Abstract
Biomolecular condensates have been proposed to mediate cellular signaling transduction. However, the mechanism and functional consequences of signal condensates are not well understood. Here we report that LATS2, the core kinase of the Hippo pathway, responds to F-actin cytoskeleton reduction and forms condensates. The proline-rich motif (PRM) of LATS2 mediates its condensation. LATS2 partitions with the main components of the Hippo pathway to assemble a signalosome for LATS2 activation and for its stability by physically compartmentalizing from E3 ligase FBXL16 complex-dependent degradation, which in turn mediates yes-associated protein (YAP)–transcriptional coactivator with PDZ-binding motif (TAZ) recruitment and inactivation. This oncogenic FBXL16 complex blocks LATS2 condensation by binding to the PRM region to promote its degradation. Disruption of LATS2 condensation leads to tumor progression. Thus, our study uncovers that the signalosomes assembled by LATS2 condensation provide a compartmentalized and reversible platform for Hippo signaling transduction and protein stability, which have potential implications in cancer diagnosis and therapeutics.
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Data availability
All data supporting the findings of this work are provided within the text and its related source data. Additional resources and reagents (including commonly used plasmids and their sequences) that support the findings of this research are available upon request from the corresponding author (S.S.). The AlphaFold Protein Structure Database29 is at https://www.alphafold.ebi.ac.uk. The BioGRID40 database is at https://thebiogrid.org. Source data are provided with this paper.
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Acknowledgements
We thank K. Irvine, L. Zhang and C. Chen for sharing reagents. This research was supported by the Ministry of Science and Technology of China (2020YFA0803201) and the National Natural Science Foundation of China (32270762, 82002972 and 82273064). We thank the Laboratory Animal Center of Huazhong University of Science and Technology for providing mouse culture support.
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M.Q., E.G., M.Y, T.D., S.L., X.Z., J.Li, H.Z., X.C. and M.S. contributed to LATS2 phase-separation property investigation and molecular and cellular function determination in cultured cells; Y.L. and J.W. contributed to protein purification from bacteria and in vitro phase-separation analysis of LATS2; M.W., L.C. and L.H. contributed to human sample analysis; S.S., Y.L., X.Y. and B.Z. contributed to experimental design, data analysis and manuscript preparation.
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Extended data
Extended Data Fig. 1 LATS2 forms puncta during cytoskeletal reorganization.
a, Representative images of agarose gel for checking the insertions of 3XHA in MCF10A cell line. b, Western blots performed on the cell lysates of indicated genotype with or without transfecting siLATS2 and stained for HA and LATS2. c, Western blot performed on the lysates of 3XHA knockin MCF10A cell lines and stained for HA. d, Western blots of coprecipitations of LATS2-3XHA with YAP from HEK293T cell lysates of MCF10A-LATS2-3XHA, blotted with LATS2, and YAP antibodies. e, Representative images of LATS2-3XHA knockin cells stained for HA (red), E-cad/LIMD1 (green), and nuclei (blue). f, g, Western blot performed on the lysates of MCF10A-LATS2-3XHA cell line treated by LatB (g) and trypsin (h), stained for p-LATS and p-YAP. h, Representative confocal sections of MCF10A-LAST2-3XHA cell line treated by FBS starvations of 24 h and stained for HA (red) and nuclei (blue). i, RT-qPCR examinations for detect the knockdown efficiency of MST1 and MST2. n = 3 independent experiments. j, The confocal images of MCF10A- LATS2-3XHA cells with double knockdown of MST1/2 treated by trypsin and stained for HA (red), F-actin (green), and nuclei (blue). Data are presented as mean ± SEM. Significant differences are labelled; One-way ANOVA was used for i statistical analysis. **P < 0.01, ***P < 0.001, ****P < 0.0001. Scale bars, 5 µm as indicated. β-actin was used for loading control.
