Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Hippo pathway regulation by phosphatidylinositol transfer protein and phosphoinositides

Abstract

The Hippo pathway plays a key role in development, organ size control and tissue homeostasis, and its dysregulation contributes to cancer. The LATS tumor suppressor kinases phosphorylate and inhibit the YAP/TAZ transcriptional co-activators to suppress gene expression and cell growth. Through a screen of marine natural products, we identified microcolin B (MCB) as a Hippo activator that preferentially kills YAP-dependent cancer cells. Structure–activity optimization yielded more potent MCB analogs, which led to the identification of phosphatidylinositol transfer proteins α and β (PITPα/β) as the direct molecular targets. We established a critical role of PITPα/β in regulating LATS and YAP. Moreover, we showed that PITPα/β influence the Hippo pathway via plasma membrane phosphatidylinositol-4-phosphate. This study uncovers a previously unrecognized role of PITPα/β in Hippo pathway regulation and as potential cancer therapeutic targets.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: MCB and VT01454 induce YAP phosphorylation, cytoplasmic localization and inactivation through the Hippo pathway.
Fig. 2: VT01454 exhibits selective cytotoxicity towards the YAP-dependent UM cells.
Fig. 3: PITPα/β are the molecular targets of VT01454.
Fig. 4: PITPα/β are the functional targets of VT01454 in YAP regulation.
Fig. 5: PI4P depletion induces YAP phosphorylation.
Fig. 6: PI4KA antagonizes Sac1 or PIP5K1c on YAP phosphorylation.

Data availability

The RNA-seq data are available at the Gene Expression Omnibus (GEO) database with accession ‘GSE198890’. The PITPα receptor model was prepared from available structures of human PITPα (PDB ID: 1UW5). All the other data are available within the article and its Supplementary Information. Source data are provided with this paper.

References

  1. Ma, S. et al. The Hippo pathway: biology and pathophysiology. Annu. Rev. Biochem. 88, 577–604 (2019).

    CAS  PubMed  Google Scholar 

  2. Zheng, Y. & Pan, D. The Hippo signaling pathway in development and disease. Dev. Cell 50, 264–282 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Harvey, K. F., Zhang, X. & Thomas, D. M. The Hippo pathway and human cancer. Nat. Rev. Cancer 13, 246–257 (2013).

    CAS  PubMed  Google Scholar 

  4. Meng, Z. et al. MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway. Nat. Commun. 6, 8357 (2015).

    CAS  PubMed  Google Scholar 

  5. Zheng, Y. et al. Identification of Happyhour/MAP4K as alternative Hpo/Mst-like kinases in the Hippo kinase cascade. Dev. Cell 34, 642–655 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Li, Q. et al. The conserved misshapen-warts-Yorkie pathway acts in enteroblasts to regulate intestinal stem cells in Drosophila. Dev. Cell 31, 291–304 (2014).

    PubMed  PubMed Central  Google Scholar 

  7. Wu, S. et al. The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway. Dev. Cell 14, 388–398 (2008).

    CAS  PubMed  Google Scholar 

  8. Zhao, B. et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 22, 1962–1971 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Yoder, M. D. et al. Structure of a multifunctional protein. Mammalian phosphatidylinositol transfer protein complexed with phosphatidylcholine. J. Biol. Chem. 276, 9246–9252 (2001).

    CAS  PubMed  Google Scholar 

  10. De Vries, K. J. et al. Fluorescently labeled phosphatidylinositol transfer protein isoforms (alpha and beta), microinjected into fetal bovine heart endothelial cells, are targeted to distinct intracellular sites. Exp. Cell. Res. 227, 33–39 (1996).

    PubMed  Google Scholar 

  11. Nile, A. H., Bankaitis, V. A. & Grabon, A. Mammalian diseases of phosphatidylinositol transfer proteins and their homologs. Clin. Lipidol. 5, 867–897 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Schaaf, G. et al. Functional anatomy of phospholipid binding and regulation of phosphoinositide homeostasis by proteins of the sec14 superfamily. Mol. Cell 29, 191–206 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Hamilton, B. A. et al. The vibrator mutation causes neurodegeneration via reduced expression of PITP alpha: positional complementation cloning and extragenic suppression. Neuron 18, 711–722 (1997).

