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.
Highlights
The proteins of the RAS superfamily are small GTPases known to shift between inactive (GDP-bound) and active (GTP-bound) conformations in a cycle regulated by activating Guanine nucleotide Exchange Factors (GEFs) that facilitate GDP/GTP exchange, and deactivating GTPase activating proteins (GAPs) that multiply their intrinsic GTPase activity (Figure 1A) [1,2,3,4]
Despite the earlier lack of focus on the functional relevance of SOS2, many subsequent studies have uncovered specific functions unambiguously attributed to SOS2 in different physiological and pathological contexts that clearly document the functional specificity of this particular SOS GEF family member
SOS1 disruption delayed the onset of tumor initiation, decreased tumor growth, and prevented malignant progression of papillomas when using the known DMBA/TPA model of chemically induced skin carcinogenesis in mice [21]. While these observations demonstrated that SOS1 is clearly predominant with regards to skin homeostasis, wound healing, and chemically induced skin carcinogenesis, it still remained unclear whether the defective phenotypes observed in the skin of SOS1-deficient mice were cell-autonomous or depended on their local manifestation in specific cell compartments of the skin. We have addressed these questions in a recent report involving extensive detailed analyses of the specific subpopulation of keratinocytes present in the skin of both newborn and adult SOS1-KO and/or SOS2-KO mice [25]
Summary
Most reports support the functional dominance of SOS1 over SOS2 regarding their participation in control of several major intracellular processes, such as proliferation, migration, inflammation, or regulation of intracellular ROS levels [20,25]. In all those processes, the defective cellular phenotypes observed in SOS1/2DKO samples are always much stronger than in single SOS1-KO cells, while undetectable in single SOS2-KO contexts, suggesting a specific, ancillary role of SOS2 that only becomes visible in the absence of SOS1 [19,20,21,30]. Regarding SOS2 functional specificities in cellular pathological contexts, a hierarchical requirement for SOS2 to mediate RAS-driven cell transformation has been reported recently in certain cell populations [31,32]
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