KSR: A novel player in the RAS pathway

Abstract

Julian Downward Imperial Cancer Research Fund Lincoln’s Inn Fields London WC2A 3PX England Over the past 5 years or so, developmental geneticists studying the nematode and the fruit fly have provided many new insights into the signaling pathways linking cell surface receptor tyrosine kinases with nuclear transcrip- tion factors. A central component in this information trans- fer mechanism is the RAS protein, a low molecular weight GTP-binding protein that is a proto-oncogene product in mammals; another key player is the RAF kinase, also a proto-oncogene product in mammals, which is directly reg- ulated by RAS and in turn controls the mitogen-activated protein (MAP) kinase cascade. The workings of this sys- tem have been elucidated largely through a combination of biochemical studies in mammalian cells and genetic analysis of the formation of the vulva in Caenorhabditis elegans and photoreceptor cells in the Drosophila eye. Until now, the biochemical and genetic approaches have moved forward fairly much together, such that some shau- vinistic biochemists have been able to claim that they have never learned much new from flies or worms. But all that has now been changed by three reports in this issue of Ce//(Therrien et al., 1995; Sundaram and Han, 1995; Korn- feld et al., 1995) characterizing a novel member of this system, KSR-1, that has not been glimpsed in mammals. The components of the RAS signaling pathways defined in flies and worms are shown in Figure 1, along with their mammalian homologs. In C. elegans, loss of function of RAS or other components results in a failure of the vulva to form in hermaphrodite worms (the vulvaless phenotype), while gain of function leads to formation of excess vulvas (the multivulva phenotype). These effects are due to changes in the developmental pathway chosen by multipo- tent vulva1 precursor cells. Of course, the function of RAS is not limited to determining the development of the vulva: a number of other pathways are affected, but this one is just the most sensitive to minor perturbations (Sternberg, 1993). In Drosophila, RAS function has been studied in detail in two signaling systems, Sevenless and Torso. In the developing eye, defects in RAS function result in failure of precursor cells to form the photoreceptor cell R7, while activation of RAS leads to nonneuronal cone cells devel- oping into extra R7 cells, resulting in a characteristic roughened appearance of the eye. Torso triggers a signal transduction cascade involved in the development of ante- rior and posterior extremities: loss of function in this path- way leads to a failure of these extremities to develop (Perri- mon, 1994). Homologs of all the various components of these signal- ing pathways have been identified in mammals. In the mammalian system, there is considerable biochemical ev- idence for branching, feedback, and cross-talk in the RAS