Cell fate decisions rely on signaling pathways that integrate external signals to coordinate specific intracellular programs. One of these pathways leads to the activation of the protein kinase p38α, which plays key roles in cell responses to many types of stresses as well as chemotherapeutic agents and oncogenes. Importantly, p38α acts in a cell context and cell type-specific manner to integrate signals that affect cell proliferation, differentiation and survival. There is good evidence indicating that p38α can negatively regulate tumor initiation at different levels. Intriguingly, recent results suggest that p38α activation might sometimes contribute to tumorigenesis. The molecular basis for the different functions of p38α are not well understood but it is likely that the network of substrates phosphorylated by p38α plays a major role. This project proposes to investigate mechanisms of signal integration by p38α with special emphasis on the re-wiring of this signaling pathway to serve oncogenic functions in cancer cells. An important part of the studies focuses on the mechanisms underlying pro-tumorigenic functions of p38α signaling, including the regulation of survival, proliferation and spreading of cancer cells. Our experimental approach combines the genetic manipulation with the use of chemical inhibitors in different mouse models and human cancer cell lines. We will also use genetically modified mice that allow the deletion of p38α in a cell type-specific manner to investigate in vivo functions of this signaling pathway during tumorigenesis, as well as how the p38α pathway regulates the interplay between tumor cells and different cell types in the tumor stroma. Taken together, this project is posed to open unique opportunities for exploration of how complex signaling networks integrate during tumor development. The results of the proposed work should provide a rationale to develop novel cancer therapies based on the use of currently available drugs that target the p38α signaling network.