot of binding energy in a hormone-receptor
interface. Science v. 267 p. 383–386.
Schindler, 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.