New insights into the mechanisms of SOS activation.

The activation of the small guanosine triphosphatase Ras is critical for many biological events. It is therefore not surprising that the ubiquitously expressed Ras guanine nucleotide exchange factor (GEF) SOS (Son of Sevenless), which couples protein tyrosine kinases to Ras activation, is under tight autoinhibitory control. Several studies have revealed how multiple regulatory domains might affect SOS activity. Most notably, a second Ras-binding site on SOS allosterically regulates the duration and amplitude of Ras activation. This allosteric Ras-GTP is produced by another GEF, Ras guanine nucleotide-releasing protein 1 (RasGRP1). SOS and RasGRP1 are both activated downstream of phospholipase D(2), and gain-of-function mutants of SOS contribute to inherited diseases. These studies not only enable us to better appreciate the complexity of the regulation of GEFs but also prompt us to reevaluate our current understanding of pathways that lead to Ras activation.