Abstract
RAF protein kinases are major RAS effectors that function by phosphorylating MEK. Although all three RAF isoforms share a conserved RAS binding ___domain and bind to GTP-loaded RAS, only ARAF uniquely enhances RAS activity. Here we uncovered the molecular basis of ARAF in regulating RAS activation. The disordered N-terminal sequence of ARAF drives self-assembly, forming ARAF–RAS condensates tethered to the plasma membrane. These structures concentrate active RAS locally, impeding NF1-mediated negative regulation of RAS, thereby fostering receptor tyrosine kinase (RTK)-triggered RAS activation. In RAS-mutant tumors, loss of the ARAF N terminus sensitizes tumor cells to pan-RAF inhibition. In hormone-sensitive cancers, increased ARAF condensates drive endocrine therapy resistance, whereas ARAF depletion reverses RTK-dependent resistance. Our findings delineate ARAF–RAS protein condensates as distinct subcellular structures sustaining RAS activity and facilitating oncogenic RAS signaling. Targeting ARAF–RAS condensation may offer a strategy to overcome drug resistance in both wild-type and mutant ARAF-mediated scenarios.
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Data availability
There are no restrictions on data availability in this paper. All data reporting the findings of this study are included in the article and within the source data found in the Supplementary Information. The METABRIC database is available through https://www.cbioportal.org/study/summary?id=brca_metabric; TCGA datasets are available through https://www.cbioportal.org/study/summary?id=prad_tcga_pan_can_atlas_2018 and https://www.cbioportal.org/study/summary?id=brca_tcga_pan_can_atlas_2018. Source data are provided with this paper.
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Acknowledgements
We thank H. Lu, W. Zhang, D. Fang and W. Fan (Life Sciences Institute, Zhejiang University) for sharing the GFP–TAZ plasmid, the MDA-MB-415 cells, the ES-E14TG2a cells and antibodies and G. Xu (National Institute of Biological Sciences, Beijing) for sharing the MCF7 cells. We thank L. Zhang and J. Huang (Life Sciences Institute, Zhejiang University) for discussions and suggestions for revision. We thank J. Ma for SPR technical support and are grateful to our colleagues at the core facility of the Life Sciences Institute for assistance with molecular and cell imaging analysis. This research was partly supported by the National Key R&D Program of China (2022YFA1305800 to W.S.); the National Natural Science Foundation of China (grants 32370754 to W.S. and 82151216/82473975 to W.X.); the Zhejiang Provincial National Science Foundation of China (LZ24H160002 to W.S.); and the Fundamental Research Funds for the Central Universities.
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W.S. conceived the hypothesis, designed the experiments and wrote the manuscript. W.X. designed and analyzed the in vitro assays and contributed to manuscript editing. W.L. and X.S. performed and analyzed most of the experiments. C.T. performed protein purification and in vitro assays. Z. Jiang performed immunogold labeling and electron microscopy analysis. M. Li, Z. Ji, J.Z., M. Luo, Z.F., Z.D. and Y.F. performed part of the experiments. J.S. and J.D. contributed to biophysical analysis of peptides. H.L. and W.M. contributed to data analysis.
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Extended data
Extended Data Fig. 1 ARAF forms solid-like granules at the plasma membrane.
a, HeLa cells were transfected with indicated plasmids. Images were taken (left) and percentages of cells with PM signals were quantified, n = 3 (right). Scale bar, 10 μm. b, HeLa cells were transfected with ARAF-GFP. Cells were then stained with CellMask plasma membrane dye and images were taken. Scale bar, 5 μm. c, Immunofluorescent staining in SKBR3 cells to validate antibody specificity. Scale bar, 5 μm. d, Immunofluorescent staining in HeLa cells. Images were taken (left), percentages of cells with PM signals were quantified, n = 3 (right). Scale bar, 10 μm. e, Immunofluorescent staining in MEF and ES-E14TG2a cells. Images were taken (left), percentages of cells with PM signals were quantified, n = 3 (right). Scale bar, 5 μm. f, HeLa cells were subjected to subcellular fractionation followed by western blot (left). PM and cytosolic protein levels were quantified by Image J, n = 3 (right). g, h, HeLa (g) or MCF7 (h) cells were subjected to subcellular fractionation, cell extracts were resolved by SDD-AGE (top) and SDS-PAGE (bottom). Immunoblots are representative of three independent experiments in f, g, h. Error bars denote the mean ± SD (biological replicates), and statistical analyses were performed using unpaired two-tailed Student’s t-test in a, d, e, f.
