Rewiring cell signaling: the logic and plasticity of eukaryotic protein circuitry

Dueber, John E.; Yeh, Brian J.; Bhattacharyya, Roby P.; Lim, Wendell A.

doi:10.1016/j.sbi.2004.10.004

Cited by 124 publications

(107 citation statements)

References 55 publications

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“…In the few examples studied to date, the localization of receptors to a signaling complex is often more important than their specific orientation within the complex. [233,236] Consistent with this view, the ability of dimeric ligands to activate signaling via ZAP-70 highlights that different RE orientations often give rise to only subtle effects. [107] ZAP-70 is a kinase whose function is required for the varied signaling functions of the T cell.…”

Section: 2a G-protein Coupledmentioning

confidence: 75%

“…Interestingly, these findings are consistent with studies in which fusion proteins have been used to test whether different assemblies of signaling domains influence output. [233,236] As with the ZAP-70 investigations, the orientation of different signaling domains was much less important than their recruitment to a signaling complex. It will be interesting to explore further the generality of these findings.…”

Section: 2a G-protein Coupledmentioning

confidence: 95%

“…[232][230] [229][225] When a signaling complex assembles, it is often unclear whether its activity is due to a specific orientation of receptors within the assembled complex or simply the localization of signaling components. [233] Thus, questions remain about the roles of receptor orientation in signaling. As discussed above, multivalent ligands can organize receptors into specific orientations; therefore, they have the potential to serve as tools for investigating the role of protein orientation in signaling.…”

Section: Receptor Orientationmentioning

confidence: 99%

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Synthetic Multivalent Ligands as Probes of Signal Transduction

2006

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Cell surface receptors acquire information from the extracellular environment and coordinate intracellular responses. Evidence from biochemical and structural studies indicates that many receptors do not operate as individual entities, but rather as part of higher-order complexes (e.g. dimers and oligomers). Coupling the functions of multiple receptors may endow signaling pathways with the sensitivity and malleability required to govern cellular responses. Moreover, multireceptor signaling complexes may provide a means of spatially segregating otherwise degenerate signaling cascades. Despite the proposed importance of receptor-receptor processes in cellular signaling, questions concerning the mechanisms, extent, and consequences of receptor co-localization and interreceptor communication remain unanswered.Chemical synthesis can provide a variety of compounds with which to address the role of receptor assembly in signal transduction. The focus of this review is one such approach -the use of synthetic multivalent ligands to characterize receptor function. Multivalent ligands can be generated that possess a variety of sizes, shapes, valencies, orientations, and densities of binding elements. Their unique architectures imbue multivalent ligands with the ability to access binding modes not available to monovalent compounds. Multivalent ligands, therefore, are capable of illuminating aspects of inter-receptor processes that are not readily probed using conventional approaches. We suggest that, as focus shifts from investigations of the function of individual proteins and toward the analysis of multi-receptor signaling complexes, multivalent ligands will become even more valuable tools with which to ask sophisticated mechanistic questions. Further, multivalent ligands may provide new opportunities for manipulating receptor systems for the deconvolution of pathways, diagnosis, and, ultimately, the treatment of disease.

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Section: 2a G-protein Coupledmentioning

confidence: 75%

Section: 2a G-protein Coupledmentioning

confidence: 95%

Section: Receptor Orientationmentioning

confidence: 99%

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Synthetic Multivalent Ligands as Probes of Signal Transduction

2006

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“…As a second example of an application that benefits from external tunability, we identified allosteric protein switches from combinatorial libraries by exploiting the ability of our band-pass selection system to be tuned to different settings as a function of time. Protein switches hold promise as selective protein therapeutics and biosensors (11,12). We have previously created maltoseactivated ␤-lactamase switches by the nonhomologous recombination of the genes encoding maltose-binding protein (MBP) and BLA and subjecting the resulting libraries to positive genetic selection for ␤-lactamase activity in the presence of maltose, followed by a time-consuming screen for maltose-dependent ␤-lactamase activity (13,14).…”

