INCREASING COMPLEXITY OF RAS SIGNALING

The initial discovery that ras genes endowed retroviruses with potent carcinogenic properties and the subsequent determination that mutated ras genes were present in a wide variety of human cancers, prompted a strong suspicion that the growth-promoting actions of mutated Ras prot eins contribute to their aberrant regulation of growth stimulatory sig naling pathways. In 1993, a remarkable convergence of experimental obs ervations from genetic analyses of Drosophila, S. cerevisiae and C. el egans as well as biochemical and biological studies in mammalian cells came together to define a clear role for Ras in signal transduction, What emerged was an elegant linear signaling pathway where Ras functio ns as a relay switch that is positioned downstream of cell surface rec eptor tyrosine kinases and upstream of a cytoplasmic cascade of kinase s that included the mitogen-activated protein kinases (MAPKs). Activat ed MAPKs in turn regulated the activities of nuclear transcription fac tors. Thus, a signaling cascade where every component between the cell surface and the nucleus was defined and conserved in worms, flies and man. This was a remarkable achievement in our efforts to appreciate h ow the aberrant function of Ras proteins may contribute to the maligna nt growth properties of the cancer cell, However, the identification o f this pathway has proven to be just the beginning, rather than the cu lmination, of our understanding of Ras in signal transduction, Instead , we now appreciate that this simple linear pathway represents but a m inor component of a very complex signaling circuitry. Ras signaling ha s emerged to involve a complex array of signaling pathways, where cros s-talk, feedback loops, branch points and multi-component signaling co mplexes are recurring themes. The simplest concept of a signaling casc ade, where each component simply relays the same message to the next, is clearly not the case. In this review, we summarize our current unde rstanding of Ras signal transduction with an emphasis on new complexit ies associated with the recognition and/or activation of cellular effe cters, and the diverse array of signaling, pathways mediated by intera ction between Ras and Ras-subfamily proteins with multiple effecters.