Tumour suppressors and the regulation of GTP-binding protein activity

GTP-binding proteins regulate a wide variety of intracellular signalling pathways in eukaryotic cells. The Ras GTP-binding proteins have received a great deal of attention since they were found to be modified by amino acid substitutions in a large number of cancers. It is now clear that Ras plays an essential role in regulating normal cell growth and differentiation, although how this is achieved biochemically is not known. The cellular concentration of Ras bound to GTP appears to be the limiting factor for signalling, and, not suprisingly, it is tightly controlled by both positive and negative regulators. There is now convincing evidence that the loss of one of these negative regulators of Ras, neurofibromin, can contribute to the development of malignancy; thus, neurofibromin behaves as a tumour suppressor gene product.