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Synthetic biology of cell signaling

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Abstract

Synthetic biology often takes cues from complex natural networks and pathways to create novel biological systems. The design modalities used in synthetic systems generally follow the different classes of gene regulation in cells such as transcriptional, post-transcriptional and post-translational regulation. The latter class is most prominent in cell signaling pathways that operate via multitude of protein–protein interactions. Engineering signaling pathways is a relatively unexplored area. This review discussed the work toward signaling pathway engineering in diverse biological contexts including bacteria, yeast, vertebrate, and plant cells. While creating synthetic signaling cascades is perhaps one of the most challenging tasks in synthetic biology, potential implications can be far-reaching and include new tools for programming cells and tissues, artificial developmental processes, and therapeutic tools.

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References

  • Acharya A et al (2002) A heterodimerizing leucine zipper coiled coil system for examining the specificity of a position interactions: amino acids I, V, L, N, A, and K. Biochemistry 41(48):14122–14131

    Article  Google Scholar 

  • Acuto O, Michel F (2003) CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nat Rev Immunol 3(12):939–951

    Article  Google Scholar 

  • Akiba H et al (1999) CD28-independent costimulation of T cells by OX40 ligand and CD70 on activated B cells. J Immunol 162(12):7058–7066

    Google Scholar 

  • Andersson J et al (2004) Differential input by Ste5 scaffold and Msg5 phosphatase route a MAPK cascade to multiple outcomes. EMBO J 23(13):2564–2576

    Article  Google Scholar 

  • Andrews BW, Yi TM, Iglesias PA (2006) Optimal noise filtering in the chemotactic response of Escherichia coli. PLoS Comput Biol 2(11):1407–1418

    Article  Google Scholar 

  • Antunes MS et al (2006) A synthetic de-greening gene circuit provides a reporting system that is remotely detectable and has a re-set capacity. Plant Biotechnol J 4(6):605–622

    Article  MathSciNet  Google Scholar 

  • Antunes MS et al (2009) Engineering key components in a synthetic eukaryotic signal transduction pathway. Mol Syst Biol 5:270

    Article  Google Scholar 

  • Antunes MS et al (2011) Programmable ligand detection system in plants through a synthetic signal transduction pathway. PLoS ONE 6(1):e16292

    Article  Google Scholar 

  • Auslaender D et al (2014) A synthetic multifunctional mammalian pH sensor and CO2 transgene-control device. Mol Cell 55(3):397–408

    Article  Google Scholar 

  • Baim SB et al (1991) A chimeric mammalian transactivator based on the lac repressor that is regulated by temperature and isopropyl beta-d-thiogalactopyranoside. Proc Natl Acad Sci USA 88(12):5072–5076

    Article  Google Scholar 

  • Banghart M et al (2004) Light-activated ion channels for remote control of neuronal firing. Nat Neurosci 7(12):1381–1386

    Article  Google Scholar 

  • Barrett DM et al (2014) Chimeric antigen receptor therapy for cancer. Annu Rev Med 65(65):333–347

    Article  Google Scholar 

  • Bashor CJ et al (2008) Using engineered scaffold interactions to reshape MAP kinase pathway signaling dynamics. Science 319(5869):1539–1543

    Article  Google Scholar 

  • Benenson Y (2012a) Biomolecular computing systems: principles, progress and potential. Nat Rev Genet 13(7):455–468

    Article  Google Scholar 

  • Benenson Y (2012b) Synthetic biology with RNA: progress report. Curr Opin Chem Biol 16(3–4):278–284

    Article  Google Scholar 

  • Busskamp V et al (2012) Optogenetic therapy for retinitis pigmentosa. Gene Ther 19(2):169–175

    Article  Google Scholar 

  • Celliere G et al (2011) The plasticity of TGF-beta signaling. BMC Syst Biol 5:184

    Article  Google Scholar 

  • Chuong AS et al (2014) Noninvasive optical inhibition with a red-shifted microbial rhodopsin. Nat Neurosci 17(8):1123–1129

    Article  Google Scholar 

  • Crivici A, Ikura M (1995) Molecular and structural basis of target recognition by calmodulin. Annu Rev Biophys Biomol Struct 24:85–116

    Article  Google Scholar 

  • Curran KJ, Pegram HJ, Brentjens RJ (2012) Chimeric antigen receptors for T cell immunotherapy: current understanding and future directions. J Gene Med 14(6):405–415

    Article  Google Scholar 

  • Darrow KN et al (2015) Optogenetic stimulation of the cochlear nucleus using channelrhodopsin-2 evokes activity in the central auditory pathways. Brain Res 1599:44–56

