Affinage

SOS1

Son of sevenless homolog 1 · UniProt Q07889

Length
1333 aa
Mass
152.5 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SOS1 is a dual guanine nucleotide exchange factor that couples activated receptor tyrosine kinases to RAS- and RAC-family GTPases, governing proliferative signaling, cytoskeletal remodeling, and developmental cell-fate decisions (PMID:17143285, PMID:17143282, PMID:15039778, PMID:10675333). It is recruited to activated receptors through Grb2, which simultaneously engages distinct proline-rich motifs of the SOS1 C-terminal domain via its nSH3 and cSH3 domains; phosphotyrosine binding to the Grb2 SH2 domain allosterically potentiates this interaction, providing a switch that links RTK activation to complex assembly (PMID:7520523, PMID:31970984, PMID:34232285). Through its catalytic CDC25/REM module SOS1 loads GTP onto RAS proteins (including M-Ras) to drive ERK activation, and genetic ablation shows it is specifically required for sustained, but not transient, RAS-ERK signaling downstream of EGFR and the TCR, with RasGRP1 supplying the opposing transient and feedback-limiting arm (PMID:10675333, PMID:9030684, PMID:10446149, PMID:24497027, PMID:26005835). A parallel RAC-GEF activity is unmasked by ABL-mediated tyrosine phosphorylation at Y1196, switching substrate specificity toward RAC and driving actin remodeling, podosome formation, and migration, and contributing to BCR-ABL leukemogenesis (PMID:15039778, PMID:26447228, PMID:28819285). SOS1 activity is negatively regulated by MAP kinase- and RSK-mediated phosphorylation of C-terminal serines, which reduces Grb2 affinity and creates 14-3-3 docking sites, constituting a negative feedback loop on the pathway (PMID:8816480, PMID:22827337, PMID:29408703). SOS1 also supports tight junction assembly, early T-cell development, and mitochondrial redox homeostasis, and acts as a GEF-independent scaffold in EGFR-NFκB signaling (PMID:21746917, PMID:25071181, PMID:25394671, PMID:27157612). Gain-of-function mutations that destabilize autoinhibition cause Noonan syndrome, a truncating mutation removing the C-terminal proline-rich domains causes hereditary gingival fibromatosis, and the catalytic SOS1-KRAS interface defined by crystal structures is a validated drug target (PMID:17143285, PMID:17143282, PMID:11868160, PMID:17510059, PMID:32816843, PMID:30683722).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1994 Medium

    Established how SOS1 is recruited to activated receptors, answering whether it engages receptors directly or via an adaptor.

    Evidence Co-immunoprecipitation and SH2/SH3 domain-binding assays in M-CSF-stimulated myeloid cells

    PMID:7520523

    Open questions at the time
    • Did not resolve the precise SH3 motifs or stoichiometry of Grb2-SOS1 binding
    • Receptor specificity beyond Fms not addressed
  2. 1996 High

    Defined a negative-regulatory mechanism on SOS1 by mapping MAP kinase phosphosites in the proline-rich domain and linking them to Grb2 affinity.

    Evidence Site-directed mutagenesis with in vitro phosphorylation and Grb2 binding affinity measurements

    PMID:8816480

    Open questions at the time
    • Did not establish in vivo kinetics of feedback
    • Cellular consequence for ERK output not measured directly
  3. 1997 High

    Demonstrated an in vivo genetic requirement for SOS1 in EGFR signaling, moving beyond biochemical association to organismal epistasis.

    Evidence Sos1/EGFR double-mutant mice and ERK assays in null fibroblasts

    PMID:9030684

    Open questions at the time
    • Mechanistic basis of embryonic lethality not dissected
    • Did not distinguish transient vs sustained signaling roles
  4. 1999 Medium

    Extended SOS1 substrate scope by showing GEF activity toward M-Ras in addition to classical RAS.

    Evidence In vitro GDP/GTP exchange assay, yeast two-hybrid, co-IP

    PMID:10446149

    Open questions at the time
    • Physiological relevance of M-Ras GEF activity unclear
    • Single-lab biochemistry
  5. 2000 High

    Showed SOS1 specifically supports sustained rather than transient RAS-ERK signaling, distinguishing it from Sos2.

    Evidence Sos1 knockout mice and ERK time-course in null cells with transformation assays

    PMID:10675333

    Open questions at the time
    • Molecular basis of the sustained-vs-transient distinction not defined
    • Placental phenotype mechanism unresolved
  6. 2001 Medium

    Identified V-ATPase E as a positive regulator of SOS1 RAC-GEF activity at endosomes, implicating subcellular localization in pathway control.

    Evidence Affinity purification, yeast two-hybrid, co-IP, fractionation, in vitro Rac1-GEF assay

    PMID:11560919

    Open questions at the time
    • In vivo significance of endosomal SOS1-Rac1 not established
    • Single lab
  7. 2004 High

    Revealed that SOS1 is a RAC-GEF activated by ABL tyrosine phosphorylation, defining a second signaling output for actin remodeling.

    Evidence In vitro RAC-GEF assay, co-IP, pharmacological/genetic ABL inhibition

    PMID:15039778

    Open questions at the time
    • Specific phosphosite not yet mapped
    • Coupling between RAS and RAC arms not resolved
  8. 2006 High

    Established SOS1 as a Noonan syndrome disease gene with a gain-of-function mechanism via disrupted autoinhibition.

    Evidence Genetic mapping in patients and ectopic expression of mutants with RAS/ERK readouts

    PMID:17143282 PMID:17143285

    Open questions at the time
    • Structural detail of autoinhibition release not resolved here
    • Tissue-specific consequences not addressed
  9. 2002 Medium

    Linked a SOS1 C-terminal truncating mutation to hereditary gingival fibromatosis, implicating loss of proline-rich regulatory domains in disease.

