Positive feedback in Ras activation through modulation of SOS activation probability.

Abstract

Ras is a membrane-bound small GTPase that links receptor signals, such as from epidermal growth factor receptor (EGFR) and T cell receptor (TCR), to downstream MAPK signaling. Son of Sevenless (SOS), a guanine-nucleotide exchange factor (GEF), is a primary Ras activator in both EGFR and TCR signaling pathways. SOS is a unique Ras GEF because it contains both catalytic and allosteric Ras binding sites. An important feature of Ras-MAPK signaling is an apparent binary—or switch-like—activation response. This behavior has been attributed to active RasGRP-driven positive feedback in SOS and corresponding kinetic bistability. More recent single-molecule studies of SOS have revealed a variety of previously unknown behaviors, including strong processivity on the membrane (an individual SOS molecule can activate hundreds of Ras molecules during a single membrane binding event) and extended delay times between membrane recruitment and initiation of GEF activity. These studies have also revealed that the catalytic rate of Ras activation by SOS is independent of the nucleotide state of Ras in the allosteric binding site on SOS, thus raising questions about the origins of such positive feedback. This study aims to elucidate a refined mechanism for the observed positive feedback in SOS activation of Ras, which includes these more recent discoveries. Experiments and stochastic modeling studies focus on how the timing of SOS autoinhibition release, rather than common mechanisms such as product-mediated recruitment or allosterically enhanced catalytic rate, may give rise to the observed behavior.