(A) Schematic representation of RAS and RAC activation/deactivation cycle mediated by SOS1/2 GEFs and GAPs, respectively. SOS2 mutations were also Kaempferol-3-rutinoside recognized in some RASopathies and malignancy forms. The relevance/specificity of the newly uncovered practical roles suggests that SOS2 should join SOS1 Kaempferol-3-rutinoside for thought as a relevant biomarker/therapy target. strong class=”kwd-title” Keywords: child of sevenless, SOS1, SOS2, RAS signaling, GEFs 1. SOS2 vs. SOS1 Function: An Introductory Timeline Perspective 1.1. Ras GEFs and the SOS Family The proteins of the RAS superfamily are small GTPases known to shift between inactive (GDP-bound) and active (GTP-bound) conformations inside a cycle controlled by activating Guanine nucleotide Exchange Factors (GEFs) that facilitate GDP/GTP exchange, and deactivating GTPase activating Kaempferol-3-rutinoside proteins (GAPs) that multiply their intrinsic GTPase activity (Number 1A) [1,2,3,4]. Open in a separate window Number 1 Practical relevance of SOS1/2 GEFs in physiological RAS signaling pathways and RASopathies. (A) Schematic representation of RAS and RAC activation/deactivation cycle mediated by SOS1/2 GEFs and GAPs, respectively. (B) Differential participation of SOS1 and SOS2 in downstream RAs signaling as suggested by current experimental evidence. (C) SOS2-specific mutational panorama in human being RASopathies (Noonan syndrome, NS9 type). HD: histone website; DH: Dbl homology; PH: pleckstrin homology; CDC25H: cell division cycle 25 homology; REM: RAS exchange motif; PR: proline-rich. Three main Ras-GEF family members (RasGRF 1/2, SOS 1/2, and RasGRP lC4) have been explained in mammalian cells with the ability to promote GDP/GTP exchange within the members of the RAS subfamily, and also some users of the RAC subfamily of small GTPases [5,6,7,8]. All mammalian Ras-GEFs share the presence of catalytic CDC25H and REM modules in their main sequences but, otherwise, each GEF family displays markedly unique patterns of protein structure, function, rules, and tissue manifestation. The users of the GRF family take action preferentially, but not specifically, in cells of the central nervous system [6,9,10], whereas the GRP family members function mostly in hematological cells and cells [11,12]. In contrast, the members of the SOS (Child of sevenless) family are the most common Ras-GEF activators, becoming recognized as the most widely indicated and functionally relevant GEFs with regards to RAS activation by numerous upstream signals in mammalian cells [5]. The SOS family encompasses two highly homologous, ubiquitously expressed users (SOS1 and SOS2) functioning in multiple signaling pathways including RAS or RAC activation downstream of a wide variety of cell surface receptors [5,13]. The initial characterization of the 1st available constitutive knockout (KO) mouse strains of the SOS family showed that SOS1 ablation causes mid-embryonic lethality in mice [14,15], whereas constitutive SOS2-KO mice are flawlessly viable and fertile [16]. Because of this and the stronger phenotypic Kaempferol-3-rutinoside traits connected to SOS1 ablation, most early practical studies of the SOS family focused almost specifically on SOS1, and rather little attention was paid to analyzing the practical relevance of SOS2 [5]. The look at that SOS1, but not SOS2, is the important GEF family member in RAS-signal transduction in metazoan cells was also probably behind the long search for, and development of, specific, small-molecule SOS1 inhibitors that have recently reached preclinical and medical screening against RAS-driven tumors [5,17,18]. 1.2. Practical Redundancy/Specificity of SOS2 vs. SOS1 Despite the earlier lack of focus on the practical relevance of SOS2, many subsequent studies possess uncovered specific functions unambiguously attributed to SOS2 in different physiological and pathological contexts that clearly document the practical specificity of this particular SOS GEF family member. In particular, the development, about 8 years ago, of conditional, tamoxifen-inducible, SOS1-null mutant mice made it possible to bypass the embryonal lethality of SOS1-null mutants and opened the way to carry out relevant practical studies of SOS2 by permitting biological samples originated from adult mouse littermates of four relevant SOS genotypes (WT, SOS1-KO, SOS2-KO and SOS1/2-DKO) to be generated and functionally compared [19]. Somewhat surprisingly, adult SOS1-KO or SOS2-KO mice were perfectly viable, but double SOS1/2-DKO animals died very rapidly [19], demonstrating a critical contribution of the SOS2 isoform (at least when SOS1 is usually absent) at the level of full organismal survival and homeostasis, and thus opening new avenues for concern of SOS2 as a functionally relevant player in mammalian RAS signaling pathways. In this regard, a number of recent functional studies of SOS1 and SOS2 using diverse genetic and pharmacological SOS ablation methods have significantly clarified, during