Extended Data Fig. 2 LATS2 as scaffold protein mediates its condensations by PRM.
a, The puncta quantitation of AD293 cells transfected by mEGFP, mEGFP-LATS2, Flag-LATS2, and HA-LATS2. n = 5 cells, thee histogram shows the puncta number of individual AD293 cells; the scatter plot shows the puncta size of individual AD293 cells with indicated plasmids transfection. b, Live imaging assay and typical images of AD293 cells with transfection of mEGFP-LATS2. The red rectangles labeled the fusion events, also see Supplementary Video 3. c, The puncta quantitation of AD293 cell with transfection of mEGFP-LATS2 treated by DMSO, 3% 1,6 Hex, and 3% 2,5 Hex respectively. The percentage of cells with cytoplasmic puncta were acquired from three random views. The puncta number were calculated in 5 cells. d, The puncta quantitation of AD293 cells expressing indicated LATS2 deletions (green) and stained for nuclei. The histograms showed the mean percentage of cell with puncta from three random views and mean puncta in 5 cells; the scatter plot showed the puncta size of indicated mEGFP-LATS2 deletions in 5 cells. e, The puncta quantitation of AD293 cells expressing indicated LATS2 mutations (green) and stained for nuclei. The histograms showed the mean percentage of cell with puncta from three random views and mean puncta number in 5 cells. f, FRAP assay of AD293 cells expressing LATS2-PRM-mCherry-Cry2. The representative images of pre-bleach, bleach, and post-bleach were shown and the red and yellow rectangles marked the bleach and control puncta. The plot is the quantitation of dynamic intensity of bleached and control puncta. The experiments were performed three independent times. Also see Supplementary Video 8. g, Live imaging traces the LATS2-PRM-mCherry-Cry2 puncta after 488 nm laser illumination. The representative images were shown and the green rectangle marked the fusion puncta. Also see Supplementary Video 8. h, FRAP assay of LATS2-PRM -Cy3. The representative images of pre-bleach, bleach, and post-bleach were shown and the red and yellow rectangles marked the bleach and control puncta. The plot is the quantitation of dynamic intensity of bleached and control puncta. The experiments were performed three independent times; also see Supplementary Video 10. Data are presented as mean ± SEM. Significant differences are labelled; One-way ANOVA was used for c statistical analysis. ***P < 0.001, ****P < 0.0001, ****P < 0.0001. Scale bars, 5 µm or 10 µm as indicated.
Extended Data Fig. 3 LATS2 condensates mediate signaling and protein stability.
a, Typical Confocal images of AD293 cells expressing indicated mEGFP fused Hippo pathway components (green) stained for nuclei (blue). b, Typical confocal images of AD293 cells co-expressing mEGFP-LATS2 (green) with TAZ forms (red) stained for nuclei (blue). c, Typical confocal images of MCF10A-LATS2-3XHA expressing indicated mEGFP fused Hippo pathway components treated by trypsin and stained for HA (red) and nuclei (blue). d, The histogram shows the quantitation of the ratio of cytoplasmic via nuclear YAP in Fig. 3c. n = 3, images acquired from three random views. e, Western blot assay for examining p-LATS and p-YAP in HEK293Tcells with indicated transfections of LATS2 forms. f, 3D simulation HA puncta by Imaris from Fig. 3e. Data are presented as mean ± SEM. Scale bars, 5 µm as indicated. β-actin was used for loading control.
Extended Data Fig. 4 LATS2 condensates mediate signaling and protein stability.
a, c, The histograms showed the quantitation of HA or YAP intensity of Fig. 3d and Fig. 3f. n = 3, images acquired from three random views. b, Western blot assay for examine endogenous LATS2 of MCF10A 3XHA cells seeded in FN coated or noncoated conditions. The histograms showed the quantitation of relative intensity. n = 3, blots across three independent experiments. d, Western blot assay to confirm LATS1/2 double knockout. e, HEK293T cells of WT (upper) and LATS1/2-/- (low) expressing mEGFP-LATS2-N (green) and stained for YAP (red) and nuclei (blue). f, g, Representative images of Hela cells overexpressing mEGFP-LATS2-N (left); Representative western blots (middle) and results of quantitation (right) from Hela cells overexpressing mEGFP-VEC, mEGFP-LATS2-N and stained for LATS2 and GFP. n = 3, blots across three independent experiments. Data are presented as mean ± SEM. Significant differences are labelled; Two-tailed student’s t-test was used for statistical analysis. **P < 0.01, ***P < 0.001. Scale bars, 5 µm as indicated. β-actin was used for loading control.