    CAS  PubMed  Google Scholar 

  14. Xie, Z. et al. A Golgi lipid signaling pathway controls apical Golgi distribution and cell polarity during neurogenesis. Dev. Cell 44, 725–740.e4 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Koehn, F. E., Longley, R. E. & Reed, J. K. Microcolins A and B, new immunosuppressive peptides from the blue–green alga Lyngbya majuscula. J. Nat. Prod. 55, 613–619 (1992).

    CAS  PubMed  Google Scholar 

  16. Zhang, L. H. & Longley, R. E. Induction of apoptosis in mouse thymocytes by microcolin A and its synthetic analog. Life Sci. 64, 1013–1028 (1999).

    CAS  PubMed  Google Scholar 

  17. Zhang, L. H., Longley, R. E. & Koehn, F. E. Antiproliferative and immunosuppressive properties of microcolin A, a marine-derived lipopeptide. Life Sci. 60, 751–762 (1997).

    CAS  PubMed  Google Scholar 

  18. Yu, F. X. et al. Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP. Cancer Cell 25, 822–830 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Feng, X. et al. Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry. Cancer Cell 25, 831–845 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Koehn, F. E. et al. Analogues of the marine immunosuppressant microcolin A: preparation and biological activity. J. Med. Chem. 37, 3181–3186 (1994).

    CAS  PubMed  Google Scholar 

  21. Wang, Y. et al. Comprehensive molecular characterization of the Hippo signaling pathway in cancer. Cell Rep. 25, 1304–1317 e5 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Liu-Chittenden, Y. et al. Genetic and pharmacological disruption of the TEAD–YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 26, 1300–1305 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Han, H. et al. Hippo signaling dysfunction induces cancer cell addiction to YAP. Oncogene 37, 6414–6424 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Pham, T. H. et al. Machine-learning and chemicogenomics approach defines and predicts cross-talk of Hippo and MAPK pathways. Cancer Discov. 11, 778–793 (2021).

    CAS  PubMed  Google Scholar 

  25. Speers, A. E. & Cravatt, B. F. Activity-based protein profiling (ABPP) and click chemistry (CC)-ABPP by MudPIT mass spectrometry. Curr. Protoc. Chem. Biol. 1, 29–41 (2009).

    PubMed  PubMed Central  Google Scholar 

  26. Wirtz, K. W. Phospholipid transfer proteins. Annu. Rev. Biochem. 60, 73–99 (1991).

    CAS  PubMed  Google Scholar 

  27. Tilley, S. J. et al. Structure–function analysis of human [corrected] phosphatidylinositol transfer protein alpha bound to phosphatidylinositol. Structure 12, 317–326 (2004).

    CAS  PubMed  Google Scholar 

  28. Grabon, A., Bankaitis, V. A. & McDermott, M. I. The interface between phosphatidylinositol transfer protein function and phosphoinositide signaling in higher eukaryotes. J. Lipid Res. 60, 242–268 (2019).

    CAS  PubMed  Google Scholar 

  29. Carvou, N. et al. Phosphatidylinositol- and phosphatidylcholine-transfer activity of PITPbeta is essential for COPI-mediated retrograde transport from the Golgi to the endoplasmic reticulum. J. Cell Sci. 123, 1262–1273 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Shadan, S. et al. Dynamics of lipid transfer by phosphatidylinositol transfer proteins in cells. Traffic 9, 1743–1756 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Hong, A. W. et al. Critical roles of phosphoinositides and NF2 in Hippo pathway regulation. Genes Dev. 34, 511–525 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Del Bel, L. M. & Brill, J. A. Sac1, a lipid phosphatase at the interface of vesicular and nonvesicular transport. Traffic 19, 301–318 (2018).

