Scaffold-Mediated Organization of Signal Transduction Networks

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The Raf-MEK-ERK kinase cascade is a highly conserved signal transduction module involved in cellular processes ranging from proliferation and differentiation to transformation and apoptosis, and is engaged in response to growth factors, cytokines, morphogens, and other extracellular stimuli. Given the ubiquitous nature of this signaling pathway, it is not clear how specialization with respect to various Raf-dependent phenomena is acquired. In theory, functional specificity could be achieved by selectively coupling the core enzymatic components of a cascade to other regulatory pathways depending on the cellular context. Here, by using loss-of-function and partial loss-of-function mutant analysis, we demonstrate that Raf can participate in cell regulatory processes independently of its ability to activate MEK. We also show that scaffolding proteins can serve as specificity determinants in Ras/MAPK signaling, and may function to coordinate the activity of this cascade with additional regulatory pathways required for an appropriate biological response. Thus, we provide evidence for functional diversification both at the level of Raf substrates and at the level of molecular organization by accessory scaffolding molecules.

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