Extended Data Fig. 5 Identifications of E3 ligase inhibiting LATS2 condensations.
a, The candidate E3 ligase list to LATS2 from BioGRID database. b, c, Representative images of AD293 cells expressing mEGFP-LATS2 (green) with mCherry fused indicated E3 ligases (red) and stained for nuclei (blue). The histogram showed the mean percentage of cells with cytoplasmic LATS2 condensates. n = 3, images acquired from three random views. d, Western blots of coprecipitation of CUL7 and indicated FBXL16 fragments in HEK293T cell lysates expressing HA-CUL7 with indicated Flag tagged FBXL16 fragments, stained for Flag and HA. e, Western blots of coprecipitation of FBXL16 and indicated CUL7 fragments in HEK293T cell lysates expressing Flag-FBXL16 with indicated HA tagged CUL7 fragments, stained for Flag and HA. f, Western blots of coprecipitation of FBXL16 with LATS2-N or LATS2-C in 293T cell lysates expressing HA-LATS2-N and HA-LATS2-C with Flag-FBXL16, stained for HA and Flag. Data are presented as mean ± SEM. β-actin was used for loading control in western blot. Scale bars, 5 μm as indicated.
Extended Data Fig. 6 E3 ligase FBXL16 inhibits LATS2 condensations.
a, b, Western blot of MDA-MB-231 cell lysates expressing VEC or FBXL16 and CUL7 proteins and stained for FBXL16 or CUL7 antibodies. β-actin was used for loading control in western blots. c, d, The histogram showed the relative mean intensity of Fig. 5a, b. n = 3, blots across three independent experiments. e, Ubiquitylation assay in cells. Flag-LATS2 was precipitated from HEK293T cells co-expressing Flag-LATS2 with indicated proteins in the presence of MG132 by immunoprecipitation using an anti-Flag antibody; LATS2 ubiquitylation was detected by western blotting. f, Knockdown FBXL16 in MDA-MB-231 cells to detect the LATS2 ubiquitylation level. The blot stained for Ub, LATS2, and FBXL16 antibodies. g, The list of lysine residues potentially ubiquitylated by E3 ligase were predicted through online tool (http://bdmpub.biocuckoo.org/). The amino acid position, peptides, and scores were shown. h, Alignment of LATS2 sequence from different species showing the potential ubiquitylated target sites (shown in black bold). i, The histogram showed the mean percentage of cells with cytoplasmic LATS2 condensates in l. n = 3, images acquired from three random views. j, Western blots of HEK293T cell lysates expressing Flag-LATS2 with SIAH2 or FBXL16 stained for Flag and MYC antibodies. k, Representative images of AD293 cells co-transfected mEGFP-LATS2 with indicated proteins and stained for Flag tag (red) and nuclei (blue). Data are presented as mean ± SEM. Significant differences are labelled; Two-tailed student’s t-test was used for statistical analysis. **P < 0.01, ***P < 0.001. Scale bars, 5 µm as indicated. β-actin was used for loading control.
Extended Data Fig. 7 FBXL16 drives tumor progression by inhibiting Hippo pathway.