    Evidence Positional cloning and segregation analysis across four generations

    PMID:11868160

    Open questions at the time
    • Functional consequence inferred from analogous transgenic data, not tested here
  10. 2007 Medium

    Provided the mechanism by which the HGF1 truncated SOS1 drives proliferation, showing constitutive membrane localization and cell-cycle entry.

    Evidence Ectopic expression, siRNA, ERK and cell-cycle marker immunoblotting

    PMID:17510059

    Open questions at the time
    • Membrane-targeting mechanism of the truncated protein not defined
    • Single-lab cell-based study
  11. 2010 High

    Defined a SOS1/EPS8/ABI1 tri-complex required for Rac-driven migration and metastasis, placing SOS1 in a cytoskeletal effector module.

    Evidence Reciprocal co-IP, knockdown, rescue, Rac-GTP and in vivo peritoneal colonization assays

    PMID:21118970

    Open questions at the time
    • Assembly hierarchy of the complex not fully resolved
    • Upstream activating signal incompletely defined
  12. 2011 High

    Showed stage-specific requirement for SOS1 in pre-TCR but not TCR signaling during T-cell development.

    Evidence Conditional knockout mice with thymocyte subset and ERK analysis

    PMID:21746917

    Open questions at the time
    • Molecular basis of pre-TCR vs TCR selectivity unresolved
  13. 2012 High

    Identified RSK as a kinase generating 14-3-3 docking sites on SOS1, defining a negative feedback loop restraining MAPK signaling.

    Evidence Quantitative MS, RSK inhibition, mutagenesis, 14-3-3 binding and ERK time-course

    PMID:22827337

    Open questions at the time
    • Magnitude of feedback in vivo modest
    • Interplay with MAP kinase phosphosites not integrated
  14. 2013 High

    Demonstrated cooperative multivalent SOS1/Grb2 engagement as a threshold mechanism for FGF-driven lineage commitment.

    Evidence Domain mutagenesis, interaction assays, ES cell differentiation and rescue

    PMID:23452850

    Open questions at the time
    • Quantitative threshold parameters not defined
    • Phospholipid contribution mechanistically incomplete
  15. 2014 Medium

    Expanded SOS1 roles to GEF-independent scaffolding (EGFR-NFκB), tight junction assembly via EMP1, sustained TCR ERK signaling, and Grb2-SUMOylation-dependent complex formation.

    Evidence RNAi, overexpression, GEF-dead mutants, microarray, reporter, and SUMOylation assays across multiple cell systems

    PMID:24497027 PMID:24775912 PMID:25071181 PMID:25394671

    Open questions at the time
    • Scaffolding partners in NFκB pathway not identified
    • Direct SOS1 role vs downstream EMP1 effect not fully separated
  16. 2015 High

    Defined SOS1 opposition to RasGRP1 in EGFR-RAS signaling and revealed loss of Sos restrains PI3K/AKT in T cells.

    Evidence Genetic mouse models with KRas/Apc mutations; conditional DKO T cells with phospho-AKT and migration assays

    PMID:25973715 PMID:26005835

    Open questions at the time
    • Molecular basis of SOS1/RasGRP1 functional partitioning unresolved
  17. 2015 Medium

    Placed SOS1 at macrophage podosomes as a Src/ABL-regulated Rac-GEF driving matrix degradation and invasion.

    Evidence siRNA, co-IP, Rac-GTP pulldown, invasion assays, live-cell imaging

    PMID:26447228

    Open questions at the time
    • Distinct contributions of Src vs ABL phosphorylation not separated
  18. 2016 High

    Linked SOS1 to mitochondrial redox homeostasis, showing its loss elevates ROS and mitophagy with antioxidant-rescuable phenotypes.

    Evidence Inducible Sos1-null MEFs, EM, ROS assays, antioxidant rescue

    PMID:27157612

    Open questions at the time
    • Whether redox role is GEF-dependent not determined
    • Mechanism connecting SOS1 to mitochondria unknown
  19. 2017 High

    Pinpointed Y1196 as the ABL phosphosite that switches SOS1 to RAC-GEF activity and drives BCR-ABL leukemogenesis.

    Evidence In vitro RAC-GEF assay with phospho-Y1196 mutants, co-IP, Sos1 conditional KO, leukemia models

    PMID:28819285

    Open questions at the time
    • Structural basis of the specificity switch not resolved
  20. 2018 Medium

    Provided structural detail of regulatory interfaces, including 14-3-3 binding to a SOS1 phosphopeptide, and a transcriptional regulator (RUNX1) driving SOS1 expression.

    Evidence X-ray crystallography of 14-3-3ζ-SOS1 peptide; RUNX1 promoter-binding and knockdown assays

    PMID:29408703 PMID:29686309

    Open questions at the time
    • RUNX1-SOS1 link is Low-confidence without full ChIP validation
    • Functional consequence of 14-3-3 binding inferred from structure
  21. 2019 High

    Validated SOS1 catalytic domain as a druggable KRAS interface and confirmed cancer-derived SOS1 mutations as oncogenic gain-of-function.

    Evidence Crystal structures of KRAS-SOS1, BAY-293 inhibitor characterization, and ectopic expression of lung adenocarcinoma mutants with xenografts

    PMID:30635434 PMID:30683722

    Open questions at the time
    • Allosteric vs catalytic-site inhibitor selectivity across SOS isoforms not fully resolved
  22. 2020 Medium

    Defined the high-affinity Grb2-SOS1 binding mode and a clinical-grade catalytic-site inhibitor (BI-3406) that blocks feedback reactivation.

    Evidence NMR and REMD of Grb2-SOS1; crystal structures and cellular RAS-GTP assays with BI-3406

    PMID:31970984 PMID:32816843

    Open questions at the time
    • In vivo durability of inhibition not addressed in these studies
  23. 2021 Medium

    Revealed the allosteric/avidity logic by which GRB2 SH2 phosphotyrosine binding couples RTK activation to SOS1 engagement.

