Abstract
The transcriptional coactivator Yes-associated protein 1 (YAP) orchestrates a proproliferative transcriptional program that controls the fate of somatic stem cells and the regenerative responses of certain tissues. As such, agents that activate YAP may hold therapeutic potential in disease states exacerbated by insufficient proliferative repair. Here we report the discovery of a small molecule, termed PY-60, which robustly activates YAP transcriptional activity in vitro and promotes YAP-dependent expansion of epidermal keratinocytes in mouse following topical drug administration. Chemical proteomics revealed the relevant target of PY-60 to be annexin A2 (ANXA2), a protein that directly associates with YAP at the cell membrane in response to increased cell density. PY-60 treatment liberates ANXA2 from the membrane, ultimately promoting a phosphatase-bound, nonphosphorylated and transcriptionally active form of YAP. This work reveals ANXA2 as a previously undescribed, druggable component of the Hippo pathway and suggests a mechanistic rationale to promote regenerative repair in disease.
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Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request. RNA-seq data that support the findings of this study have been deposited in GEO with the accession code GSE164801. Source data are provided with this paper.
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Acknowledgements
This work was supported by the Skaggs Institute for Chemical Biology and Calibr. We thank A. Davila and members of the compound management group at Calibr for excellent technical assistance.
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Contributions
S.Z.S. performed mouse experiments, isothermal titration calorimetry, biolayer interferometry experiments and primary keratinocyte proliferation experiments. P.-Y.Y. performed pilot screens, identified hit compounds, synthesized chemical analogs and designed and identified PY-60 and PY-PAP. E.M.G. expressed all recombinant proteins and performed reporter assays. K.N. performed fluorescence polarization experiments. S.S. performed proliferation assays and gene expression experiments. C.Z. synthesized the PY-60 and PY-PAP used in this work. J.I. and S.R.C. constructed and prepared expression vectors. P.-Y.Y., E.C., S.L. and M.H. performed the high-throughput chemical screens and validated hit compounds. L.I. retrieved historical expression data from skin. C.S. performed docking studies. M.J.B. carried out the target identification work, performed imaging, did in situ target engagement work, performed RNA-seq, did immunoprecipitation experiments, performed RT–qPCR experiments and performed all immunoblotting. S.Z.S., P.-Y.Y., E.M.G., K.N., S.S., L.I., C.S., E.C., S.L., M.H. and M.J.B. analyzed primary data. P.-Y.Y., W.S., P.G.S. and M.J.B. conceived the project idea. M.D. and X.W. contributed the reporter cell line and experimental advice on evaluation of expression data. A.K.C and P.-Y.Y. designed chemical analogs. A.K.C., W.S., F.D.C., P.G.S. and M.J.B. supervised the work. S.Z.S., F.D.C., P.G.S. and M.J.B. wrote the paper.
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Extended data
Extended Data Fig. 1 PY-60 activates a robust, YAP- dependent transcriptional program in multiple cell types.
a, 14xTEAD-LUC assay, comparing PY-60 treatment (10 µM) to concomitant siRNA-mediated NF2/LATS1/2 knockdown (n=3, mean and s.d.). b, BRET ratio of the TEAD-YAP interaction (mBU = BRET units; n=3, mean and s.d.), comparing PY-60 treatment (10 µM) to NF2/LATS1/2 siRNA treatment. c, Luminance values from a split luciferase assay measuring the association of between YAP and TEAD in the presence of PY-60 (n=3, mean and s.d.) d, Nuclear to cytoplasmic ratios of anti- YAP immunofluorescence intensities from high content image analysis from MDCK cells at the indicated cell densities (cells per well in 384-well plates) for 48 hours with PY-60 (10 µM; mean and s.d.). e-h, Transcript levels of YAP-controlled genes from human cell lines treated with PY-60 for 24 hours (n=3, mean and s.d.). i, TEAD- LUC activity in response to PY-60 treatment (n=3; mean and s.e.m.) and Western blots of YAP knockdown from 293A cells with stably integrated shRNAs that are non- targeting (scramble) or that target YAP1. j, Transcript levels of YAP dependent genes or YAP1 itself and anti- YAP Western blot analysis in response to PY-60 treatment (10 µM; n=3, mean and s.d.; perecentage indicative of transcript knockdown) in 293A cells with stable shRNAs that are non-targeting (scramble) or targeting YAP1 (univariate two-sided t-test; NS= not statistically significant). Exeriments are mean and s.d. or s.e.m. as noted of biologically independent samples. Western blots (i, j) are representative of experimental replicates (n = 2).