    Article  Google Scholar 

  • Deuschle U, Meyer WKH, Thiesen HJ (1995) Tetracycline-reversible silencing of eukaryotic promoters. Mol Cell Biol 15(4):1907–1914

    Article  Google Scholar 

  • Elowitz MB, Leibler S (2000) A synthetic oscillatory network of transcriptional regulators. Nature 403(6767):335–338

    Article  Google Scholar 

  • Fackler OT, Grosse R (2008) Cell motility through plasma membrane blebbing. J Cell Biol 181(6):879–884

    Article  Google Scholar 

  • Falke JJ et al (1997) The two-component signaling pathway of bacterial chemotaxis: a molecular view of signal transduction by receptors, kinases, and adaptation enzymes. Annu Rev Cell Dev Biol 13:457–512

    Article  Google Scholar 

  • Ferrell JE (1996) Tripping the switch fantastic: how a protein kinase cascade can convert graded inputs into switch-like outputs. Trends Biochem Sci 21(12):460–466

    Article  Google Scholar 

  • Furukawa K, Hohmann S (2015) A fungicide-responsive kinase as a tool for synthetic cell fate regulation. Nucleic Acids Res 43(14):7162–7170

    Article  Google Scholar 

  • Fussenegger M et al (2000) Streptogramin-based gene regulation systems for mammalian cells. Nat Biotechnol 18(11):1203–1208

    Article  Google Scholar 

  • Gambetta GA, Lagarias JC (2001) Genetic engineering of phytochrome biosynthesis in bacteria. Proc Natl Acad Sci USA 98(19):10566–10571

    Article  Google Scholar 

  • Ganesh I et al (2013) Engineered fumarate sensing Escherichia coli based on novel chimeric two-component system. J Biotechnol 168(4):560–566

    Article  Google Scholar 

  • Gardner TS, Cantor CR, Collins JJ (2000) Construction of a genetic toggle switch in Escherichia coli. Nature 403(6767):339–342

    Article  Google Scholar 

  • Gasser C et al (2014) Engineering of a red-light-activated human cAMP/cGMP-specific phosphodiesterase. Proc Natl Acad Sci USA 111(24):8803–8808

    Article  Google Scholar 

  • Geiger TL, Jyothi MD (2001) Development and application of receptor-modified T lymphocytes for adoptive immunotherapy. Transfus Med Rev 15(1):21–34

    Article  Google Scholar 

  • Gilbert W, Mullerhi B (1967) Lac operator in DNA. Proc Natl Acad Sci USA 58(6):2415

    Article  Google Scholar 

  • Goldbeter A, Koshland DE (1981) An amplified sensitivity arising from covalent modification in biological systems. Proc Natl Acad Sci USA Biol Sci 78(11):6840–6844

    Article  MathSciNet  Google Scholar 

  • Gossen M, Bujard H (1992) Tight control of gene-expression in mammalian-cells by tetracycline-responsive promoters. Proc Natl Acad Sci USA 89(12):5547–5551

    Article  Google Scholar 

  • Gramaglia I et al (1998) Ox-40 ligand: a potent costimulatory molecule for sustaining primary CD4 T cell responses. J Immunol 161(12):6510–6517

    Google Scholar 

  • Gunaydin LA et al (2010) Ultrafast optogenetic control. Nat Neurosci 13(3):387–392

    Article  MathSciNet  Google Scholar 

  • Hansen J et al (2014) Transplantation of prokaryotic two-component signaling pathways into mammalian cells. Proc Natl Acad Sci USA 111(44):15705–15710

    Article  Google Scholar 

  • Heinrich R, Neel BG, Rapoport TA (2002) Mathematical models of protein kinase signal transduction. Mol Cell 9(5):957–970

    Article  Google Scholar 

  • Hoch JA (2000) Two-component and phosphorelay signal transduction. Curr Opin Microbiol 3(2):165–170

    Article  Google Scholar 

  • Howell AS et al (2009) Singularity in polarization: rewiring yeast cells to make two buds. Cell 139(4):731–743

    Article  MathSciNet  Google Scholar 

  • Hughes RM et al (2012) Light-mediated control of DNA transcription in yeast. Methods 58(4):385–391

    Article  Google Scholar 

  • Hwang I, Sheen J (2001) Two-component circuitry in Arabidopsis cytokinin signal transduction. Nature 413(6854):383–389

