# The complexity of complexes in signal transduction

@article{Hlavacek2003TheCO,
title={The complexity of complexes in signal transduction},
author={William S. Hlavacek and James R. Faeder and Michael L. Blinov and Alan S. Perelson and Byron Goldstein},
journal={Biotechnology and Bioengineering},
year={2003},
volume={84}
}
• Published 30 December 2003
• Biology, Chemistry
• Biotechnology and Bioengineering
Many activities of cells are controlled by cell‐surface receptors, which in response to ligands, trigger intracellular signaling reactions that elicit cellular responses. A hallmark of these signaling reactions is the reversible nucleation of multicomponent complexes, which typically begin to assemble when ligand‐receptor binding allows an enzyme, often a kinase, to create docking sites for signaling molecules through chemical modifications, such as tyrosine phosphorylation. One function of…
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## References

SHOWING 1-10 OF 112 REFERENCES

### Scaffold proteins may biphasically affect the levels of mitogen-activated protein kinase signaling and reduce its threshold properties.

• Biology
Proceedings of the National Academy of Sciences of the United States of America
• 2000
A quantitative computer model of MAPK cascade with a generic scaffold protein reveals that formation of scaffold-kinase complexes can be used effectively to regulate the specificity, efficiency, and amplitude of signal propagation.

### The biophysics of ligand-receptor interactions.

• C. DeLisi
• Biology
Quarterly reviews of biophysics
• 1980
It is apparent that irrespective of the range of interaction, a cell must be able to distinguish, with a high degree of precision, the signals relevant to it from an enormous flow of background noise.

### Kinetic proofreading in T-cell receptor signal transduction.

• T. McKeithan
• Biology
Proceedings of the National Academy of Sciences of the United States of America
• 1995
A model for the T-cell receptor is proposed in which this feature greatly enhances the receptor's ability to discriminate between a foreign antigen and self-antigens with only moderately lower affinity, a form of kinetic proofreading, known to be essential for the fidelity of protein and DNA synthesis.

### T cell receptor ligation induces the formation of dynamically regulated signaling assemblies

• Biology
The Journal of cell biology
• 2002
It is indicated that these complexes can form within seconds of TCR engagement, in the absence of either lipid raft aggregation or the formation of a central TCR-rich cluster.

### Specificity is complex and time consuming: mutual exclusivity in tyrosine kinase-mediated signaling.

• Biology
Accounts of chemical research
• 2003
Most fundamental cellular processes are transduced through tyrosine kinase (TK)-mediated pathways, and Stimulation of TK-mediated signals is often accompanied by recruitment of a precise, multimolecular protein complex that is itself capable of imposing specificity.

### Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors

• Biology
Nature Biotechnology
• 2002
The model provides insight into signal–response relationships between the binding of EGF to its receptor at the cell surface and the activation of downstream proteins in the signaling cascade, showing that EGF-induced responses are remarkably stable over a 100-fold range of ligand concentration.

### Computer-based analysis of the binding steps in protein complex formation.

• Biology, Chemistry
Proceedings of the National Academy of Sciences of the United States of America
• 1997
It is suggested that the prozone phenomenon will occur widely in living cells and that it could be a crucial factor in the regulation of protein complex formation.