Two nearly identical proteins control the activation of Ras, a cancer-driving gene, but scientists have largely ignored one of them—leaving a blind spot in understanding how tumours grow. This project addresses that gap. SOS1 and SOS2 are the two proteins that switch Ras on, even when Ras is mutated and driving cancer. Most research has focused on SOS1, so the role of SOS2 remains poorly understood. Without knowing how both proteins work, efforts to block Ras signalling are incomplete. The team will use biochemical assays, structural biology, and custom-designed Affimer proteins—tiny engineered tools that can block SOS1 or SOS2 individually—to compare the two isoforms in detail. If successful, this research will produce a clear map of how each SOS protein activates Ras, including how they interact with different Ras mutations. It will also deliver validated Affimer tools that other labs can use to study Ras regulation. This is fundamental science: it will not produce a drug tomorrow. But understanding the molecular mechanics of Ras activation is a necessary step before anyone can design therapies that target it intelligently. Past work on Ras was once considered purely academic; today, drugs that target specific Ras mutants are in clinical use.
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Ras is an oncogene, frequently mutated in cancers, where it drives cell growth and signalling. SOS1 and SOS2 are key proteins that activate Ras by enabling it to switch from an inactive to an active state, even when Ras is acting as an oncogene. While these two proteins share similarities, most research has focused on SOS1, leaving the function of SOS2 much less understood. This gap in our knowledge limits our understanding of how Ras activity is regulated in normal and disease states. Our project aims to address this by investigating how SOS1 and SOS2 function and regulate Ras activation. By uncovering the differences and similarities between these proteins, we will gain new insights into Ras-driven cellular processes and identify potential strategies to target Ras activity in diseases. Specifically, we will: Study the active regions of SOS1 and SOS2 (SOScat): Using biochemical assays and advanced structural biology techniques, we will examine how these regions interact with different Ras variants, including those with disease-causing mutations. This will help us understand how SOS1 and SOS2 activate Ras and identify isoform-specific mechanisms. Use Affimers as research tools: Affimers are small, engineered proteins we have developed to block the activity of SOS1 and SOS2. These Affimers effectively inhibit Ras activation and downstream signalling in cells. We will use them to study the distinct roles of SOS1 and SOS2 in cells and visualize their interactions with Ras using high-resolution imaging methods. Link molecular findings to cellular function: By combining biochemical tests, cell-based experiments, and cutting-edge imaging techniques, we will investigate how SOS1 and SOS2 are regulated over time and in different locations within cells. This project builds on our expertise in structural biology, cell biology, imaging and the development of Affimers as research tools. We have already visualised SOS-Affimer complexes, demonstrated the ability of Affimers to block Ras signalling in cells, and used these tools for imaging and structural studies. By uncovering the mechanisms of SOS1- and SOS2-specific regulation of Ras, this research will fill a critical gap in our understanding of Ras activation. The tools and knowledge will provide a foundation for better understanding basic cellular signalling and biology and support efforts to develop new therapies targeting Ras-driven diseases.
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