KSR: a MAPK scaffold of the Ras pathway?

Kinase Suppressor of Ras (KSR) is an intriguing component of the Ras pathwa y that was first identified by genetic studies performed in Drosophila mela nogaster and Caenorhabditis elegans. In both organisms, inactivating mutati ons in KSR suppress the phenotypic effects induced by activated Ras, These findings together with the fact that KSR contains many structural features characteristic of a protein kinase led to early speculation that KSR is a k inase functioning upstream of the Ras pathway component Raf-1 or in a paral lel Ras-dependent pathway. However, in the six years since its discovery, K SR has been found to lack several key properties of known protein kinases, which has cast doubt on whether KSR is indeed a functional enzyme, A major breakthrough in our understanding of the role of KSR in signal transduction has come from recent findings that KSR interacts with several components o f the MAP kinase cascade, including Raf-1, MEK1/2 and ERK1/2, The model now emerging is that KSR acts as a scaffolding protein that coordinates the as sembly of a membrane-localized, multiprotein MAP kinase complex, a vital st ep in Ras-mediated signal transduction. Thus, while Kinase Suppressor of Ra s may be its name, phosphorylation may not be its game.