Extended Data Fig. 2 PY-60 promotes anchorage- and contact inhibition- independent growth of epithelial cell lines.
a, Quantification and representative images of MCF10A colonies formed in soft agar after 2-week treatment with PY-60 (n=3, mean and s.e.m.,univariate two sided t-test; scale bar = 100 µm). b, Representative confocal images (n = 4) of MDCK cells treated with DMSO or PY-60 (10 µM) for 10 days and stained with Hoechst 33342 (DNA) and Phalloidin-488 (F-actin), depicting the loss cell contact inhibition of growth (scale bar = 5 µm). c, Relative transcript levels of Yap1 and Taz from mouse skin, epidermis, and primary keratinocytes from publicly available RNA-seq data accessed from the indicated GEO database entries (n=3 biologically ditinct samples; mean and s.e.m.).
Extended Data Fig. 3 PY-60 promotes YAP dephosphorylation and activates a more robust YAP-dependent transcriptional program than MST1/2 inhibitor XMU-MP-1.
a, Representative (n=3) Western blot analysis of P-YAP (S127) and total YAP levels from 293A cells treated with the indicated compounds for 24 hours. b, Relative TEAD- LUC luminance values from 293A-TEAD-LUC cells treated for 24 hours with PY-60 or XMU-MP-1 (n=3, mean and s.e.m.) c,d, Transcript levels of YAP target genes ANKRD1 and CYR61 from 293A cells treated for 24 hours with PY-60 and XMU-MP-1 (n=3, mean and s.d.). e,f, Quantification and representative images of nuclei from 293A cells treated with PY-60 (20 µM) or XMU-MP-1 (1 µM) for 24 hours (n =3 biologically indepent samples, mean and s.d.; scale bar = 5 µm). Statistical tests are two sided univariate t-tests. Data are mean and s.d. or s.e.m. as noted of biologically independent samples.
Extended Data Fig. 4 Chemical proteomics identifies ANXA2 as a druggable component of the Hippo pathway.
a, Activities of the indicated Hippo pathway kinases in the presence of PY-60 and positive control inhibitors XMU- MP-1 (MST1/2) and Staurosporine (STS; LATS1/2, n=3; mean and s.e.m.). b, Represenative fluorescent gel scans of rhodamine-azide labeled 293A cell lysates after in situ crosslinking with PY-PAP (n=2). c, Anti-biotin Western blot and silver stained gel of streptavidin-enriched material after in situ crosslinking with PY-PAP (10 µM) in 293A cells (n=4). d, Anti-biotin and anti-ANXA2 Western blot analyses of streptavidin-enriched material after in situ treatment of 293A cells with PY-PAP (10 µM) or excess PY-60 (100 µM). Arrows indicate the competitively labeled band corresponding to ANXA2 and the band not competed by PY-60 corresponding to CTSD (n=2). e, Summary of MS/MS results, depicting the identified tryptic peptides and Metlin scores of ANXA2 (n=5). f, Isothermal titration calorimetry analysis of ANXA2 association with PY-60 (Kd = 22 µM; n=3) g, h, Quantification and representative Western blotting analysis of ANXA2 levels in the presence of PY-60 (20 µM) in cellular thermal shift assays with 293A cells (n=3; mean and s.d.). i, Dye-based thermal denaturation assay with recombinant ANXA2 protein in the presence of PY-60 (20 µM) or DMSO (n = 3; mean and s.d.). j, Quantification of ANXA2 transcript knockdown in 293A cells subjected to the indicated siRNAs. k, Western blot analyses of P-YAP levels in response to siRNA mediated knockdown of ANXA2 (n=2). l, Relative ANXA2 transcript levels from 293A cells stably lentivirally transduced with the indicated ANXA2-targeted shRNAs as in Fig. 3h. m, Relative transcript levels of YAP-driven transcript of CYR61 in response to stable knockdown of CTSD or ANXA2 in 293A cells with respective quantification of target transcript knockdown (middle, right; n =3; mean and s.d.). n, Relative ANXA2 levels from 293A cells stably expressing ANXA2-targeted shRNA as in Fig. 3i. o, Western blot analyses of ANXA2 levels from 293A and 293A-TEAD-LUC cells stably overexpressing ANXA2 as in Fig. 3h,i (n=2). Statistical tests are two sided univariate t-tests. Data are mean and s.d. or s.e.m. as noted of biologically independent samples.
