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Significance Scaffold proteins are key regulators of signal transduction that bind multiple proteins of a signaling pathway. This simple tethering model explains how the scaffold colocalizes the components for signal propagation, but it is unclear whether scaffolds ensure signal amplification. Here, we use arrestin-3 and the ASK1-MKK4/7-JNK3 kinase cascade as a model system to explore whether scaffolding amplifies signaling. Our studies suggest a model of scaffold-dependent signal amplification that may be conceptually applicable to other scaffold-dependent signaling pathways.

Arrestin-3 scaffolding of the JNK3 cascade suggests a mechanism for signal amplification