    Article  Google Scholar 

  • Jacob F, Monod J (1961) Genetic regulatory mechanisms in synthesis of proteins. J Mol Biol 3(3):318–356

    Article  Google Scholar 

  • Johnson LN (2009) The regulation of protein phosphorylation. Biochem Soc Trans 37:627–641

    Article  Google Scholar 

  • Kapp GT et al (2012) Control of protein signaling using a computationally designed GTPase/GEF orthogonal pair. Proc Natl Acad Sci USA 109(14):5277–5282

    Article  Google Scholar 

  • Kawahara M, Ueda H, Nagamune T (2010) Engineering cytokine receptors to control cellular functions. Biochem Eng J 48(3):283–294

    Article  Google Scholar 

  • Kiel C, Yus E, Serrano L (2010) Engineering signal transduction pathways. Cell 140(1):33–47

    Article  Google Scholar 

  • Kobayashi H et al (2004) Programmable cells: interfacing natural and engineered gene networks. Proc Natl Acad Sci USA 101(22):8414–8419

    Article  Google Scholar 

  • Krell T et al (2010) Bacterial sensor kinases: diversity in the recognition of environmental signals. In: Gottesman S, Harwood CS (eds) Annual Review of Microbiology, vol 64. Annual Reviews, Palo Alto, pp 539–559

  • Laub MT, Goulian M (2007) Specificity in two-componen signal transduction pathways. Annu Rev Genet 41:121–145

    Article  Google Scholar 

  • Le H et al (2013) Dynamic gene expression for metabolic engineering of mammalian cells in culture. Metab Eng 20:212–220

    Article  Google Scholar 

  • Lee MJ et al (2012) Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks. Cell 149(4):780–794

    Article  Google Scholar 

  • Levskaya A et al (2005) Engineering Escherichia coli to see light: these smart bacteria ‘photograph’ a light pattern as a high-definition chemical image. Nature 438(7067):441–442

    Article  Google Scholar 

  • Li F et al (2010) Cell culture processes for monoclonal antibody production. Mabs 2(5):466–479

    Article  Google Scholar 

  • Lunt B et al (2010) Inference of direct residue contacts in two-component signaling. In: Simon MI, Crane BR, Crane A (eds) Methods in enzymology: two-component signaling systems, Part C, vol 471. Elsevier, New York, pp 17–41

  • Mezard M, Mora T (2009) Constraint satisfaction problems and neural networks: a statistical physics perspective. J Physiol Paris 103(1–2):107–113

    Article  Google Scholar 

  • Miller MB, Bassler BL (2001) Quorum sensing in bacteria. Annu Rev Microbiol 55:165–199

    Article  Google Scholar 

  • Mills E, Kevin T (2011) Ca2+-mediated synthetic biosystems offer protein design versatility, signal specificity, and pathway rewiring. Chem Biol 18(12):1611–1619

    Article  Google Scholar 

  • Mueller K et al (2014) Orthogonal optogenetic triple-gene control in mammalian cells. ACS Synth Biol 3(11):796–801

    Article  Google Scholar 

  • Nagel G et al (2003) Channelrhodopsin-2, a directly light-gated cation-selective membrane channel. Proc Natl Acad Sci USA 100(24):13940–13945

    Article  Google Scholar 

  • Novak B, Tyson JJ (2008) Design principles of biochemical oscillators. Nat Rev Mol Cell Biol 9(12):981–991

    Article  Google Scholar 

  • O’Shaughnessy EC et al (2011) Tunable signal processing in synthetic MAP kinase cascades. Cell 144(1):119–131

    Article  Google Scholar 

  • Park SH, Zarrinpar A, Lim WA (2003) Rewiring MAP kinase pathways using alternative scaffold assembly mechanisms. Science 299(5609):1061–1064

    Article  Google Scholar 

  • Pawson T, Warner N (2007) Oncogenic re-wiring of cellular signaling pathways. Oncogene 26(9):1268–1275

    Article  Google Scholar 

  • Procaccini A et al (2011) Dissecting the specificity of protein–protein interaction in bacterial two-component signaling: orphans and crosstalks. PLoS ONE 6(5):e19729

    Article  Google Scholar 

  • Ptashne M (1967) Specific binding of lambda phage repressor to lambda DNA. Nature 214(5085):232

    Article  Google Scholar 

  • Pule MA et al (2005) A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells. Mol Ther 12(5):933–941

    Article  Google Scholar 

  • Puttick J, Baker EN, Delbaere LTJ (2008) Histidine phosphorylation in biological systems. Biochim Biophys Acta Proteins Proteom 1784(1):100–105