    PubMed  Google Scholar 

  33. Burke, J. E. Structural basis for regulation of phosphoinositide kinases and their involvement in human disease. Mol. Cell 71, 653–673 (2018).

    CAS  PubMed  Google Scholar 

  34. Ile, K. E. et al. Zebrafish class 1 phosphatidylinositol transfer proteins: PITPbeta and double cone cell outer segment integrity in retina. Traffic 11, 1151–1167 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Hammond, G. R., Machner, M. P. & Balla, T. A novel probe for phosphatidylinositol 4-phosphate reveals multiple pools beyond the Golgi. J. Cell Biol. 205, 113–126 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Stauffer, T. P., Ahn, S. & Meyer, T. Receptor-induced transient reduction in plasma membrane PtdIns(4,5)P2 concentration monitored in living cells. Curr. Biol. 8, 343–346 (1998).

    CAS  PubMed  Google Scholar 

  37. Hammond, G. R. et al. PI4P and PI(4,5)P2 are essential but independent lipid determinants of membrane identity. Science 337, 727–730 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Nakatsu, F. et al. PtdIns4P synthesis by PI4KIIIalpha at the plasma membrane and its impact on plasma membrane identity. J. Cell Biol. 199, 1003–1016 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Kanai, F. et al. The PX domains of p47phox and p40phox bind to lipid products of PI(3)K. Nat. Cell Biol. 3, 675–678 (2001).

    CAS  PubMed  Google Scholar 

  40. D’Angelo, G. et al. The multiple roles of PtdIns(4)P–not just the precursor of PtdIns(4,5)P2. J. Cell Sci. 121, 1955–1963 (2008).

    PubMed  Google Scholar 

  41. Delage, E. et al. Signal transduction pathways involving phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate: convergences and divergences among eukaryotic kingdoms. Prog. Lipid Res. 52, 1–14 (2013).

    CAS  PubMed  Google Scholar 

  42. Zewe, J. P. et al. SAC1 degrades its lipid substrate PtdIns4. eLife 7, e35588 (2018).

    PubMed  PubMed Central  Google Scholar 

  43. Blagoveshchenskaya, A. et al. Integration of Golgi trafficking and growth factor signaling by the lipid phosphatase SAC1. J. Cell Biol. 180, 803–812 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Bojjireddy, N. et al. Pharmacological and genetic targeting of the PI4KA enzyme reveals its important role in maintaining plasma membrane phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate levels. J. Biol. Chem. 289, 6120–6132 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Hirao, M. et al. Regulation mechanism of ERM (ezrin/radixin/moesin) protein/plasma membrane association: possible involvement of phosphatidylinositol turnover and Rho-dependent signaling pathway. J. Cell Biol. 135, 37–51 (1996).

    CAS  PubMed  Google Scholar 

  46. Balla, T. Phosphoinositides: tiny lipids with giant impact on cell regulation. Physiol. Rev. 93, 1019–1137 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Plouffe, S. W. et al. Characterization of Hippo pathway components by gene inactivation. Mol. Cell 64, 993–1008 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Bar-Peled, L. et al. Chemical proteomics identifies druggable vulnerabilities in a genetically defined cancer. Cell 171, 696–709 e23 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Inloes, J. M. et al. The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase. Proc. Natl Acad. Sci. USA 111, 14924–14929 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Niphakis, M. J. et al. A global map of lipid-binding proteins and their ligandability in cells. Cell 161, 1668–1680 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Weerapana, E. et al. Quantitative reactivity profiling predicts functional cysteines in proteomes. Nature 468, 790–795 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Ran, F. A. et al. Genome engineering using the CRISPR–Cas9 system. Nat. Protoc. 8, 2281–2308 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank E. Fatti and F.-X. Yu for assistance in the initial chemical library screen. This work was supported by National Institutes of Health (NIH) grants GM51586, CA217642 and CA268179 to K.-L.G. J.M.F. is supported by NIH grant T32CA009523.