    Evidence Biochemical, NMR, and fluorescence polarization assays with phosphopeptides and SOS1 fragments

    PMID:34232285

    Open questions at the time
    • Cellular dynamics of the allosteric switch not measured
  24. 2022 Medium

    Identified PPDPF as a GTP-supplying cofactor that enhances SOS1 GEF activity, adding a new layer to KRAS activation in pancreatic cancer.

    Evidence GTP-binding/transfer assay, co-IP, mutagenesis, in vitro GEF assay, PDAC mouse model

    PMID:36453576

    Open questions at the time
    • Generality of the PPDPF-SOS1 axis beyond pancreatic cancer unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SOS1 mechanistically controls mitochondrial redox state, and whether its non-canonical scaffolding and Rho-GEF functions are GEF-domain-independent, remains unresolved.
  • No mechanism connecting SOS1 to mitochondrial ROS established
  • Structural basis for RAS-vs-RAC substrate switching not defined
  • GEF-independent functions lack defined molecular partners

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 5 GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 3
Localization
GO:0005856 cytoskeleton 3 GO:0005886 plasma membrane 2 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-1266738 Developmental Biology 3
Partners
14-3-3ABI1ABL1EPS8GRB2PLCG1PPDPFTKS5
Complex memberships
Grb2-SOS1 complexSOS1/EPS8/ABI1 complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Missense mutations in SOS1 that cluster at residues maintaining autoinhibition cause Noonan syndrome by acting as hypermorphs: ectopic expression of two Noonan syndrome-associated SOS1 mutants enhances RAS and ERK activation, identifying SOS1 as a RAS guanine nucleotide exchange factor whose gain-of-function causes disease. Ectopic expression of mutant SOS1 constructs in cell lines with RAS-GTP and ERK activation readouts; genetic mapping in human patients Nature genetics High 17143282 17143285
1996 MAP kinase phosphorylates human SOS1 on five C-terminal serine residues (S1137, S1167, S1178, S1193, S1197) clustered within the proline-rich SH3-binding domain; replacing four of these sites with alanine increases Grb2 binding affinity, indicating that MAP kinase-mediated phosphorylation negatively regulates Grb2–SOS1 interaction and thereby modulates RAS activation. Site-directed mutagenesis combined with in vitro phosphorylation assays and Grb2 binding affinity measurements Molecular and cellular biology High 8816480
1994 After M-CSF stimulation, SOS1 forms complexes with Grb2 and the Fms receptor (M-CSF receptor) in myeloid cells; SOS1 also co-immunoprecipitates with Shc, and neither Grb2 nor SOS1 in these complexes contains phosphotyrosine, indicating SOS1 is recruited to the activated receptor via Grb2 adaptor interactions. Co-immunoprecipitation and SH2/SH3 domain-binding assays in M-CSF-stimulated myeloid progenitor cells Molecular and cellular biology Medium 7520523
2004 The non-receptor tyrosine kinase Abl phosphorylates SOS1 on tyrosine after RTK activation; Abl-induced tyrosine phosphorylation of SOS1 is sufficient to elicit its RAC-GEF activity in vitro, and SOS1 interacts with Abl in vivo, defining an RTK–Abl–SOS1–Rac pathway for actin remodeling. In vitro RAC-GEF activity assay, co-immunoprecipitation, pharmacological and genetic Abl inhibition Nature cell biology High 15039778
2000 Targeted disruption of mouse sos1 causes mid-gestational embryonic lethality due to impaired placental trophoblast development with very low ERK activity; sos1-null cells show reduced transformation by v-Src or overexpressed EGFR and reduced long-term ERK activation, whereas Sos2 compensates only for short-term signaling, demonstrating that SOS1 is specifically required for sustained RAS–ERK signaling downstream of EGFR. Homologous recombination knockout mice; transformation assays; ERK activation time-course in sos1−/− cell lines The EMBO journal High 10675333
1997 Heterozygous Sos1 mutation dominantly enhances the phenotype of a weak EGFR allele (wa-2) in mice, producing eye defects resembling EGFR or TGF-α nulls; homozygous Sos1-null embryos die mid-gestation with cardiovascular/yolk sac defects and reduced EGF-stimulated MAP kinase activation in fibroblasts, establishing a genetic requirement for SOS1 in EGFR signaling in vivo. Genetic epistasis in mice (Sos1/EGFR double mutant); ERK activation assay in null fibroblasts Genes & development High 9030684
2002 A frameshift insertion mutation in codon 1083 of SOS1 (insertion of cytosine between nucleotides 126,142 and 126,143) is responsible for hereditary gingival fibromatosis type 1 (HGF1); the mutation abolishes four C-terminal proline-rich SH3-binding domains, creating a truncated SOS1 chimera that retains the catalytic domain and, based on analogous transgenic mouse constructs, produces skin/tissue hypertrophy. Positional cloning, sequencing of SOS1 in affected family members, segregation analysis over four generations American journal of human genetics Medium 11868160
2007 Truncated SOS1 carrying the hereditary gingival fibromatosis mutation localizes to the plasma membrane without growth factor stimulation, producing sustained RAS/MAPK/ERK activation, phosphorylation of Rb, and upregulation of cyclins C, D, E and E2F/DP transcription factors, driving cell cycle G1-to-S progression and increased fibroblast proliferation. Ectopic expression of wild-type and mutant SOS1 constructs; siRNA knockdown; ERK phosphorylation and cell-cycle marker immunoblotting The Journal of biological chemistry Medium 17510059
2010 SOS1 forms a tri-complex with EPS8 and ABI1 in ovarian cancer cells; the integrity of this SOS1/EPS8/ABI1 complex is required for LPA-induced Rac activation and subsequent cell migration and peritoneal metastatic colonization; re-expression of the missing complex member in non-metastatic cells confers metastatic capability. Co-immunoprecipitation, knockdown, ectopic re-expression, Rac-GTP assay, in vivo peritoneal colonization assay Cancer research High 21118970
2012 RSK phosphorylates SOS1 on Ser1134 and Ser1161 in cultured cells; these phosphorylations create 14-3-3 docking sites, and mutating these residues disrupts 14-3-3 binding and modestly increases and extends MAP kinase activation, identifying RSK-mediated SOS1 phosphorylation as a negative feedback mechanism restraining MAPK signaling. Quantitative mass spectrometry, pharmacological RSK inhibition, mutagenesis of phosphorylation sites, 14-3-3 binding assays, ERK activation time-course The Biochemical journal High 22827337
