SOS GEFs in health and disease

Baltanás, Fernando C.; Zarich, Natasha; Rojas-Cabañeros, José M.; Santos, Eugenio

doi:10.1016/j.bbcan.2020.188445

Cited by 49 publications

(79 citation statements)

References 283 publications

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“…The Ras GTPases are able to shift between inactive (GDP bound) and active (GTP bound) states in a cycle regulated through their interaction with activating guanine nucleotide exchange factors (GEFs) that facilitate GDP/GTP exchange and deactivating GTPase activating proteins (GAPs) that multiply their intrinsic GTPase activity. Sos1 and Sos2 form the most widely expressed and functionally relevant family of GEFs involved in activation of mammalian RAS proteins by upstream cellular signals [ 4 , 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…Despite their similar protein structures and cellular expression patterns, a variety of specific functionalities have been reported for Sos1 and Sos2 in different biological contexts [ 7 ]. Initial studies showed that Sos1 ablation in constitutive Sos1 knockout (KO) mice causes embryonic lethality [ 8 , 9 ], whereas adult, constitutive Sos2 KO mice are viable and fertile [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Functional Specificity of the Members of the Sos Family of Ras-GEF Activators: Novel Role of Sos2 in Control of Epidermal Stem Cell Homeostasis

Baltanás

Mucientes-Valdivieso

Lorenzo‐Martín

et al. 2021

Cancers

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Prior reports showed the critical requirement of Sos1 for epithelial carcinogenesis, but the specific functionalities of the homologous Sos1 and Sos2 GEFs in skin homeostasis and tumorigenesis remain unclear. Here, we characterize specific mechanistic roles played by Sos1 or Sos2 in primary mouse keratinocytes (a prevalent skin cell lineage) under different experimental conditions. Functional analyses of actively growing primary keratinocytes of relevant genotypes—WT, Sos1-KO, Sos2-KO, and Sos1/2-DKO—revealed a prevalent role of Sos1 regarding transcriptional regulation and control of RAS activation and mechanistic overlapping of Sos1 and Sos2 regarding cell proliferation and survival, with dominant contribution of Sos1 to the RAS-ERK axis and Sos2 to the RAS-PI3K/AKT axis. Sos1/2-DKO keratinocytes could not grow under 3D culture conditions, but single Sos1-KO and Sos2-KO keratinocytes were able to form pseudoepidermis structures that showed disorganized layer structure, reduced proliferation, and increased apoptosis in comparison with WT 3D cultures. Remarkably, analysis of the skin of both newborn and adult Sos2-KO mice uncovered a significant reduction of the population of stem cells located in hair follicles. These data confirm that Sos1 and Sos2 play specific, cell-autonomous functions in primary keratinocytes and reveal a novel, essential role of Sos2 in control of epidermal stem cell homeostasis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functional Specificity of the Members of the Sos Family of Ras-GEF Activators: Novel Role of Sos2 in Control of Epidermal Stem Cell Homeostasis

Baltanás

Mucientes-Valdivieso

Lorenzo‐Martín

et al. 2021

Cancers

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“…The most recent studies have demonstrated that the SOS GEFs are the most widely expressed and functionally relevant RAS activators in Metazoa, having a critical relevant role not only in individual cells but also in the control of organismal viability and homeostasis (rev. in [ 55 ]). In contrast, the RASGRFs exert most of their activating RAS functions in the central nervous system (rev.…”

Section: The Progress Of Ras Biology and Signaling During The 20th Centurymentioning

confidence: 99%

“…Another very relevant finding regarding the regulatory mechanisms of RAS activation was the discovery of an allosteric binding site for RAS in SOS1, showing that the specific binding of an activated RAS.GTP molecule to SOS1, in a region independent of the catalytic region responsible for nucleotide exchange, results in a significant increase in the overall exchange activity on other RAS molecules through the establishment of a positive feedback loop ensuring that many more inactive RAS molecules are then processively activated by the same allosterically activated SOS molecule [ 118 ]. Mutations in the SOS allosteric region are known to have profound functional consequences on RAS downstream signaling in different physiological and pathological contexts [ 55 ]. Importantly, in this regard, the allosteric activation of SOS1 GEF activity by WT RAS.GTP ultimately explains the seminal and somewhat surprising (at the time) demonstration of the critical requirement of the contribution of activated non-mutated WT RAS for the development of oncogenic RAS-driven tumors [ 119 , 120 ].…”

Section: Further Advances On Ras Signaling During the 21st Centurymentioning

confidence: 99%

“…In this regard, many reports have been published describing the isolation of small molecule RAS inhibitors, either blocking RAS/effector interactions [ 192 ] or inhibiting the interaction with SOS proteins (rev. in [ 55 ]). Happily, some of these inhibitors have already overcome most barriers in drug development and are being tested in the clinic.…”

Section: Therapeutic Approaches To Ras-driven Cancermentioning

confidence: 99%

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40 Years of RAS—A Historic Overview

Fernández‐Medarde

Rivas

Santos

2021

Genes

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It has been over forty years since the isolation of the first human oncogene (HRAS), a crucial milestone in cancer research made possible through the combined efforts of a few selected research groups at the beginning of the 1980s. Those initial discoveries led to a quantitative leap in our understanding of cancer biology and set up the onset of the field of molecular oncology. The following four decades of RAS research have produced a huge pool of new knowledge about the RAS family of small GTPases, including how they regulate signaling pathways controlling many cellular physiological processes, or how oncogenic mutations trigger pathological conditions, including developmental syndromes or many cancer types. However, despite the extensive body of available basic knowledge, specific effective treatments for RAS-driven cancers are still lacking. Hopefully, recent advances involving the discovery of novel pockets on the RAS surface as well as highly specific small-molecule inhibitors able to block its interaction with effectors and/or activators may lead to the development of new, effective treatments for cancer. This review intends to provide a quick, summarized historical overview of the main milestones in RAS research spanning from the initial discovery of the viral RAS oncogenes in rodent tumors to the latest attempts at targeting RAS oncogenes in various human cancers.

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Targeting KRAS mutant lung cancer: light at the end of the tunnel

Drosten

Barbacid

2022

Molecular Oncology

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For decades, KRAS mutant lung adenocarcinomas (LUAD) have been refractory to therapeutic strategies based on personalized medicine owing to the complexity of designing inhibitors to selectively target KRAS and downstream targets with acceptable toxicities. The recent development of selective KRAS G12C inhibitors represents a landmark after 40 years of intense research efforts since the identification of KRAS as a human oncogene. Here, we discuss the mechanisms responsible for the rapid development of resistance to these inhibitors, as well as potential strategies to overcome this limitation. Other therapeutic strategies aimed at inhibiting KRAS oncogenic signaling by targeting either upstream activators or downstream effectors are also reviewed. Finally, we discuss the effect of targeting the mitogen-activated protein kinase (MAPK) pathway, both based on the failure of MEK and ERK inhibitors in clinical trials, as well as on the recent identification of RAF1 as a potential target due to its MAPK-independent activity. These new developments, taken together, are likely to open new avenues to effectively treat KRAS mutant LUAD.

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SOS GEFs in health and disease

Cited by 49 publications

References 283 publications

Functional Specificity of the Members of the Sos Family of Ras-GEF Activators: Novel Role of Sos2 in Control of Epidermal Stem Cell Homeostasis

Functional Specificity of the Members of the Sos Family of Ras-GEF Activators: Novel Role of Sos2 in Control of Epidermal Stem Cell Homeostasis

40 Years of RAS—A Historic Overview

Targeting KRAS mutant lung cancer: light at the end of the tunnel

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