Author information

Authors and Affiliations

Authors

Contributions

F.-L.L., V.F., G.L. and K.-L.G. conceived the study. F.-L.L., V.F., G.L., J.E.D. and K.-L.G. conducted experiments and data analyses. T.T., A.K. and X.P. performed the compound optimization. W.H.G. provided the marine compound library and advice. J.M.F. assisted in cell imaging experiments. Z.W. assisted in RNA-seq experiments and gene set enrichment analysis. E.K. and B.F.C. assisted in mass spectrometry experiments. J.M. performed the docking simulation. V.F., F.-L.L. and K.-L.G. wrote the manuscript with input from all other authors.

Corresponding author

Correspondence to Kun-Liang Guan.

Ethics declarations

Competing interests

K.-L.G. is a cofounder of and has equity interest in Vivace Therapeutics. T.T., A.K. and X.P. are Vivace Therapeutics employees. The other authors declare no competing interests.

Peer review

Peer review information

Nature Chemical Biology thanks the anonymous reviewers for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 MCB induce YAP inactivation, phosphorylation and cytoplasmic localization.

a, MCB inhibits the YAP transcription reporter. HEK293A clone, which has the 8X TBD-luciferase reporter stably integrated in the genome, was treated with increasing concentration of MCB. Luciferase activity was determined to measure YAP transcriptional activity. n = 4 biologically independent samples. b, MCB induces YAP phosphorylation in a dose-dependent manner. HEK293A cells were treated with indicated concentration of MCB for 2 hours. Western blot was performed with indicated antibodies. c, MCB induce YAP phosphorylation in a time-dependent manner. HEK293A cells were treated with MCB (270 nM) for the indicated times. Cell lysates were analyzed by Western blot with indicated antibodies. d, MCB induces YAP phosphorylation in 92.1 cells. Cells were treated with 0.7 μM MCB for the indicated times. e, MCB induces YAP cytoplasmic translocation. HEK293A cells were treated with 270 nM MCB for 2 hours and subjected to immunofluorescence for YAP localization. Scale bar = 10 μm. The right panel shows quantification of a representative experiment.

Source data

Extended Data Fig. 2 MCB and derivatives induce YAP phosphorylation and cytoplasmic localization through the Hippo pathway.

a, VT01454 induces YAP phosphorylation in a dose- or time- dependent manner. HEK293A cells were treated with indicated concentration of VT01454 for 1 hour or 50 nM VT01454 for indicated time. b, Structures of MCB and derivatives. c, VT01454 inhibits the expression of YAP target genes CTGF, ANKRD, and Cyr61. RT-PCR experiment was performed with HEK293A cells treated with indicated concentrations of VT01454 for 2 hours. Results are mean ± SD of three biologically independent samples. d, MCB induces the phosphorylation of YAP, but not the YAP-5SA mutant. HEK293A cells were transfected with Flag-YAP or YAP-5SA, which has all LATS phosphorylation sites mutated to alanine residues. Cells were treated with MCB and then analyzed by Western Blot on phos-tag gel. e, LATS1/2 are required for MCB to induce YAP phosphorylation. HEK293A WT, LATS1 KO, LATS2 KO, and LATS1/2 dKO cells were treated with 270 nM MCB for 2 hours and Western blotted with indicated antibodies. f, LATS1/2 double knockout blocks the effect of MCB on YAP localization. Scale bar = 10 μm. Quantification of YAP subcellular localization is shown in the right. g, VT01454 has little effect on the expression of key Hippo pathway components. Heatmap analysis of the RNA-seq data in Fig. 1d. h, VT01454 does not regulate NF2 plasma membrane localization. Flag-tagged NF2 construct was transfected into HEK293A cells. After 24 hours, cells were treated with indicated concentrations of VT01454 for 2 hours before subject to immunofluorescence staining. Scale bar = 10 μm. i, VT01454 does not affect LATS-NF2 interaction. Flag-tagged NF2 and HA-tagged LATS1 was co-transfected into HEK293A cells. After 24 hours, cells were treated with indicated concentrations of VT01454 for 2 hours before subjecting to immunoprecipitation with Flag antibody.