2011 Conditional deletion of Sos1 in thymocytes reveals that SOS1 is required for pre-TCR-stimulated (DN-to-DP transition) but not TCR-stimulated developmental signals; Sos1-deficient thymocytes show reduced pre-TCR-induced proliferation, differentiation, and ERK phosphorylation, while TCR-dependent positive and negative selection remain intact. Conditional (floxed allele) knockout mice; thymocyte subset analysis; ERK phosphorylation assays Proceedings of the National Academy of Sciences of the United States of America High 21746917
2013 SOS1 and Grb2 cooperatively control embryonic stem cell fate toward the primitive endoderm lineage via FGF signaling; this requires collective binding of multiple SOS1/Grb2 domains (SH3, SH2, REM, PH domains) to both protein and phospholipid ligands, providing a cooperative threshold mechanism for lineage commitment. Domain mutagenesis, protein-protein interaction assays, ES cell differentiation assays, genetic rescue experiments Cell High 23452850
1999 SOS1 acts as a guanine nucleotide exchange factor for M-Ras (R-Ras3) in addition to classical RAS proteins; M-Ras GTP/GDP cycling is sensitive to SOS1 and GRF1 (GEFs) and to p120 RasGAP, demonstrating that SOS1 GEF activity extends to the M-Ras subfamily. GDP/GTP exchange assay, yeast two-hybrid, co-immunoprecipitation The Journal of biological chemistry Medium 10446149
2000 SOS1 directly binds the SH3 domain of PLC-γ1 through its C-terminal proline-rich domain; this interaction is detected both in vitro (GST pulldown) and in cells (co-immunoprecipitation); overexpression of PLC-γ1 or its SH2-SH2-SH3 domain elevates p21Ras and ERK activity, and a PLC-γ1 mutant lacking the SH3 domain cannot activate RAS, linking PLC-γ1 SH3 binding to SOS1-mediated RAS activation. GST pulldown, co-immunoprecipitation, transient expression with RAS-GTP and ERK activity assays Biochemistry Medium 10913276
2014 SOS1 silencing inhibits EGF-induced NFκB activation in cancer cells, and SOS1 overexpression increases NFκB activation; importantly, the guanine nucleotide exchange activity of SOS1 is NOT required for NFκB activation, indicating SOS1 has a GEF-independent scaffolding role in the EGFR–NFκB pathway. RNAi knockdown, SOS1 overexpression, NFκB reporter assays, GEF-dead mutant analysis Proceedings of the National Academy of Sciences of the United States of America Medium 25071181
2014 SOS1 is required for sustained but not transient TCR-mediated ERK activation in primary human T cells; RasGRP1 mediates transient ERK activation while both SOS1 and RasGRP1 are required for sustained ERK signaling and T-cell activation. RNAi-mediated knockdown of SOS1, SOS2, and RasGRP1 in primary human T cells; ERK phosphorylation kinetics under transient vs. sustained TCR stimulation European journal of immunology Medium 24497027
2014 SOS1, acting through the RAS/MEK/ERK pathway, is essential for tight junction formation in human bronchial epithelial cells; global microarray analysis identifies EMP1 as a major SOS1-dependent transcriptional target, and EMP1 itself is required for tight junction assembly. RNAi screen for GEFs, SOS1-specific knockdown, microarray analysis, tight junction assembly assay EMBO reports Medium 25394671
2015 SOS1 localizes to macrophage podosomes; its silencing results in podosome disassembly, reduced Rac-GTP loading, and impaired matrix degradation, 3D migration, transmigration through endothelial monolayers, and invasion into tumor spheroids. Abl and Src kinases (Hck, Fgr) phosphorylate SOS1 to mediate Abl/SOS1 interaction and podosome-associated Rac GEF activity. siRNA knockdown, co-immunoprecipitation, Rac-GTP pull-down assay, Matrigel invasion assay, live cell imaging of podosome markers Journal of immunology Medium 26447228
2016 Sos1-specific knockout in primary mouse embryonic fibroblasts causes impaired proliferation and migration, altered cytoskeletal organization, accumulation of autophagosomes containing degraded mitochondria (mitophagy), and elevated intracellular reactive oxygen species and mitochondrial superoxide; antioxidant treatment restores proliferation and morphology, establishing a mechanistic link between SOS1 and control of mitochondrial oxidative stress. Conditional 4-OHT-inducible Sos1-null MEFs; electron microscopy; mitophagy/autophagosome markers; ROS and mitochondrial superoxide fluorescent labeling; antioxidant rescue Oncogene High 27157612
2017 SOS1 is tyrosine phosphorylated on Y1196 by ABL; this phosphorylation controls SOS1 inter-molecular interactions, is required for RAC nucleotide exchange in vitro, and is needed for PDGF-induced RAC activation and actin remodeling/cell migration. In BCR-ABL leukemic cells, Y1196 phosphorylation by BCR-ABL drives SOS1-dependent RAC activation, cell proliferation, and transformation; genetic Sos1 removal delays BCR-ABL leukemogenesis in vivo. In vitro RAC-GEF assay with phospho-Y1196 SOS1; co-immunoprecipitation; mutagenesis; Sos1 conditional knockout in bone marrow; xenograft leukemogenesis model Leukemia High 28819285
2015 Two distinct RAS exchange factors, RasGRP1 and SOS1, act downstream of EGFR but in functional opposition: SOS1 drives proliferative EGFR-Ras signals, while RasGRP1 creates a negative feedback loop that limits EGFR-SOS1-RAS signals; genetic Rasgrp1 depletion in KRas-mutant or Apc-mutant mice exacerbates Ras-ERK signaling, confirming the epistatic relationship. Genetic mouse models (Rasgrp1 depletion combined with KRas or Apc mutations), ERK signaling assays, cell proliferation measurements Nature cell biology High 26005835
2001 The vacuolar H+-ATPase E subunit (V-ATPase E) binds the Dbl-homology (DH) domain of SOS1, co-immunoprecipitates with SOS1 physiologically, and co-localizes with SOS1 and Rac1 in early endosomes; overexpression of V-ATPase E enhances SOS1-mediated RAC1 guanine nucleotide exchange activity and downstream JNK kinase activity, implicating V-ATPase E as a positive regulator of the SOS1-Rac1 pathway at endosomes. GST-affinity chromatography protein purification, peptide sequencing, yeast two-hybrid, co-immunoprecipitation, subcellular fractionation, in vitro Rac1-GEF assay The Journal of biological chemistry Medium 11560919