Section: Resultsmentioning

confidence: 99%

An externally tunable bacterial band-pass filter

Sohka¹,

Heins²,

Phelan

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

139

154

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The current paradigm for tuning synthetic biological systems is through re-engineering system components. Biological systems designed with the inherent ability to be tuned by external stimuli will be more versatile. We engineered Escherichia coli cells to behave as an externally tunable band-pass filter for enzyme activity and small molecules. The band's location can be positioned within a range of 4 orders of magnitude simply by the addition of compounds to the growth medium. Inclusion in the genetic network of an enzyme-substrate pair that functions as an attenuator is a generalizable strategy that enables this tunability. The genetic circuit enabled bacteria growth to be patterned in response to chemical gradients in nonintuitive ways and facilitated the isolation of engineered allosteric enzymes. The application of this strategy to other biological systems will increase their utility for biotechnological applications and their usefulness as a tool for gaining insight into nature's underlying design principles.biological circuit ͉ biological engineering ͉ pattern formation ͉ protein switch ͉ synthetic biology E xternal control over cellular processes is invaluable for research and technology. For example, inducible promoters allow one to control the amount of gene transcription from the outside the cell, obviating the need to engineer different cell strains with different promoters for each level of transcription desired. Moreover, inducible promoters enable control of transcription levels as a function of time and position. They consist of a simple genetic circuit that has a set input-output relation between inducer concentration and transcription level. This input-output relation cannot be conveniently altered from outside the cell. Thus, although the inducer can be said to ''tune'' the level of transcription, the circuit itself is not externally tunable. To tune these circuits, researchers must modify system components (e.g., by changing a repressor's affinity for its inducer). This approach to tuning currently predominates in the design of synthetic biological systems. However, such an approach is tantamount to building a unique biological system for each desired behavior and precludes the possibility of dynamic tuning or spatially patterned tuning. For example, Basu et al.(1) created a multicellular system that functioned as a band-detect filter for a small molecule. They demonstrated how the position of the band could be shifted to different concentration ranges by changing a repressor's affinity for a signaling molecule and by altering gene copy number. Tuning was achieved through building a different biological system for each desired band position. However, electronic band-detect filters can be built such that any desired range can be set dynamically through adjusting knobs from outside the device. The ability to create analogous externally tuneable biological systems would greatly expand their versatility. We describe how proper inclusion of an enzymesubstrate pair in the network results in an exter...

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“…1,2 Proteins and peptides can undergo conformation and activity changes in response to changes in pH or temperature, small-molecule binding, 3,4 or enzymatic activity. 5 Such sophisticated input/output control has proven useful in the development of biosensors, 6,7 cell internalizing agents, 5 and selective in vivo diagnostics and therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Proligands with protease‐regulated binding activity identified from cell‐displayed prodomain libraries

Thomas

Daugherty

2009

Protein Science

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A general method was developed for the discovery of protease-activated binding ligands, or proligands, from combinatorial prodomain libraries displayed on the surface of E. coli. Peptide libraries of candidate prodomains were fused with a matrix metalloprotease-2 substrate linker to a vascular endothelial growth factor-binding peptide and sorted using a two-stage flow cytometry screening procedure to isolate proligands that required protease treatment for binding activity. Prodomains that imparted protease-mediated switching activity were identified after three sorting cycles using two unique library design strategies. The best performing proligand exhibited a 100-fold improvement in apparent binding affinity after exposure to protease. This method may prove useful for developing therapeutic and diagnostic ligands with improved systemic targeting specificity.

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Rewiring cell signaling: the logic and plasticity of eukaryotic protein circuitry

Cited by 124 publications

References 55 publications

Synthetic Multivalent Ligands as Probes of Signal Transduction

Synthetic Multivalent Ligands as Probes of Signal Transduction

An externally tunable bacterial band-pass filter

Proligands with protease‐regulated binding activity identified from cell‐displayed prodomain libraries

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