Extended Data Fig. 2 N-terminal disordered sequence of ARAF drives PM clustering.
a, 293FT cells transfected with indicated constructs were subjected for active RAS pulldown and western blot analysis. b, SKBR3 cells were transfected with indicated plasmids. Images were taken (left), percentages of cells with PM signals were quantified, n = 3 (right). Scale bar, 5 μm. c, Schematic representation of ARAF mutations identified in human cancers from cBioportal. d, 293FT cells transfected with NRAS and indicated constructs were collected and NRAS was immunoprecipitated. e, SKBR3 transfected with ARAF 255-GFP were stained with CellMask PM dye. Scale bars, 5 μm. f, ARAF 255 granule persistence after 5 minutes of 5% hexanediol treatment. Images were taken (left), percentages of remaining puncta signals were quantified, n = 5 (right). Scale bar, 5 μm. g, SKBR3 cells transfected with indicated plasmids were subjected for imaging (left), percentages of cells with PM signals were quantified, n = 3 (right). Scale bar, 5 μm. h, Immunofluorescent staining in HeLa and MCF7 cells. Scale bar, 5 μm. i, PM sub-localization of signaling components in SKBR3 cells were examined by western blot. j, ARAF or ARAF 255 granule persistence after 24 hours lapatinib or SHP099 treatment. Images were taken (left), percentages of remaining puncta signals were quantified, n = 3 (right). Scale bar, 5 μm. Immunoblots are representative of three independent experiments in a, d, i. Error bars denote the mean ± SD (biological replicates), and statistical analyses were performed using unpaired two-tailed Student’s t-test in b, f, g, j.
Extended Data Fig. 3 N-terminal disordered sequence of ARAF drives PM clustering.
a, SKBR3 cells co-transfected with indicated plasmids were subjected for imaging. Scale bar, 5 μm. b, Upper panel, schematic representation of engineered GFP fusion proteins. Lower panel, images of SKBR3 cells transfected with the indicated plasmids. Scale bar, 5 μm. c, SKBR3 cells transfected with indicated ARAF 255 mutants were subjected for imaging (left), percentages of cells with PM signals were quantified, n = 3 (right). Scale bars, 5 μm. d, Circular dichroism spectroscopy analysis of the biophysical properties of chemically synthesized the N-terminal region of ARAF and a series of its mutants. e, NIH3T3 cells expressing WT ARAF together with increasing amounts of ARAF P/F mutant were subjected for immunoprecipitation. f, NIH3T3 cells expressing indicated constructs were subjected to subcellular fractionation, PM fractions were resolved by SDD-AGE (top) and SDS-PAGE (bottom). Immunoblots are representative of three independent experiments in e, f. Error bars denote the mean ± SD (biological replicates), and statistical analyses were performed using unpaired two-tailed Student’s t-test in c.
Extended Data Fig. 4 ARAF’s N terminus mediates ARAF-RAS granule formation.
a, 5 μM GFP-tagged proteins were incubated for 60 minutes. Images were taken (left), granule numbers were quantified, n = 3 (right). Scale bar, 5 μm. Error bars, mean ± SD (biological replicates), unpaired two-tailed Student’s t-test. b, Plot of association rate (x-axis) and dissociation rate (y-axis) of RAF variants. Dotted lines refer to equilibrium affinity constants (KD) calculated from the on- and off rates. c, SPR binding analysis for the interactions of ARAF variants with GTP-γ-S loaded K, N, and H-RAS. Data were fitted using a 1:1 kinetic binding model. d, SPR binding analysis for the interactions of BRAF and CRAF variants with GTP-γ-S loaded K, N, and H-RAS. Data were fitted using a 1:1 kinetic binding model.
Extended Data Fig. 5 ARAF’s N terminus mediates ARAF-RAS granule formation.
a, 5 μM mCherry-RAS proteins were incubated with 5 μM ARAF 255 ∆N-GFP for 60 minutes. Images were taken. Scale bar, 5 μm. b, 5 μM mCherry-RAS proteins were incubated with 5 μM ARAF 255 or ARAF 255 ∆N for 60 minutes. Images were taken (left), scale bar, 5 μm. Granule numbers were quantified, n = 3 (right). Error bars, mean ± SD (biological replicates), unpaired two-tailed Student’s t-test. c, 5 μM mCherry-RAS proteins were incubated with 5 μM ARAF 255BF-GFP for 60 minutes. BF, RAS binding deficient. Images were taken. Scale bar, 5 μm. d, 5 μM mCherry-RAS proteins were incubated with 5 μM GFP-NF1 GRD for 60 minutes. Scale bar, 5 μm. e, f, 2.5 μM Alexa fluor 647-labeled ARAF 255 were incubated with 2.5 μM indicated RAS proteins (e) or GFP-NF1 GRD (f) for 60 minutes. Scale bar, 5 μm.
