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Signaling: How Activation Leads to Specificity

Module: 
4
Section: 
C

Instructor: Bernard Mathey-Prevot
Summary: Detection of external cues at the cell membrane sets in motion a cascade of events that culminates in the deployment of a nuclear program, ensuring the appropriate response of that cell to an external ligand. Signal propagation is carried by a series of effector proteins that have been identified through genetic and biochemical approaches and shown to belong to distinct signal transduction pathways. The dominant view until recently had been to consider each of these pathway as a separate cassette consisting of tens of core proteins, being highly compartmentalized, hierarchical, and independent from the rest of the proteome. Recent high-throughput genetic and biochemical data suggest two major revisions to this traditional, canonical view: (1) a massive increase in the number of components linked to a particular pathway and (2) extensive crosstalk between these pathways. This new understanding, however, raises the important question of how specificity can be achieved in such a highly interconnected network.
This module will concentrate on general principles of signaling pathways. It will not dwell on an enumeration of the various components for each pathway. Rather, through students’ presentations of primary research articles, we will focus on how experimental strategies and technical innovations have changed our ability to measure and follow pathway activation. We will discuss various strategies used by the cell to insure specificity, and look into the increasing role that systems biology and quantitative approaches have had on current views of signaling networks under normal and disease conditions.

Readings: 

1) Domains, Motifs, and Scaffolds: The Role of Modular Interactions in the Evolution and Wiring of Cell Signaling Circuits. Roby P. Bhattacharyya et al., Annu. Rev. Biochem. 75:655–80 (2006)
2) Assembly of Cell Regulatory Systems Through Protein Interaction Domains. Pawson and Nash, Science 300:445-­‐452 (2003)
3) Scaffold Proteins: Hubs for Controlling the Flow of Cellular Information. Matt C. Good et al., Science 332:680-­‐686 (2011)