Mitogen-activated protein kinase (MAPK) cascades, termed MAPK modules, channel extracellular signals into specific cellular responses. Chimeric molecules were constructed between p38 and p44 MAPKs, which transduce stress and growth factor signals, respectively. A discrete region of 40 residues located in the amino-terminal p38MAPK lobe directed the specificity of response to extracellular signals, whereas the carboxyl-terminal half of the molecule specified Substrate recognition. One p38-p44MAPK chimera, expressed in vivo, redirected stress signals into early mitogenic responses, demonstrating the functional independence of these domains.