Extended Data Fig. 5 Loss of ANXA2 promotes proliferation in growth-limiting conditions.
a,b, Number of colonies and Western blotting of ANXA2 levels with quantification of protein levels from MCF10A cells transduced with ANXA2 targeted shRNAs (n = 3; mean and s.d.). c,d, Number of colonies and representative anti-FLAG Western blot of MCF10A cells in soft agar after transduction with lentiviruses encoding a vector or ANXA2-FLAG transgene and treated with PY-60 (n = 6; mean and s.d). e,f, Quantification of cell density and representative Western blotting for ANXA2 levels from MDCK cells stably expressing ANXA2-targeted shRNAs (n = 3; mean and s.d.). g,h, Quantification of cell density and representative Western blotting for ANXA2 levels from MDCK cells stably overexpressing vector or ANXA2-FLAG transgene and exposed to PY-60 for 7 days (n = 3; mean and s.d.; t test). i-k, Number of cells, representative rhodamine B staining, and anti-ANXA2 Western blotting of human keratinocytes (HaCaT) stably expressing the indicated shRNAs (0.5% FBS, 7 days; n = 3; mean and s.d.; scale bar = 7 mm). l-n, Number of cells, representative Rhodamine B staining (2% FBS), and anti- FLAG Western blotting of human keratinocytes stably overexpressing vector or ANXA2-FLAG transgene and treated with PY-60 (1 µM; 7 days; n = 3; mean and s.d.; t test; scale bar = 7 mm). Statistical tests are two sided univariate t-tests. Data are mean and s.d. or s.e.m. as noted of biologically independent samples.
Extended Data Fig. 6 Hippo pathway member ANXA2 binds to MST2.
a, Western blotting analysis for HA-MST2 from anti-FLAG immunoprecipitated material from confluent 293A cells transiently overexpressing MST2-HA and ANXA2-FLAG treated with DMSO or PY-60 (20 µM; n=2). b, Western blotting for MST1-HA or MST2-HA from anti-FLAG immunoprecipitated material from confluent 293A cells transiently overexpressing MST1-HA or MST2-HA and ANXA2-FLAG. c,d, Schematic and Western blotting analysis of HA-tagged transgenes after anti-FLAG immunoprecipitation from 293A cells expressing MST1/2 domain swapped proteins and ANXA2-FLAG (ID = inhibitory domain; SARAH = Sav-RASSF-Hpo SARAH domain; n=3).e, Biolayer interferometry-based quantification of the dissociation constant of MST2 with ANXA2 (n=3 biologically independent samples; mean and s.e.m.). Western blotting is representative of independent experimental replicates as noted.
Extended Data Fig. 7 ANXA2 binds YAP and MST2, an interaction not competed by PY- 60.
a, Western blotting for endogenous YAP from anti-FLAG immunoprecipitated material from 293A cells transiently overexpressing ANXA2-FLAG then subjected to chemical crosslinker DSS. b, Western blotting analysis of endogenous MST2 prtein from anti-FLAG immunoprecipitation from 293A cells transiently overexpressing ANXA2-FLAG then subjected to crosslinker DSS (0.1-5 mM). c, Western blotting analysis of endogenous YAP from anti-FLAG immunoprecipitated material from 293A cells transiently overexpressing ANXA2-FLAG subjected to PY-60 for 24 hours and then treated with crosslinker DSS (1 mM). d, Western blotting of endogenous MST2 from anti-FLAG immunoprecipitated material from 293A cells transiently overexpressing ANXA2-FLAG treated with PY-60 for 24 hours and then exposed to DSS (1 mM). Western blotting are representative of biologically distinct experimental replicates (n=3).