the last decade, the mechanistic details underlying the functional specificity/redundancy of the SOS1 and SOS2 GEFs in a wide array of tissues.In this regard, our comparison of transcriptional networks of primary cells derived from SOS1-KO and/or SOS2-KO mice has revealed a remarkably higher impact of SOS1 ablation than SOS2 ablation around the resulting transcriptomic profiles. specific SOS2 functions, including a critical role in regulation of the RASCPI3K/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 recognized in some RASopathies and malignancy forms. The relevance/specificity of the newly uncovered functional roles suggests that SOS2 should join SOS1 for concern as a relevant biomarker/therapy target. strong class=”kwd-title” Keywords: child of sevenless, SOS1, SOS2, RAS signaling, GEFs 1. SOS2 vs. SOS1 Function: An Introductory Timeline Perspective 1.1. Ras GEFs and the SOS Family 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 (Physique 1A) [1,2,3,4]. Open in a separate window Physique 1 Functional relevance of SOS1/2 GEFs in physiological RAS signaling pathways and RASopathies. (A) Schematic representation of RAS and RAC activation/deactivation cycle mediated by SOS1/2 GEFs and GAPs, respectively. (B) Differential participation of SOS1 and SOS2 in downstream RAs signaling as suggested by current experimental evidence. (C) SOS2-specific mutational scenery in human RASopathies (Noonan syndrome, NS9 type). HD: histone domain name; DH: Dbl homology; PH: pleckstrin homology; CDC25H: cell division cycle 25 homology; REM: RAS exchange motif; PR: proline-rich. Three main Ras-GEF families (RasGRF 1/2, SOS 1/2, and RasGRP lC4) have been explained in mammalian cells with the ability to promote GDP/GTP exchange around the members of the RAS subfamily, and also some members of the RAC subfamily of small GTPases [5,6,7,8]. All mammalian Ras-GEFs share the presence of catalytic CDC25H and REM modules in their main sequences but, normally, each GEF family displays markedly unique patterns of protein structure, function, regulation, and tissue expression. The members of the GRF family act preferentially, but not exclusively, in cells of the central nervous system [6,9,10], whereas the GRP family members function mostly in hematological cells and tissues [11,12]. In contrast, the members of the SOS (Child of sevenless) family are the most universal Ras-GEF activators, being recognized as the most widely expressed and functionally relevant GEFs with regards to RAS activation by numerous upstream signals in mammalian cells [5]. The SOS family encompasses two highly homologous, ubiquitously expressed users (SOS1 and SOS2) functioning in multiple signaling pathways including RAS or RAC activation downstream of a wide variety of cell surface receptors [5,13]. The initial characterization of the first available constitutive knockout (KO) mouse strains of the SOS family showed that SOS1 ablation causes mid-embryonic lethality in mice [14,15], whereas constitutive SOS2-KO mice are perfectly viable and fertile [16]. Because of this and the stronger phenotypic traits associated to SOS1 ablation, most Agt early functional studies Kaempferol-3-rutinoside of the SOS family focused almost exclusively on SOS1, and rather little attention was paid to analyzing the functional relevance of SOS2 [5]. The view that SOS1, but not SOS2, is the important GEF family member in RAS-signal transduction in metazoan cells was also probably behind the long search for, and development of, specific, small-molecule SOS1 inhibitors that have recently reached preclinical and clinical screening against RAS-driven tumors [5,17,18]. 1.2. Functional Redundancy/Specificity of SOS2 vs. SOS1 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. In particular, the development, about 8 years ago, of conditional, tamoxifen-inducible, SOS1-null mutant mice made it possible to bypass the embryonal lethality of SOS1-null mutants and opened the way to carry out relevant functional studies of SOS2 by allowing biological samples originated from adult mouse littermates of four relevant SOS genotypes (WT, SOS1-KO, SOS2-KO and SOS1/2-DKO) to be generated and functionally compared [19]. Somewhat surprisingly, adult SOS1-KO or SOS2-KO mice were perfectly viable, but double SOS1/2-DKO animals died very rapidly [19], demonstrating a critical contribution of the SOS2 isoform (at least when SOS1 is usually absent) at the level of full organismal survival and homeostasis, and thus opening new avenues for concern of SOS2 as a functionally relevant player in mammalian RAS signaling pathways. In this regard, a number of recent functional studies of SOS1 and SOS2 using diverse genetic and pharmacological SOS ablation methods have significantly clarified, during the last decade, the mechanistic details underlying the functional specificity/redundancy of the SOS1 and SOS2 GEFs in a wide array of tissues and cells, both under physiological and pathological conditions [20,21,22,23,24,25] (observe.