Extended Data Fig. 6 Plasma membrane assembly of ARAF drives RAS activation.
a, SKBR3 cells co-transfected with indicated plasmids were subjected for imaging. Scale bar, 5 μm. b, NIH3T3 cells transfected with the indicated plasmids were subjected for active RAS pulldown (upper panel). The corresponding N-terminal disorder probabilities of ARAF mutants were shown in the lower panel. c, NIH3T3 cells stably expressing RAS variants were transfected with ARAF. RAS-GTP levels were examined (left) and quantified, n = 3 (right). Immunoblots are representative of three independent experiments in b, c. Error bars denote the mean ± SD (biological replicates), and statistical analyses were performed using unpaired two-tailed Student’s t-test in c.
Extended Data Fig. 7 Plasma membrane assembly of ARAF drives RAS activation.
a, b, Immunofluorescent staining in SKBR3 cells transfected with indicated constructs. Images were taken (a), percentages of cells with PM RAS signals were quantified, n = 3 (b). None, no membrane RAS signal; partial PM, discontinuous signals covering <50% of PM area; uniform PM, continuous signals covering > 60% of PM area. Scale bar, 5 μm. c, Immunofluorescent staining in SKBR3 cells transfected with indicated constructs. Images were taken (left), percentages of cells with PM RAS signals were quantified, n = 3 (right). Scale bar, 5 μm. d, SKBR3 cells transfected with the indicated plasmids were subjected for imaging (left), scale bar, 5 μm. Percentages of cells with PM signals were quantified, n = 3 (right). Error bars, mean ± SD (biological replicates), unpaired two-tailed Student’s t-test. e, 293FT cells transfected with the indicated plasmids were subjected for active RAS pulldown. Immunoblots are representative of three independent experiments.
Extended Data Fig. 8 ARAF N terminus loss boosts effect of RAF dimer inhibitors.
a, A549 and MIA PaCa-2 isogenic clones were subjected to western blot. b, Isogenic A549 cells were subjected to endogenous CRAF immunoprecipitation. c, Genetically engineered MIA PaCa-2 cells were treated with Belvarafenib or Naporafenib for 72 hours. Cell survival was normalized to untreated controls, n = 6. Drug concentrations inducing 50% inhibition in survival (IC50 nmol/L) are indicated. d, Genetically engineered MIA PaCa-2 cells were treated with Belvarafenib or Naporafenib for 1 hour. ERK pathway activities were examined by western blot. e, Genetically engineered MIA PaCa-2 cells treated with the indicated compounds were subjected for growth analysis, n = 6. f, Colony formation assay in the engineered MIA PaCa-2 cells treated with either vehicle, Belvarafenib or Naporafenib. The colonies were stained with crystal violet. g, Engineered MIA PaCa-2 cells were subcutaneously injected into nude mice. Mice were treated with either vehicle, Belvarafenib (30 mg/kg once a day) or Naporafenib (100 mg/kg once a day). Bars, mean ± SEM, n = 5. Immunoblots are representative of three independent experiments in a, b, d. Error bars denote the mean ± SD (biological replicates) in c, e.
Extended Data Fig. 9 ARAF condensates drive RTK-related cancer drug resistance.
a, MCF7 cells were treated with HRG for the indicated time points. Immunoblots are representative of three independent experiments. b, MCF7 cells treated with HRG for the indicated time points were subjected for imaging (left). Percentages of cells with PM signals were quantified, n = 3 (right). Scale bar, 5 μm. c, MCF7 cells transfected with indicated siRNAs were subjected for HRG-induced differentiation. Images were taken, bar, 50 μm (left). Oil Red staining was quantified, n = 3 (right). d, e, MDA-MB-415 cells transfected with the indicated siRNAs were subjected to cell growth, n = 4 (d) or colony formation analysis, n = 4 (e). f, MCF7 cells stably expressing the indicated constructs were subjected for HRG-induced differentiation. Images were taken, bar, 50 μm (left). Oil Red staining was quantified, n = 3 (right). g, h, 22RV1 cells transfected with the indicated siRNAs were subjected to cell growth, n = 5 (g) or colony formation analysis, n = 3 (h). i, LNCaP cells stably expressing the indicated constructs were subjected for cell growth analysis, n = 5 control and ARAF, n = 4 P/F. j, Colony formation assay in the infected LNCaP cells treated with enzalutamide, n = 4. Error bars denote the mean ± SD (biological replicates), and statistical analyses were performed using unpaired two-tailed Student’s t-test in b, c, d, e, f, g, h, i, j.
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Li, W., Shi, X., Tan, C. et al. Plasma membrane-associated ARAF condensates fuel RAS-related cancer drug resistance. Nat Chem Biol (2025). https://doi.org/10.1038/s41589-024-01826-8
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DOI: https://doi.org/10.1038/s41589-024-01826-8
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