2019 SOS1 mutations found in lung adenocarcinoma function as oncogenic gain-of-function: ectopic expression induces anchorage-independent growth and tumor formation in vivo; these effects require both the RAS-GEF and putative RAC-GEF activities of SOS1, and mutant SOS1-expressing cancer cells are sensitive to MEK inhibition. Ectopic expression of lung adenocarcinoma-derived SOS1 mutants; anchorage-independent growth assay; mouse xenograft tumor formation; domain mutagenesis; transcriptional profiling; MEK inhibitor sensitivity assay Molecular cancer research High 30635434
2020 Crystal structures of KRAS-SOS1, SOS1, and SOS2 were solved; BI-3406 binds to the catalytic domain of SOS1, preventing SOS1–KRAS interaction; this blocks GTP loading of RAS, reduces RAS-GTP levels, limits cancer cell proliferation, and attenuates feedback reactivation of MEK inhibitors, validating the SOS1 catalytic domain as a druggable interface. Crystal structure determination, biochemical SOS1–KRAS interaction assay, cellular RAS-GTP loading assay, proliferation assays, in vivo xenograft experiments Cancer discovery High 32816843
2019 Crystal structures of KRAS-SOS1 and SOS1 alone were determined; small-molecule inhibitors (e.g., BAY-293, IC50 21 nM) bind the SOS1 catalytic domain at the KRAS–SOS1 interface, disrupting complex formation, blocking KRAS GTP reloading, and exerting antiproliferative activity in KRAS-driven cells. X-ray crystallography, biophysical interaction assays (SPR/ITC), cellular RAS-GTP assay, antiproliferation assay Proceedings of the National Academy of Sciences of the United States of America High 30683722
2018 The crystal structure of a 14-3-3ζ dimer bound to a 13-mer SOS1 phosphopeptide motif was determined at high resolution, demonstrating that 14-3-3 proteins directly bind SOS1 at a defined PPI interface to modulate SOS1 activity in the RAS–MAPK pathway. X-ray crystallography, biochemical PPI assays Journal of structural biology Medium 29408703
2014 SUMOylation of Grb2 at K56 by SUMO1 increases formation of the Grb2–SOS1 complex, leading to enhanced RAS/MEK/MAPK activation; the Grb2-K56R mutant, which cannot be SUMOylated, fails to rescue ERK activity or cell transformation when re-expressed in Grb2-knockdown cells. In vivo and in vitro SUMOylation assay, co-immunoprecipitation, ERK activation assay, cell transformation and migration assays, xenograft model Molecular cancer Medium 24775912
2016 SOS1 mediates JAK-dependent LFA-1 activation in human T lymphocytes in response to CXCL12; SOS1 downregulation impairs rapid LFA-1-mediated adhesion, underflow arrest on ICAM-1, LFA-1 affinity triggering, and CXCL12-induced RhoA and Rac1 activation, indicating a SOS1 specificity shift to Rho-GEF activity in chemokine signaling context. siRNA knockdown of SOS1 in primary human T lymphocytes; LFA-1 adhesion assays; Rac1/RhoA-GTP pull-down; phosphotyrosine analysis; JAK inhibitor experiments Journal of immunology Medium 27986909
2009 Tks5/FISH interacts with SOS1 through synergistic binding of its tandem SH3A and SH3B domains to the proline-rich domain of SOS1; a splice-variant-specific basic insertion between SH3A and SH3B in the long Tks5 isoform reduces SOS1 binding affinity ~10-fold and alters recognition of SOS1 binding motifs, establishing isoform-selective SOS1 interaction. Peptide arrays, GST pulldown, isothermal titration calorimetry, analytical ultracentrifugation, co-localization in cells Journal of molecular biology Medium 19464300
2017 Phosphorylation of Y1196 on SOS1 by ABL promotes SOS1 RAC-GEF activity in vitro; the non-phosphorylatable Y1196F mutant fails to support RAC nucleotide exchange, directly linking this specific phosphorylation event to the switch in SOS1 substrate specificity from RAS-GEF to RAC-GEF. In vitro RAC nucleotide exchange assay with phosphomimetic/phospho-dead SOS1 mutants, co-IP for ABL-SOS1 interaction Leukemia High 28819285
2018 RUNX1 transcriptionally activates SOS1 expression by binding to a RUNX1-binding DNA sequence in the SOS1 promoter; RUNX1 knockdown reduces SOS1 expression and dephosphorylates ErbB2/HER2, suppressing gastric cancer cell proliferation. Promoter-binding assay (ChIP-like), RUNX1 knockdown, SOS1 mRNA/protein measurement, ErbB2 phosphorylation assay Scientific reports Low 29686309
2022 PPDPF binds GTP and transfers GTP to SOS1, enhancing SOS1 GEF activity; mutations at the PPDPF GTP-binding sites or at SOS1 residues mediating SOS1–PPDPF interaction impair SOS1 GEF activity and the tumor-promoting effects of PPDPF, defining a PPDPF–SOS1 axis for KRAS activation in pancreatic cancer. GTP-binding/transfer assay, co-immunoprecipitation, mutagenesis of interaction sites, in vitro GEF activity assay, genetic mouse PDAC model Advanced science Medium 36453576
2020 High-affinity Grb2–SOS1 interaction involves nSH3 binding to the PVPPPVPPRRRP motif and cSH3 binding to the PKLPPKTYKREH motif of the SOS1 proline-rich domain; NMR data and replica-exchange simulations define the most probable Grb2–SOS1 binding mode as simultaneous engagement of both SH3 domains at distinct SOS1 sites. NMR spectroscopy with selective methyl labeling, peptide binding assays, replica-exchange molecular dynamics simulations Journal of the American Chemical Society Medium 31970984
2021 GRB2 displays intramolecular allostery: phosphotyrosine-peptide binding to the SH2 domain potentiates SH3 domain interactions with SOS1 (allosteric mechanism), and the SH2 domain blocks cSH3 to enable sequential nSH3-then-cSH3 binding to SOS1 (avidity-based mechanism), providing mechanistic insight into how RTK activation promotes GRB2–SOS1 complex formation. Biochemical binding assays, NMR, fluorescence polarization with phosphotyrosine peptides and SOS1 fragments The Biochemical journal Medium 34232285
2015 Absence of both Sos1 and Sos2 in peripheral CD4+ T cells increases AKT phosphorylation upon TCR and IL-2 stimulation, likely due to increased PI3K recruitment to Grb2; this elevated PI3K/AKT activity causes downregulation of surface CD62L and impaired T-cell migration. Conditional double-knockout mice, phospho-AKT immunoblotting, PI3K–Grb2 co-immunoprecipitation, CD62L surface staining, T-cell migration assay European journal of immunology Medium 25973715

