The study by Kam Yeung et al. describes the identification and characterization of RKIP (Raf kinase inhibitor protein), a Raf-1-interacting protein that inhibits the activation of MEK and ERK kinases. RKIP was isolated using a yeast two-hybrid screen and found to bind to Raf-1, MEK, and ERK but not to Ras. In vitro and in vivo experiments demonstrated that RKIP competitively disrupts the interaction between Raf-1 and MEK, inhibiting MEK phosphorylation by Raf-1. Overexpression of RKIP reduced the activation of MEK and ERK, AP-1-dependent transcription, and Raf-induced transformation. Downregulation of endogenous RKIP by antisense RNA or antibody microinjection activated MEK, ERK, and AP-1-dependent transcription. The authors propose that RKIP functions as a rheostat, regulating the sensitivity threshold for the activation of the Raf/MEK/ERK pathway, which is crucial for various cellular responses such as cell-cycle arrest, transformation, mitogenesis, and differentiation.The study by Kam Yeung et al. describes the identification and characterization of RKIP (Raf kinase inhibitor protein), a Raf-1-interacting protein that inhibits the activation of MEK and ERK kinases. RKIP was isolated using a yeast two-hybrid screen and found to bind to Raf-1, MEK, and ERK but not to Ras. In vitro and in vivo experiments demonstrated that RKIP competitively disrupts the interaction between Raf-1 and MEK, inhibiting MEK phosphorylation by Raf-1. Overexpression of RKIP reduced the activation of MEK and ERK, AP-1-dependent transcription, and Raf-induced transformation. Downregulation of endogenous RKIP by antisense RNA or antibody microinjection activated MEK, ERK, and AP-1-dependent transcription. The authors propose that RKIP functions as a rheostat, regulating the sensitivity threshold for the activation of the Raf/MEK/ERK pathway, which is crucial for various cellular responses such as cell-cycle arrest, transformation, mitogenesis, and differentiation.