SOS2 Comes to the Fore: Differential Functionalities in Physiology and Pathology

Area of Science:

• Molecular Biology
• Cell Signaling
• Oncology

Background:

• The SOS family of Ras-guanine nucleotide exchange factors (Ras-GEFs) includes SOS1 and SOS2, which are highly homologous and widely expressed.
• Initial studies suggested SOS1 was the primary Ras-GEF due to embryonic lethality in SOS1-knockout mice, while SOS2-knockout mice were viable.

Purpose of the Study:

• To elucidate the functional specificity and redundancy between SOS1 and SOS2.
• To investigate the roles of SOS1 and SOS2 in various cellular processes and disease contexts, including RASopathies and cancer.

Main Methods:

• Utilized genetic (constitutive and conditional knockout) and pharmacological ablation tools to study SOS1 and SOS2 function.
• Analyzed phenotypes in single and double knockout contexts (SOS1/2-DKO) to assess functional redundancy.
• Examined the role of SOS2 in specific signaling pathways (RAS-PI3K/AKT) and cellular processes (stem cell homeostasis).

Main Results:

• Concomitant ablation of SOS1 and SOS2 (SOS1/2-DKO) often resulted in more severe phenotypes than single SOS1-KO, indicating functional redundancy.
• Single SOS2-KO cells showed minimal defects, suggesting an ancillary role for SOS2 when SOS1 is present.
• Specific roles for SOS2 were identified in keratinocyte signaling, KRAS-driven tumors, and epidermal stem cell regulation.
• Specific SOS2 mutations were found in certain RASopathies and cancers.

Conclusions:

• SOS1 and SOS2 exhibit significant functional redundancy in RAS signaling.
• SOS2 possesses unique functions critical for specific cellular processes and signaling pathways.
• Both SOS1 and SOS2, particularly SOS2 due to its specific roles, are relevant targets for biomarkers and therapies in RASopathies and cancer.