Signal Transduction Through Small GTPases—A Tale Of Two GAPs

Alan Hall Chester Beatty Laboratories Institute of Cancer Research London SW3 6JB England Small GTP-binding proteins related to ras regulate many basic processes in all eukaryotes (Hall, 1990). p21’** is an essential component of receptor-mediated signal trans- duction pathways regulating growth and differentiation, and although its exact biochemical function is unknown, one potential target protein is rasGAP, a protein that can stimulate the intrinsic GTPase activity of ras. The rho sub- family of small GTPases is functionally distinct from ras. p21”O, for example, controls the organization of polymer- ized actin in cells. It interacts with a GTPase-activating protein, rhoGAP, which is unrelated in sequence to ras- GAP. GAP domains have subsequently been identified in two clinically important genes, NF7 (the neurofibromatosis type 1 susceptibility gene) and bcr (the breakpoint cluster region gene), and the role of GAP proteins in signal trans- duction pathways has now become a focus of attention. In this issue, the plot thickens still further with the sequence analysis of two proteins that bind to rasGAP-one has homology to proteins involved in mRNA processing, and the other is a multidomain protein that looks like a GTP- binding protein, a transcription factor, and rhoGAP! rasGAP is a 120 kd cytosolic protein found in all mamma- lian cells. It can stimulate the intrinsic GTPase activity of normal but not oncogenic ras proteins, providing an explanation for why oncogenic ~21”” is hyperactive and constitutively in the GTP-bound form-it is insensitive to down-regulation in vivo. Mutations in ras (between amino acids 30 and 40, the so-called effector domain) block bio- logical activity and GAP-stimulated GTP hydrolysis, sug- gesting either that the ras target and GAP recognize over- lapping sequences, or that GAP is the ras target. Sequence analysis of GAP doesn’t help much in decid-