Source data

Extended Data Fig. 3 MCB and VT01454 preferentially kills YAP dependent cancer cells.

a and b, MCB induces cell death in the GNAQ/11 mutant 92.1 and OMM1, but not the B-Raf mutant OCM1 and OCM8 cells where VP displays general toxicity. The concentrations of MCB and VP were 2.7μM and 2 μM, respectively. Scale bar = 50 μm. Results are mean ± SD of three biologically independent samples. c, 92.1 cells are more sensitive than OCM1 cells to MCB-induced apoptosis. The MCB concentrations were 2.7 and 5.4 μM. d, MCB is more selective than verteporfin to induce PARP cleavage. Concentration gradients (0, 0.27, 0.68, 1.36, 2.72, 6.8 μM) of MCB or verteporfin (0, 0.28, 0.70, 1.39, 2.78, 6.9 μM) were used to treat cells. PARP cleavage was determined by Western blot. e, MCB (2.7 μM) preferentially inhibits colony formation in 92.1 cells over OCM1 cells. Both images and quantification of colonies in soft agar assays are shown. Results are mean ± SD of three biologically independent samples. f, VT01454 does not induce YAP-5SA phosphorylation. The stable 92.1 cell pools were generated by infection with lentivirus expressing YAP-5SA or empty-vector. These cells were treated with 20 nM or 50 nM of VT01454 for 1 hours before subjecting to western blot with indicated antibodies. g, VT01454 sensitivity in multiple cancer cell lines. 1.5 × 105 cells were seeded and treated with VT01454 (20 nM) or DMSO for 48 hours. Scale bar = 100 μm. Representative images were taken by a phase-contrast microscope. h, Quantification of live cell numbers (left panel) was performed by cell counting after trypan blue staining. The right panel was the normalized result of the left panel by setting the DMSO control as 1. Experiments were similar to panel g. Results were mean ± SD of three biologically independent samples.

Source data

Extended Data Fig. 4 VT01454 covalently modifies Cys94 in PITPβ.

a, Chemical structure of VT01702. b, VT01702 induces YAP phosphorylation and inhibits YAP reporter activity. c, Structure of the trifunctional 545-biotin-azide compound used to conjugate VT01702. d, Optimization of purification conditions for the VT01702 modified protein by streptavidin beads. e. VT01454 covalently modifies Cys94 in PITPβ. HA-tagged wild-type or indicated mutants of PITPβ were transfected into HEK293A cells. After 24 hours, cells were treated with 50 nM VT01454 for 1 hour before being subjected to western blot with indicated antibodies.

Source data

Extended Data Fig. 5 PITPα/β knockout induces YAP phosphorylation independent of cell types.

a, Genomic characterization of the PITPβ knockout cell clone #1.12. The HEK293A cell line has three alleles of PITPβ. DNA sequence confirms mutations of the three alleles. b, The PITPα siRNA knockdown efficiency was measured by Quantitative Real-time PCR. Results are mean ± SD of three technically replicates. c, PITPα/β knockout induces YAP phosphorylation independent of cell types. These knockout cell pools were generated by co-infecting lentiviruses stably expressing Cas9 and guide RNA targeting PITPNA and PITPNB. Cells were lysed and subjected to Western Blot with indicated antibodies. d, PITPα/β knockout blocks LPA-induced YAP de-phosphorylation. HEK293A wild-type and PITPα/β dKO cell pool were treated with Latrunculin B or LPA and then analyzed by Western blot with indicated antibodies.

Source data

Extended Data Fig. 6 VT01454 preferentially depletes plasma membrane PI4P.

a, Volume (combined) view of the Z-section confocal images in Fig. 5a. Scale bar = 10 μm. b, Zoomed out view of area with multiple cells to indicate that the single cell images in Fig. 5a are representative. Scale bar = 10μm. c, VT01454 treatment preferentially depletes plasma membrane PI4P. Scale bar = 10 μm. d, VT01454 has little effect on PI3P. HEK293A cells were transfected with RFP-p40px, which is a reporter for PI3P, then treated with VT01454. Scale bar = 10 μm. e, Expression of Sac1-GRIP does not induce YAP cytoplasmic translocation. Scale bar = 20 μm.