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nature genetics 449 17143285
2006 Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nature genetics 431 17143282
2020 BI-3406, a Potent and Selective SOS1-KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition. Cancer discovery 345 32816843
1996 SOS1, a Genetic Locus Essential for Salt Tolerance and Potassium Acquisition. The Plant cell 327 12239394
2019 Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. Proceedings of the National Academy of Sciences of the United States of America 314 30683722
2009 Loss of halophytism by interference with SOS1 expression. Plant physiology 170 19571313
2002 A mutation in the SOS1 gene causes hereditary gingival fibromatosis type 1. American journal of human genetics 159 11868160
1996 Identification of the mitogen-activated protein kinase phosphorylation sites on human Sos1 that regulate interaction with Grb2. Molecular and cellular biology 152 8816480
1994 Shc, Grb2, Sos1, and a 150-kilodalton tyrosine-phosphorylated protein form complexes with Fms in hematopoietic cells. Molecular and cellular biology 126 7520523
2004 Abl-dependent tyrosine phosphorylation of Sos-1 mediates growth-factor-induced Rac activation. Nature cell biology 114 15039778
1999 M-Ras/R-Ras3, a transforming ras protein regulated by Sos1, GRF1, and p120 Ras GTPase-activating protein, interacts with the putative Ras effector AF6. The Journal of biological chemistry 102 10446149
2011 SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations. Human mutation 99 21387466
2000 The Sos1 and Sos2 Ras-specific exchange factors: differences in placental expression and signaling properties. The EMBO journal 96 10675333
2010 Intracellular consequences of SOS1 deficiency during salt stress. Journal of experimental botany 95 20054031
2007 SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome. Journal of medical genetics 95 17586837
2008 PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype correlation in Korean patients with Noonan syndrome. Journal of human genetics 82 19020799
2010 Integrity of SOS1/EPS8/ABI1 tri-complex determines ovarian cancer metastasis. Cancer research 79 21118970
2020 Severe Lymphatic Disorder Resolved With MEK Inhibition in a Patient With Noonan Syndrome and SOS1 Mutation. Pediatrics 77 33219052
2022 Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the SOS1:KRAS Protein-Protein Interaction. Journal of medicinal chemistry 76 35833726
2017 SOS1, HKT1;5, and NHX1 Synergistically Modulate Na+ Homeostasis in the Halophytic Grass Puccinellia tenuiflora. Frontiers in plant science 73 28450879
2015 Nax loci affect SOS1-like Na+/H+ exchanger expression and activity in wheat. Journal of experimental botany 71 26585227
2012 RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation. The Biochemical journal 71 22827337
2025 Elemental cryo-imaging reveals SOS1-dependent vacuolar sodium accumulation. Nature 63 39814877
2015 RasGRP1 opposes proliferative EGFR-SOS1-Ras signals and restricts intestinal epithelial cell growth. Nature cell biology 62 26005835
1997 Mutation in Sos1 dominantly enhances a weak allele of the EGFR, demonstrating a requirement for Sos1 in EGFR signaling and development. Genes & development 62 9030684
2010 Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations. Genes, chromosomes & cancer 60 19953625
2009 Enhanced expression of SOS1 is detected in prostate cancer epithelial cells from African-American men. International journal of oncology 57 19724911
2023 Structure and activation mechanism of the rice Salt Overly Sensitive 1 (SOS1) Na+/H+ antiporter. Nature plants 55 37884653
2014 SUMOylation of Grb2 enhances the ERK activity by increasing its binding with Sos1. Molecular cancer 55 24775912
2011 Targeted Sos1 deletion reveals its critical role in early T-cell development. Proceedings of the National Academy of Sciences of the United States of America 55 21746917
2013 Interaction domains of Sos1/Grb2 are finely tuned for cooperative control of embryonic stem cell fate. Cell 54 23452850
2021 One Atom Makes All the Difference: Getting a Foot in the Door between SOS1 and KRAS. Journal of medicinal chemistry 52 33719426
2000 Direct interaction of SOS1 Ras exchange protein with the SH3 domain of phospholipase C-gamma1. Biochemistry 51 10913276
2013 Functional redundancy of Sos1 and Sos2 for lymphopoiesis and organismal homeostasis and survival. Molecular and cellular biology 49 24043312
2014 EGF receptor uses SOS1 to drive constitutive activation of NFκB in cancer cells. Proceedings of the National Academy of Sciences of the United States of America 48 25071181
2014 Rational design of small molecule inhibitors targeting the Ras GEF, SOS1. Chemistry & biology 48 25455859
2015 Constitutive high-level SOS1 expression and absence of HKT1;1 expression in the salt-accumulating halophyte Salicornia dolichostachya. Plant science : an international journal of experimental plant biology 46 25804817
2020 The plasma-membrane polyamine transporter PUT3 is regulated by the Na+ /H+ antiporter SOS1 and protein kinase SOS2. The New phytologist 45 31901205
2009 Characterization of Salt Overly Sensitive 1 (SOS1) gene homoeologs in quinoa (Chenopodium quinoa Willd.). Genome 45 19767895
2022 Development of SOS1 Inhibitor-Based Degraders to Target KRAS-Mutant Colorectal Cancer. Journal of medicinal chemistry 44 36459180
2010 The SOS1 transporter of Physcomitrella patens mediates sodium efflux in planta. The New phytologist 40 20696009
2009 SOS1 and PTPN11 mutations in five cases of Noonan syndrome with multiple giant cell lesions. European journal of human genetics : EJHG 40 19352411
2008 SOS1 mutations are rare in human malignancies: implications for Noonan Syndrome patients. Genes, chromosomes & cancer 38 18064648
2016 Sos1 disruption impairs cellular proliferation and viability through an increase in mitochondrial oxidative stress in primary MEFs. Oncogene 37 27157612
2014 Sos1 regulates sustained TCR-mediated Erk activation. European journal of immunology 37 24497027
2012 Isolation and characterisation of Chrysanthemum crassum SOS1, encoding a putative plasma membrane Na(+) /H(+) antiporter. Plant biology (Stuttgart, Germany) 37 22404736
2007 Germ line gain of function with SOS1 mutation in hereditary gingival fibromatosis. The Journal of biological chemistry 36 17510059
2018 RUNX1 positively regulates the ErbB2/HER2 signaling pathway through modulating SOS1 expression in gastric cancer cells. Scientific reports 35 29686309
2020 High-Affinity Interactions of the nSH3/cSH3 Domains of Grb2 with the C-Terminal Proline-Rich Domain of SOS1. Journal of the American Chemical Society 33 31970984
2017 Targeted Covalent Inhibition of Grb2-Sos1 Interaction through Proximity-Induced Conjugation in Breast Cancer Cells. Molecular pharmaceutics 33 28060514
2010 Noonan syndrome, the SOS1 gene and embryonal rhabdomyosarcoma. Genes, chromosomes & cancer 33 20461756
2023 EIF4A3-mediated circ_0042881 activates the RAS pathway via miR-217/SOS1 axis to facilitate breast cancer progression. Cell death & disease 32 37626035
2019 Identification and Characterization of Oncogenic SOS1 Mutations in Lung Adenocarcinoma. Molecular cancer research : MCR 32 30635434
2017 Phosphorylation of SOS1 on tyrosine 1196 promotes its RAC GEF activity and contributes to BCR-ABL leukemogenesis. Leukemia 32 28819285
2024 SOS1 tonoplast neo-localization and the RGG protein SALTY are important in the extreme salinity tolerance of Salicornia bigelovii. Nature communications 30 38769297
2019 Fucoidan⁻Fucoxanthin Ameliorated Cardiac Function via IRS1/GRB2/ SOS1, GSK3β/CREB Pathways and Metabolic Pathways in Senescent Mice. Marine drugs 30 30669571
2018 MicroRNA 628 suppresses migration and invasion of breast cancer stem cells through targeting SOS1. OncoTargets and therapy 29 30233203
2015 miR-146a and miR-370 coordinate enterovirus 71-induced cell apoptosis through targeting SOS1 and GADD45β. Cellular microbiology 29 25469565
2024 The SOS1 Inhibitor MRTX0902 Blocks KRAS Activation and Demonstrates Antitumor Activity in Cancers Dependent on KRAS Nucleotide Loading. Molecular cancer therapeutics 28 38904222
2023 SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status. Proceedings of the National Academy of Sciences of the United States of America 28 37972068
2000 Refinement of the locus for autosomal dominant hereditary gingival fibromatosis (GINGF) to a 3.8-cM region on 2p21. Genomics 28 10995566
2014 SOS1 and Ras regulate epithelial tight junction formation in the human airway through EMP1. EMBO reports 26 25394671
2022 Discovery of Orally Bioavailable SOS1 Inhibitors for Suppressing KRAS-Driven Carcinoma. Journal of medicinal chemistry 25 36173339
2021 Epigenetic and Posttranscriptional Modulation of SOS1 Can Promote Breast Cancer Metastasis through Obesity-Activated c-Met Signaling in African-American Women. Cancer research 25 33446575
2021 lncRNA DUXAP8 inhibits papillary thyroid carcinoma cell apoptosis via sponging the miR‑20b‑5p/SOS1 axis. Oncology reports 25 33760128
2018 Discovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS. ACS medicinal chemistry letters 25 30258545
2015 Nuclear EGFR impairs ASPP2-p53 complex-induced apoptosis by inducing SOS1 expression in hepatocellular carcinoma. Oncotarget 25 25980493
2010 Decreased expression of FGFR1, SOS1, RAF1 genes in cryptorchidism. Urologia internationalis 25 20389169
2024 Discovery of a Potent Dual Son of Sevenless 1 (SOS1) and Epidermal Growth Factor Receptor (EGFR) Inhibitor for the Treatment of Prostate Cancer. Journal of medicinal chemistry 24 38630077
2021 The intramolecular allostery of GRB2 governing its interaction with SOS1 is modulated by phosphotyrosine ligands. The Biochemical journal 24 34232285
2021 Targeting RAS oncogenesis with SOS1 inhibitors. Advances in cancer research 24 35101230
2020 Discovery of Sulfonamide-Derived Agonists of SOS1-Mediated Nucleotide Exchange on RAS Using Fragment-Based Methods. Journal of medicinal chemistry 24 32673492
1996 Sos1 rapidly associates with Grb2 and is hypophosphorylated when complexed with the EGF receptor after EGF stimulation. Oncogene 24 8649846
2021 Salicylic acid modulates ACS, NHX1, sos1 and HKT1;2 expression to regulate ethylene overproduction and Na+ ions toxicity that leads to improved physiological status and enhanced salinity stress tolerance in tomato plants cv. Pusa Ruby. Plant signaling & behavior 23 34252347
2015 Absence of both Sos-1 and Sos-2 in peripheral CD4(+) T cells leads to PI3K pathway activation and defects in migration. European journal of immunology 23 25973715
2015 Sos1 Regulates Macrophage Podosome Assembly and Macrophage Invasive Capacity. Journal of immunology (Baltimore, Md. : 1950) 23 26447228
2001 The Sos1-Rac1 signaling. Possible involvement of a vacuolar H(+)-ATPase E subunit. The Journal of biological chemistry 23 11560919
2023 Development of Son of Sevenless Homologue 1 (SOS1) Modulators To Treat Cancers by Regulating RAS Signaling. Journal of medicinal chemistry 22 36987571
2022 Knockdown of circRNA-Memo1 Reduces Hypoxia/Reoxygenation Injury in Human Brain Endothelial Cells Through miRNA-17-5p/SOS1 Axis. Molecular neurobiology 22 35041140
2022 Cytotoxicity of combinations of the pan-KRAS SOS1 inhibitor BAY-293 against pancreatic cancer cell lines. Discover oncology 22 36048281
2020 miR-429-CRKL axis regulates clear cell renal cell carcinoma malignant progression through SOS1/MEK/ERK/MMP2/MMP9 pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 22 32413671
2019 Expression and detergent free purification and reconstitution of the plant plasma membrane Na+/H+ antiporter SOS1 overexpressed in Pichia pastoris. Biochimica et biophysica acta. Biomembranes 22 31678368
2018 Structural characterization of 14-3-3ζ in complex with the human Son of sevenless homolog 1 (SOS1). Journal of structural biology 22 29408703
2023 Design, Synthesis, and Bioevaluation of Pyrido[2,3-d]pyrimidin-7-ones as Potent SOS1 Inhibitors. ACS medicinal chemistry letters 20 36793426
2022 Comparing Essentiality of SOS1-Mediated Na+ Exclusion in Salinity Tolerance between Cultivated and Wild Rice Species. International journal of molecular sciences 19 36077294
2018 Footprints of divergent evolution in two Na+/H+ type antiporter gene families (NHX and SOS1) in the genus Populus. Tree physiology 17 29394412
2016 SOS1, ARHGEF1, and DOCK2 rho-GEFs Mediate JAK-Dependent LFA-1 Activation by Chemokines. Journal of immunology (Baltimore, Md. : 1950) 17 27986909
2012 Modeling and simulation of aggregation of membrane protein LAT with molecular variability in the number of binding sites for cytosolic Grb2-SOS1-Grb2. PloS one 17 22396725
2022 SOS1 regulates HCC cell epithelial-mesenchymal transition via the PI3K/AKT/mTOR pathway. Biochemical and biophysical research communications 16 36403479
2020 14-3-3 Proteins and Other Candidates form Protein-Protein Interactions with the Cytosolic C-terminal End of SOS1 Affecting Its Transport Activity. International journal of molecular sciences 16 32397251
2009 Isoform-selective interaction of the adaptor protein Tks5/FISH with Sos1 and dynamins. Journal of molecular biology 16 19464300
2019 Small Molecule SOS1 Agonists Modulate MAPK and PI3K Signaling via Independent Cellular Responses. ACS chemical biology 15 30735352
2019 Inhibitory short peptides targeting EPS8/ABI1/SOS1 tri-complex suppress invasion and metastasis of ovarian cancer cells. BMC cancer 15 31488087
2024 A Potent SOS1 PROTAC Degrader with Synergistic Efficacy in Combination with KRASG12C Inhibitor. Journal of medicinal chemistry 14 38316747
2022 PPDPF Promotes the Development of Mutant KRAS-Driven Pancreatic Ductal Adenocarcinoma by Regulating the GEF Activity of SOS1. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 14 36453576
2019 miR-152-3p Sensitizes Glioblastoma Cells Towards Cisplatin Via Regulation Of SOS1. OncoTargets and therapy 14 31807027
2025 SOS1 Inhibition Enhances the Efficacy of KRASG12C Inhibitors and Delays Resistance in Lung Adenocarcinoma. Cancer research 13 39437166
2021 Sos1 Modulates Extracellular Matrix Synthesis, Proliferation, and Migration in Fibroblasts. Frontiers in physiology 13 33889087
2019 SOS1 mutations in Noonan syndrome: Cardiomyopathies and not only congenital heart defects! Report of six patients including two novel variants and literature review. American journal of medical genetics. Part A 13 31368652
2015 Differential allelic expression of SOS1 and hyperexpression of the activating SOS1 c.755C variant in a Noonan syndrome family. European journal of human genetics : EJHG 13 25712082

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