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SOS2 Comes to the Fore: Differential Functionalities in Physiology and Pathology
Fernando C Baltanás1, Rósula García-Navas1, Eugenio Santos1
1Lab. 1, CIC-IBMCC, Universidad de Salamanca-CSIC and CIBERONC, 37007 Salamanca, Spain.
Abstract:
The SOS family of Ras-GEFs encompasses two highly homologous and widely expressed members, SOS1 and SOS2. Despite their similar structures and expression patterns, early studies of constitutive KO mice showing that SOS1-KO mutants were embryonic lethal while SOS2-KO mice were viable led to initially viewing SOS1 as the main Ras-GEF linking external stimuli to downstream RAS signaling, while obviating the functional significance of SOS2. Subsequently, different genetic and/or pharmacological ablation tools defined more precisely the functional specificity/redundancy of the SOS1/2 GEFs. Interestingly, the defective phenotypes observed in concomitantly ablated SOS1/2-DKO contexts are frequently much stronger than in single SOS1-KO scenarios and undetectable in single SOS2-KO cells, demonstrating functional redundancy between them and suggesting an ancillary role of SOS2 in the absence of SOS1. Preferential SOS1 role was also demonstrated in different RASopathies and tumors. Conversely, specific SOS2 functions, including a critical role in regulation of the RAS-PI3K/AKT signaling axis in keratinocytes and KRAS-driven tumor lines or in control of epidermal stem cell homeostasis, were also reported. Specific SOS2 mutations were also identified in some RASopathies and cancer forms. The relevance/specificity of the newly uncovered functional roles suggests that SOS2 should join SOS1 for consideration as a relevant biomarker/therapy target.
Insights
SOS1 and SOS2 proteins, crucial for RAS signaling, show functional redundancy. While SOS1 is vital, SOS2 plays a key role in specific pathways and is a potential therapeutic target in diseases like RASopathies and cancer.
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.
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