Extended Data Fig. 7 PI4KA overexpression dampens the effect of VT01454.

a, Inhibition of PI4KA increases YAP cytoplasmic localization. HEK293A cells were treated with PI4KA inhibitor GSK-A1 or PI4KB inhibitor PI4KIIIb-IN-10 prior to YAP staining. Scale bar = 20 μm. Quantification is shown on the right. b, GSK-A1 stimulates phosphorylation of LATS and YAP. c, PI4KA overexpression dampens the effect of VT01454 on YAP phosphorylation. Flag-YAP was co-expressed with HA-PI4KA or vector in HEK293A cells. After 24 hours, these cells were treated with DMSO or VT01454 for 1 hour, then Western blotted with the indicated antibodies.

Source data

Extended Data Fig. 8 NF2 is required for the phosphorylation of LATS1 and YAP induced by VT01454.

a, Characterization of FERM protein (Protein 4.1/ Ezrin/ Radixin/ Moesin). knockout efficiency in HEK293A. The knockout cell pool was generated with individual or combinatory lentivirus stably expressing Cas9 and specific guide RNAs. These cells were selected with puromycin for 48 hours before subjecting to western blot with indicated antibodies. b, Knockout of Protein 4.1, Ezrin, Radixin, and Moesin did not affect YAP phosphorylation. The cells as described in panel a were treated with DMSO or 20 nM VT01454 for 1 hour before western blot with indicated antibodies. c, NF2 is required for the phosphorylation of LATS1 and YAP induced by VT01454. The wild-type or NF2 knockout cells were treated with 20 nM VT01454 for indicated times before subjecting to western blot with indicated antibodies.

Source data

Supplementary information

Supplementary Information

Supplementary Fig. 1 and Notes 1 and 2.

Reporting Summary

Supplementary Data

Supplementary Dataset 1. Information of the marine compounds library; Supplementary Dataset 2. List of proteins enriched by VT01702 over DMSO; Supplementary Dataset 3. Proteins list of excised gel identified by MS.

Source data

Source Data Fig. 1

Statistical source data.

Source Data Fig. 1

Unprocessed western blots.

Source Data Fig. 2

Statistical source data.

Source Data Fig. 2

Unprocessed western blots.

Source Data Fig. 3

Unprocessed western blots.

Source Data Fig. 4

Statistical source data.

Source Data Fig. 4

Unprocessed western blots.

Source Data Fig. 5

Statistical source data.

Source Data Fig. 5

Unprocessed western blots.

Source Data Fig. 6

Statistical source data.

Source Data Fig. 6

Unprocessed western blots.

Source Data Extended Data Fig. 1

Statistical source data.

Source Data Extended Data Fig. 1

Unprocessed western blots.

Source Data Extended Data Fig. 2

Statistical source data.

Source Data Extended Data Fig. 2

Unprocessed western blots.

Source Data Extended Data Fig. 3

Statistical source data.

Source Data Extended Data Fig. 3

Unprocessed western blots.

Source Data Extended Data Fig. 4

Statistical source data.

Source Data Extended Data Fig. 4

Unprocessed western blots.

Source Data Extended Data Fig. 5

Statistical source data.

Source Data Extended Data Fig. 5

Unprocessed western blots.

Source Data Extended Data Fig. 7

Statistical source data.

Source Data Extended Data Fig. 7

Unprocessed western blots.

Source Data Extended Data Fig. 8

Unprocessed western blots.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Li, FL., Fu, V., Liu, G. et al. Hippo pathway regulation by phosphatidylinositol transfer protein and phosphoinositides. Nat Chem Biol (2022). https://doi.org/10.1038/s41589-022-01061-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41589-022-01061-z

Further reading

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer