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

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.

Downregulation of miR‐193a/b‐3p during HPV‐induced cervical carcinogenesis contributes to anchorage‐independent growth through PI3K–AKT pathway regulators

“…Another way of PI3K activation is through Ras signaling. KRAS belongs to the RAS family of small GTPases, of which the activation could lead to various cellular outcomes such as cell proliferation, differentiation, growth, apoptosis, and cell survival 49 . Sheffels et al 50 reported that SOS2 expression is critical in mediating mutant KRAS‐driven transformation.…”

Neurodevelopmental disorders, immunity, and cancer are connected

“…For further discussion and data see ( Shieh, 2019 ). The connection between neurodevelopmental disorders and cancer has also been reviewed for pathologies such as RASopathies, including NF1, Noonan syndrome (NS), Costello syndrome (CS), [e.g., ( Baltanas et al., 2020 , 2021 ; Bergqvist and Wolkenstein, 2021 ; Castel et al., 2020 ; Christou et al., 2022 ; Gripp et al., 2020 ; Gross et al., 2020 ; Inoue et al., 2021 ; Kessler et al., 2021 ; Klomp et al., 2021 ; Leclerc et al., 2021 ; Lee et al., 2021 ; Malaquias and Jorge, 2021 ; Mitri et al., 2021 ; Prior, 2021 ; Rauen et al., 2021 ; Riller and Rieux-Laucat, 2021 ; Van et al., 2020 ; Weber and Carroll, 2021 ),], PROS ( Madsen et al., 2018 ; Martinez-Lopez et al., 2017 ; Venot et al., 2018 ; Venot and Canaud, 2017 ), ASD ( Hanly et al., 2021 ; Liu et al., 2021 ; Spina Nagy et al., 2021 ; Tiwari et al., 2021 ; Valentine et al., 2020 ; Yehia et al., 2019 , 2020 ), cerebral palsy, and more ( Bartels et al., 2020 ; Curry and Glasgow, 2021 ; Fahey et al., 2017 ; Gabriele et al., 2018 ). All have been linked to the Ras small GTPases superfamily and their signaling components.…”

Development of Son of Sevenless Homologue 1 (SOS1) Modulators To Treat Cancers by Regulating RAS Signaling

“…Thompson summarized the SOS1 inhibitors published in the patent documents . Two other reviews focused on the physiology and pathology of SOS proteins. , Given the potential of SOS1 to target refractory RAS-driven cancers and the recently disclosed important progress, we provide the following in this Perspective: (i) a comprehensive summary of all SOS1 modulators including newly discovered SOS1 inhibitors and PROTACs; (ii) a substantial structure–activity relationship (SAR) analysis and optimization strategies of representative SOS1 modulators from a medicinal chemistry view; (iii) a profound computational structural analysis of SOS1 activators and inhibitors. We conclude by providing insights into the challenges and opportunities in this field.…”