The integration of signaling by multiprotein complexes containing Raf kinases

In vivo, eukaryotic cells are subjected simultaneously to a broad array of signals ranging from mitogens and inflammatory inputs to environmental stresses and developmental cues. The combinatorial nature of cellular signaling necessitates that a cell integrate its signal transduction pathways so as to implement rapidly and efficiently an appropriate suite of responses. Emerging evidence indicates that, over the course of evolution, cells have developed multiprotein signaling complexes, or “signalosomes” that mediate the coordinate regulation of different signaling pathways. Such molecular signal integration contrasts with the classical notion of signaling complexes assembled by scaffold proteins—entities that function to segregate specific pathways from one another. This review will focus on two signal integrating multiprotein complexes that involve Raf family kinases: the MLK3-B-Raf–Raf-1 complex and the Raf-1–Mst-2 complex.