a, The histogram shows the alternation frequency of FBXL16 in breast cancer patients based on TCGA database. b, c, The mRNA expression analysis of FBXL16 in tumor and normal tissues in invasive breast cancers from TCGA database. n = 1222. Box plot represents the 25th percentile, median, 75th percentile and whiskers represent the maxima and minima. d, Representative IHC staining of FBXL16 and YAP in tissue chips of invasive breast cancers patients. The plot shows Pearson correlation between FBXL16 and YAP in lung cancer from left IHC. Correlation analysis was performed by linear regression analysis in graphpad software. Statistical significance (p values) was calculated using two tailed correlation tests. e, f, MDA-MB-231 cells with indicated genotypes were plated for 6–7 d (n = 3 independent experiments); The histogram showed the average percentile of colony counts. n = 3 independent experiments. g, The cytometric flow assay for the cell cycle distribution of WT, FBXL16, CUL7 and FBXL16 + CUL7 expressing cells are shown. Quantization of flow cytometry data according to cell cycle phase for the indicated groups. n = 3 independent experiments. h, Relative mRNA level examination by RT-qPCR in MDA-MB-231 cell lines expressing indicated shRNAs targeting FBXL16. n = 3 independent experiments. i, Western blots for examining the proteins of FBXL16 in the lysates. β-actin was used for loading control. j, The xenograft tumor formation assay of MDA-MB-231 cells with the indicated genotypes. Representative quantification of tumor volume in indicate timepoints and final tumor weights were shown. n = 3 mice each group. Data are presented as mean ± SEM. Two-tailed student’s t-test was used for b, c statistical analysis. Statistical significance for d were calculated using Two tailed correlation test. 95% confidence intervals was selected for parameters. One-way ANOVA was used for e, f statistical analysis. **P < 0.01, ***P < 0.01, n.s., no significance. Scale bars, 100 μm as indicated.
Extended Data Fig. 8 Disruption of LATS2 phase separation promotes tumor progression.
a, b, The plate clone (a) and soft agar (b) assays of HEK293T cells with indicated genotypes were performed. Representative photographs (left) and quantification (right) are shown. n = 3, images acquired from three random views. c, Anoikis assay of HEK293T cells with indicated genotypes. The cells were seeded in polyhema coated surface for 24 h and stained for Calcein-AM (green) and EthD-1 (red). n = 3, images acquired from three random views. Data are presented as mean ± SEM. One-way ANOVA was used for a, b statistical analysis. **P < 0.01, ***P < 0.001, ****P < 0.0001, n.s., no significance. Scale bars, 20 μm and 200 μm as indicated.
Supplementary information
Supplementary Information
Supplementary Tables 1–4
Supplementary Video 1
Three-dimensional simulations of LATS2 formed submicrometer-sized punctate structures in the cytoplasm after AD293 cells were treated with LatB.
Supplementary Video 2
Three-dimensional simulations of LATS2 formed submicrometer-sized punctate structures in the cytoplasm in many discrete tumor cells.
Supplementary Video 3
Three-dimensional simulations of LATS2 formed submicrometer-sized punctate structures in the cytoplasm in AD293 cells transfected to express mEGFP–LATS2.
Supplementary Video 4
Recording of fluorescence signal of LATS2 recovered after photobleaching.
Supplementary Video 5
Recording of the fusion of individual puncta of LATS2.
Supplementary Video 6
Recording of the optoDroplet assay of cells expressing mCherry–CRY2.
Supplementary Video 7
Recording of the optoDroplet assay of cells expressing mCherry–LATS2-PRM–CRY2.
Supplementary Video 8
Recording of the FRAP assay of mCherry–LATS2-PRM–CRY2.
Supplementary Video 9
Recording of the FRAP assay of MBP–LATS2-PRM–mEGFP.
Supplementary Video 10
Recording of the FRAP assay of Cy3–LATS2-PRM.
Source data
Source Data Fig. 1
Unprocessed western blots.
Source Data Fig. 2
Analysis of protein sequencing by PONDR software, conserved domains of LATS2 and the PRM region of LATS2.
Source Data Fig. 3
IF colocalization analysis.
Source Data Fig. 4
Unprocessed western blots.
Source Data Fig. 5
Unprocessed western blots.
Source Data Fig. 6
Unprocessed western blots.
Source Data Extended Data Fig. 1
Gene sequencing results and unprocessed western blots.
Source Data Extended Data Fig. 3
IF colocalization analysis and unprocessed western blots.
Source Data Extended Data Fig. 4
Gene sequencing results and unprocessed western blots.
Source Data Extended Data Fig. 5
Unprocessed western blots.
Source Data Extended Data Fig. 6
Unprocessed western blots.
Source Data Extended Data Fig. 7
Unprocessed western blots.
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Qin, M., Geng, E., Wang, J. et al. LATS2 condensates organize signalosomes for Hippo pathway signal transduction. Nat Chem Biol 20, 710–720 (2024). https://doi.org/10.1038/s41589-023-01516-x
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DOI: https://doi.org/10.1038/s41589-023-01516-x