Raf-1 phosphorylates and activates MEK-1, a kinase that activates the extracellular signal-regulated kinases (ERK). The Ras/Raf/MEK/ERK module is a ubiquitously expressed signaling pathway that conveys mitogenic and differentiation signals from the cell membrane to the nucleus1. This kinase cascade controls the proliferation and differentiation of different cell types. The small G protein Ras is activated by several growth factor receptors, and when activated binds Raf-1 kinase with high affinity. This induces the recruitment of Raf-1 from the cytosol to the cell membrane and its subsequent activation. Activated Raf-1 then phosphorylates the kinase MEK, thus activating it. MEK in turn phosphorylates and activates ERK, the prototypic mitogen-activated protein kinase (MAPK). Activated ERKs can translocate to the nucleus and regulate gene expression by the phosphorylation of transcription factors. Raf kinase inhibitor protein (RKIP) is a Raf-1 interacting protein that inhibits the phophorylation and activation of MEK by Raf-1. RKIP is not a substrate for either Raf-1 or MEK, but competitively disrupts the interaction between these kinases.