    Article  Google Scholar 

  • Qin L et al (2000) A monomeric histidine kinase derived from EnvZ, an Escherichia coli osmosensor. Mol Microbiol 36(1):24–32

    Article  Google Scholar 

  • Regot S et al (2011) Distributed biological computation with multicellular engineered networks. Nature 469(7329):207–211

    Article  Google Scholar 

  • Rinaudo K et al (2007) A universal RNAi-based logic evaluator that operates in mammalian cells. Nat Biotechnol 25(7):795–801

    Article  Google Scholar 

  • Rowley JD (1990) The philadelphia-chromosome translocation: a paradigm for understanding leukemia. Cancer 65(10):2178–2184

    Article  Google Scholar 

  • Sadelain M, Riviere I, Brentjens R (2003) Targeting tumours with genetically enhanced T lymphocytes. Nat Rev Cancer 3(1):35–45

    Article  Google Scholar 

  • Shimizu TS, Tu YH, Berg HC (2010) A modular gradient-sensing network for chemotaxis in Escherichia coli revealed by responses to time-varying stimuli. Mol Syst Biol 6(1):382

    Google Scholar 

  • Skerker JM et al (2008) Rewiring the specificity of two-component signal transduction systems. Cell 133(6):1043–1054

    Article  Google Scholar 

  • Tabor JJ et al (2009) A synthetic genetic edge detection program. Cell 137(7):1272–1281

    Article  Google Scholar 

  • Tay S et al (2010) Single-cell NF-kappa B dynamics reveal digital activation and analogue information processing. Nature 466(7303):267–271

    Article  Google Scholar 

  • Thattai M, van Oudenaarden A (2002) Attenuation of noise in ultrasensitive signaling cascades. Biophys J 82(6):2943–2950

    Article  Google Scholar 

  • Tyson JJ, Chen KC, Novak B (2003) Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. Curr Opin Cell Biol 15(2):221–231

    Article  Google Scholar 

  • Tyszkiewicz AB, Muir TW (2008) Activation of protein splicing with light in yeast. Nat Methods 5(4):303–305

    Google Scholar 

  • Wang R, Brattain MG (2007) The maximal size of protein to diffuse through the nuclear pore is larger than 60 kDa. FEBS Lett 581(17):3164–3170

    Article  Google Scholar 

  • Wang X et al (2014) Optogenetic stimulation of locus ceruleus neurons augments inhibitory transmission to parasympathetic cardiac vagal neurons via activation of brainstem alpha 1 and beta 1 receptors. J Neurosci 34(18):6182–6189

    Article  Google Scholar 

  • Weber W et al (2002) Macrolide-based transgene control in mammalian cells and mice. Nat Biotechnol 20(9):901–907

    Article  Google Scholar 

  • Weigt M et al (2009) Identification of direct residue contacts in protein–protein interaction by message passing. Proc Natl Acad Sci USA 106(1):67–72

    Article  Google Scholar 

  • Wilkinson MG, Millar JBA (2000) Control of the eukaryotic cell cycle by MAP kinase signaling pathways. Faseb J 14(14):2147–2157

    Article  Google Scholar 

  • Wu CL et al (2003) Phosphorylation of the MAPKKK regulator Ste50p in Saccharomyces cerevisiae: a casein kinase I phosphorylation site is required for proper mating function. Eukaryot Cell 2(5):949–961

    Article  Google Scholar 

  • Yamamoto K et al (2005) Functional characterization in vitro of all two-component signal transduction systems from Escherichia coli. J Biol Chem 280(2):1448–1456

    Article  Google Scholar 

  • Yang X et al (2013) A light-inducible organelle-targeting system for dynamically activating and inactivating signaling in budding yeast. Mol Biol Cell 24(15):2419–2430

    Article  Google Scholar 

  • Ye HF et al (2011) A synthetic optogenetic transcription device enhances blood-glucose homeostasis in mice. Science 332(6037):1565–1568

    Article  Google Scholar 

  • Yeh BJ et al (2007) Rewiring cellular morphology pathways with synthetic guanine nucleotide exchange factors. Nature 447(7144):596–600

    Article  Google Scholar 

  • Zhang F et al (2006) Channelrhodopsin-2 and optical control of excitable cells. Nat Methods 3(10):785–792

    Article  Google Scholar 

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Correspondence to Yaakov Benenson.

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Hansen, J., Benenson, Y. Synthetic biology of cell signaling. Nat Comput 15, 5–13 (2016). https://doi.org/10.1007/s11047-015-9526-1

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