The activation of Ras by SOS

The link between tyrosine kinases and Ras activation is provided by a nucleotide exchange factor known as Son-of-Sevenless (SOS). Our group has provided a near complete structural description of SOS, in collaboration with Dafna Bar-Sagi (NYU), and we made the unexpected discovery that SOS has two binding sites for Ras, and is itself dependent on Ras for its own activation (Boriack-Sjodin et al, Nature 1998; Margarit et al., Cell 2003). This unanticipated feedback loop in Ras activation by SOS was later shown by others to underlie the sharp response of T-cells to the strength of input stimuli. By reconstituting the Ras activation reaction on lipid vesicles, we have shown that SOS integrates multiple signals at the membrane before activating Ras, in collaboration with the group of Jay Groves (Gureasko et al., Nat Struct Mol Biol 2008).

The mechanisms by which the activity of SOS is controlled are unexpectedly complex, and different from those of related nucleotide exchange factors. This diversity in the regulation of related signaling proteins is common, and runs counter to our expectation that important mechanisms would be conserved. In an “Insight” article in Nature (2007), Dr. Kuriyan and David Eisenberg (UCLA) point out that colocalization, such as at the membrane, can amplify the effect on one protein of random mutations in another protein and can therefore, through natural selection, lead to random interactions between proteins being strengthened and to a startling variety of complex allosteric controls.

At the workplace - An interview with SOS