Extended Data Fig. 8 ANXA2 binds to YAP and TAZ, an interaction not competed by PY-60 treatment.
a, Biolayer interferometry analysis demonstrating no change in interaction between ANXA2 and YAP in the presence of the indicated concentration response of PY-60 (n=3; mean and s.e.m of biologically independent replicates). b, Western blotting analysis for the presence of HA-tagged TAZ of anti-FLAG precipitated material from 293A cells transiently transfected with ANXA2-FLAG and HA-TAZ with PY-60 treatment (20 µM) for 24 hours. c, Western blotting analysis for anti-phospho-TAZ content from 293A cells treated for 24 hours with the indicated compounds. Western blots are representative of biologically distinct experimental replicates (n=2).
Extended Data Fig. 9 Characterization of PY-60 binding to ANXA2, a phosphoinositide associated membrane protein.
a, Colocalization coefficients of ANXA2 and pan-cadherin co-staining from 293A cells treated with PY-60 as depicted in Fig. 6a (n=3). b,c, Schematic and representative anti-ANXA2 Western blotting analysis of recombinant ANXA2 binding to the phosphoinositide membrane array (PIP strips, Echelon Biosciences; LPA = lysophosphatidic acid; LPC= lysophosphatidylcholine; PtdIns = phosphatidylinositol; PE = phosphoethanolamine; PA = phosphatidic acid; PS = phosphatidylserine). d, Quantification of ANXA2 binding to phosphoinositides in the PIP strip array (n=3). e, Structure of BODIPY fluorophore conjugated phosphoinositides, PtdIns-BODIPY and PtdIns-(4,5)P2-BODIPY. f,g, Fluorescent scan and quantification of Rhodamine azide (Rh-N3) labeled ANXA2-FLAG following immunoprecipitation after in situ crosslinking with PY-PAP (n=3). h, Schematic depicting the FLAG- tagged annexin repeat transgenes used. i, Fluorescent scan and anti-FLAG Western blot of Rhodamine azide (Rh-N3) labeled ANXA2-FLAG transgenes following anti-FLAG immunoprecipitation after in situ treatment with PY-PAP and UV crosslinking. j, Docked pose of PY-60 and PY-PAP to ANXA2 (reference structure PDB ID: 1XJL) with annexin repeats color coded. k, Isolated pose of PY-60 and PY-PAP docked to the first repeat of ANXA2 with residues deemed essential or dispensable by in situ labeling studies indicated in magenta and blue respectively. l,m, Fluorescent scans and quantification of Rhodamine azide labeled ANXA2-FLAG after anti-FLAG precipitation from 293A cells treated in situ with PY-PAP (10 µM) and crosslinked (n=3). Data reported are mean and s.d. of biologically independent samples. Statistical tests are two sided univariate t-tests.
Extended Data Fig. 10 PPP2CA is essential for YAP activation by PY-60.
a, Representative biolayer interferometry curve (n=4 independent experimental replicates) demonstrating the association of PPP2CA with ANXA2. b, Representative anti-PPP2CA Western blotting analysis (n=2) from stable 293A-TEAD-LUC reporter cells harboring the indicated shRNAs. c, Relative transcript levels of YAP-dependent transcripts from 293A cells treated with PY-60 (10 µM) for 24 hours (n=3 biologically independent samples, mean and s.d.). d, Representative Western blotting anlaysis (n=2) from 293A cell lines stably expressing the indicated PPP2CA shRNAs. Western blots are representative of independent experimental replicates as noted.
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Shalhout, S.Z., Yang, PY., Grzelak, E.M. et al. YAP-dependent proliferation by a small molecule targeting annexin A2. Nat Chem Biol 17, 767–775 (2021). https://doi.org/10.1038/s41589-021-00755-0
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DOI: https://doi.org/10.1038/s41589-021-00755-0
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