Sos2, a member of the SOS family of Ras-GEFs along with its highly homologous counterpart SOS1, functions as a guanine nucleotide exchange factor for RAS proteins. It is involved in the regulation of multiple signaling pathways, such as the RAS-PI3K/AKT signaling axis, and plays important roles in various biological processes including cell growth, development, and homeostasis [1]. In plants, it is a key component of the Salt Overly Sensitive (SOS) pathway, which is crucial for maintaining sodium/potassium (Na+/K+) homeostasis under salt stress [2,4,5,7,8]. Genetic models, like KO mouse models, have been instrumental in understanding its functions.

Initial constitutive KO mouse studies showed that SOS1-KO mutants were embryonic lethal while SOS2-KO mice were viable, initially suggesting a more prominent role for SOS1 in linking external stimuli to downstream RAS signaling [1]. However, further genetic and pharmacological ablation studies revealed functional redundancy between SOS1 and SOS2, as the defective phenotypes in SOS1/2-DKO contexts were often much stronger than in single SOS1-KO scenarios and undetectable in single SOS2-KO cells [1]. In lung adenocarcinoma, SOS2 deletion (SOS2KO) sensitized EGFR-mutated cells to perturbations in EGFR signaling caused by reduced serum and/or osimertinib treatment, inhibiting PI3K/AKT pathway activation, oncogenic transformation, and survival, and also reduced osimertinib resistance associated with bypass RTK reactivation of PI3K/AKT signaling [6,9].

In plants, SOS2-related functional studies have shown its role in salt tolerance. For example, in Arabidopsis, SOS2 physically interacts with and phosphorylates PHYTOCHROME-INTERACTING FACTORS PIF1 and PIF3, decreasing their stability and relieving their repressive effect on plant salt tolerance [2]. Phosphatidic acid binds to SOS2 under salt stress, promoting its activity and plasma membrane localization, which in turn activates the Na+/H+ antiporter SOS1 to promote Na+ efflux, and also promotes the phosphorylation of SCaBP8 by SOS2, attenuating the SCaBP8-mediated inhibition of AKT1 to promote K+ influx [4]. The receptor-like kinase GSO1 activates SOS2 independently of SOS3 binding, forming a GSO1-SOS2-SOS1 module that protects the Arabidopsis root stem cell niche by enhancing sodium ion extrusion [5]. Rare missense variants in SOS2 have been associated with Noonan syndrome, expanding the molecular spectrum of RASopathies [3].

In conclusion, Sos2 has diverse functions in both mammalian and plant systems. In mammals, studies using KO mouse models have revealed its role in regulating the threshold of EGFR signaling and osimertinib resistance in lung adenocarcinoma. In plants, it is essential for maintaining Na+/K+ homeostasis and salt tolerance. These model-based studies have significantly enhanced our understanding of Sos2's functions and its implications in disease and plant stress responses.

References:

1. Baltanás, Fernando C, García-Navas, Rósula, Santos, Eugenio. 2021. SOS2 Comes to the Fore: Differential Functionalities in Physiology and Pathology. In International journal of molecular sciences, 22, . doi:10.3390/ijms22126613. https://pubmed.ncbi.nlm.nih.gov/34205562/

2. Ma, Liang, Han, Run, Yang, Yongqing, Li, Jigang, Guo, Yan. . Phytochromes enhance SOS2-mediated PIF1 and PIF3 phosphorylation and degradation to promote Arabidopsis salt tolerance. In The Plant cell, 35, 2997-3020. doi:10.1093/plcell/koad117. https://pubmed.ncbi.nlm.nih.gov/37119239/

3. Yamamoto, Guilherme Lopes, Aguena, Meire, Gos, Monika, Passos-Bueno, Maria Rita, Bertola, Débora Romeo. 2015. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. In Journal of medical genetics, 52, 413-21. doi:10.1136/jmedgenet-2015-103018. https://pubmed.ncbi.nlm.nih.gov/25795793/

4. Li, Jianfang, Shen, Like, Han, Xiuli, Zhang, Wenhua, Guo, Yan. 2023. Phosphatidic acid-regulated SOS2 controls sodium and potassium homeostasis in Arabidopsis under salt stress. In The EMBO journal, 42, e112401. doi:10.15252/embj.2022112401. https://pubmed.ncbi.nlm.nih.gov/36811145/

5. Chen, Changxi, He, Gefeng, Li, Jianfang, Kudla, Jörg, Guo, Yan. 2023. A salt stress-activated GSO1-SOS2-SOS1 module protects the Arabidopsis root stem cell niche by enhancing sodium ion extrusion. In The EMBO journal, 42, e113004. doi:10.15252/embj.2022113004. https://pubmed.ncbi.nlm.nih.gov/37211994/

6. Theard, Patricia L, Linke, Amanda J, Sealover, Nancy E, Cox, Katherine, Kortum, Robert L. 2023. SOS2 regulates the threshold of mutant EGFR-dependent oncogenesis. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.01.20.524989. https://pubmed.ncbi.nlm.nih.gov/37425733/

7. Zhu, Jian-Kang. . Salt and drought stress signal transduction in plants. In Annual review of plant biology, 53, 247-73. doi:. https://pubmed.ncbi.nlm.nih.gov/12221975/

8. Bertorello, Alejandro Mario, Zhu, Jian-Kang. 2009. SIK1/SOS2 networks: decoding sodium signals via calcium-responsive protein kinase pathways. In Pflugers Archiv : European journal of physiology, 458, 613-9. doi:10.1007/s00424-009-0646-2. https://pubmed.ncbi.nlm.nih.gov/19247687/

9. Theard, Patricia L, Linke, Amanda J, Sealover, Nancy E, Cox, Katherine, Kortum, Robert L. 2024. SOS2 modulates the threshold of EGFR signaling to regulate osimertinib efficacy and resistance in lung adenocarcinoma. In Molecular oncology, 18, 641-661. doi:10.1002/1878-0261.13564. https://pubmed.ncbi.nlm.nih.gov/38073064/