Dissecting SOS1 and SOS2 isoform-specific regulation of Ras signalling through biochemical, structural, and Affimer-based approaches

Project title

Dissecting SOS1 and SOS2 isoform-specific regulation of Ras signalling through biochemical, structural, and Affimer-based approaches

Description

Project Overview

SOS1 and SOS2 are key, widely expressed guanine exchange factors for Ras.  Despite their high homology, they exhibit functional differences; gain of function mutations in SOS1 lead to hyperactivation of Ras, leading to cancers (RTK-Ras-ERK signalling) and other diseases (RASopathies). Mutations in SOS2 while also implicated in tumour formation, may be more important for EGF-stimulated PI3K/AKT signalling pathways. We hypothesise that these functional differences are driven by isoform specific interactions and spatiotemporal regulation, both of which confer signalling specificity during Ras activation,  dictating unique physiological and pathological cellular outcomes. Understanding the mechanisms that underly them will shed light on key cellular processes regulated by Ras signalling and identify potential avenues for targeting SOS isoform specific functions in disease. Our interdisciplinary project aims to define the molecular, biochemical, and structural mechanisms underlying the activity of SOS isoforms and their regulation of Ras signalling.