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.

  • Article
  • Published:

SUMOylation activates large tumour suppressor 1 to maintain the tissue homeostasis during Hippo signalling

Oncogene volume 40, pages 5357–5366 (2021)Cite this article

Subjects

Abstract

Large tumour suppressor (LATS) 1/2, the core kinases of Hippo signalling, are critical for maintaining tissue homeostasis. Here, we investigate the role of SUMOylation in the regulation of LATS activation. High cell density induces the expression of components of the SUMOylation machinery and enhances the SUMOylation and activation of Lats1 but not Lats2, whereas genetic deletion of the SUMOylation E2 ligase, Ubc9, abolishes this Lats1 activation. Moreover, SUMOylation occurs at the K830 (mouse K829) residue to activate LATS1 and depends on the PIAS1/2 E3 ligase. Whereas the K830 deSUMOylation mutation of LATS1 found in the human metastatic prostate cancers eliminates the kinase activity by attenuating the formation of the phospho-MOB1/phospho-LATS1 complex. As a result, the LATS1(K830R) transgene phenocopies Yap transgene to cause the oversized livers in mice, whereas Lats1(K829R) knock-in phenocopies the deletion of Lats1 in causing the reproductive and endocrine defects and ovary tumours in mice. Thus, SUMOylation-mediated LATS1 activation is an integral component of Hippo signalling in the regulation of tissues homeostasis.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Activation of Hippo signalling induces the SUMOylation and activation of Lats1 in primary mouse hepatocytes.
Fig. 2: SUMOylation activates LATS1 through PIAS1/2 E3 ligases.
Fig. 3: K830 residue is responsible for SUMOylation-induced activation of LATS1.
Fig. 4: Potential mechanisms govern SUMOylation-induced activation of LATS1.
Fig. 5: K830R mutation of LATS1 attenuates Hippo signalling and the tumour-suppressor function.
Fig. 6: Phenotypic analyses of LATS1(WT) and LATS1(K830R) transgenic mice.
Fig. 7: Phenotypic analyses of Lats1(K829) knock-in mice.

Similar content being viewed by others

References

  1. Meng Z, Moroishi T, Guan KL. Mechanisms of Hippo pathway regulation. Genes Dev. 2016;30:1–17. https://doi.org/10.1101/gad.274027.115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Yu FX, Zhao B, Guan KL. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell. 2015;163:811–28. https://doi.org/10.1016/j.cell.2015.10.044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. John M, Tao WF, Fei XL, Fukumoto R, Carcangiu ML, Brownstein DG, et al. Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction. Nat Genet. 1999;21:182–6. https://doi.org/10.1038/5965

    Article  Google Scholar 

  4. Pantalacci S, Tapon N, Léopold P. The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Nat Cell Biol. 2003;5:921–7. https://doi.org/10.1038/ncb1051

    Article  CAS  PubMed  Google Scholar 

  5. Moroishi T, Hansen CG, Guan KL. The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer. 2015;15:73–9. https://doi.org/10.1038/nrc3876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Moroishi T, Park HW, Qin B, Chen Q, Meng Z, Plouffe SW, et al. A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis. Genes Dev. 2015;29:1271–84. https://doi.org/10.1101/gad.262816.115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dong JX, Feldmann G, Huang JB, Wu S, Zhang NL, Comerford SA, et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007;130:1120–33. https://doi.org/10.1016/j.cell.2007.07.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, Jaenisch R, et al. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol. 2007;17:2054–60. https://doi.org/10.1016/j.cub.2007.10.039

    Article  CAS  PubMed  Google Scholar 

  9. Hay RT. SUMO: a history of modification. Mol Cell. 2005;18:1–12. https://doi.org/10.1016/j.molcel.2005.03.012

    Article  CAS  PubMed  Google Scholar 

  10. Gareau JR, Lima CD. The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition. Nat Rev Mol Cell Biol. 2010;11:861–71. https://doi.org/10.1038/nrm3011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Seeler JS, Dejean A. SUMO and the robustness of cancer. Nat Rev Cancer. 2017;17:184–97. https://doi.org/10.1038/nrc.2016.143

    Article  CAS  PubMed  Google Scholar 

  12. Galanty Y, Belotserkovskaya R, Coates J, Polo S, Miller KM, Jackson SP. Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks. Nature. 2009;462:935–9. https://doi.org/10.1038/nature08657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yagil Z, Nechushtan H, Kay G, Yang CM, Kemeny DM, Razin E. The enigma of the role of protein inhibitor of activated STAT3 (PIAS3) in the immune response. Trends Immunol. 2010;31:199–204. https://doi.org/10.1016/j.it.2010.01.005

    Article  CAS  PubMed  Google Scholar 

  14. Schimmel J, Eifler K, Sigurðsson JO, Cuijpers SA, Hendriks IA, Verlaan-de Vries M, et al. Uncovering SUMOylation dynamics during cell-cycle progression reveals FoxM1 as a key mitotic SUMO target protein. Mol cell. 2014;53:1053–66. https://doi.org/10.1016/j.molcel.2014.02.001

    Article  CAS  PubMed  Google Scholar 

  15. Eifler K, Vertegaal AC. SUMOylation-mediated regulation of cell cycle progression and cancer. Trends Biochem Sci. 2015;40:779–93. https://doi.org/10.1016/j.tibs.2015.09.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Flotho A, Melchior F. Sumoylation: a regulatory protein modification in health and disease. Ann Rev Biochem 2013;82:357–85. https://doi.org/10.1146/annurev-biochem-061909-093311

    Article  CAS  PubMed  Google Scholar 

  17. Mei L, Yuan LW, Shi W, Fan SH, Tang C, Fan XY, et al. SUMOylation of large tumor suppressor 1 at Lys751 attenuates its kinase activity and tumor-suppressor functions. Cancer Lett. 2017;386:1–11. https://doi.org/10.1016/j.canlet.2016.11.009

    Article  CAS  PubMed  Google Scholar 

  18. Lu L, Li Y, Kim SM, Bossuyt W, Liu P, Qiu Q, et al. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc Natl Acad Sci USA 2010;107:1437–42. https://doi.org/10.1073/pnas.0911427107

    Article  PubMed  PubMed Central  Google Scholar 

  19. Yi J, Lu L, Yanger K, Wang W, Sohn BH, Stanger BZ, et al. Large tumor suppressor homologs 1 and 2 regulate mouse liver progenitor cell proliferation and maturation through antagonism of the coactivators YAP and TAZ. Hepatology. 2016;64:1757–72. https://doi.org/10.1002/hep.28768

    Article  CAS  PubMed  Google Scholar 

  20. Nacerddine K, Lehembre F, Bhaumik M, Artus J, Cohen-Tanoudji M, Babinet C, et al. The SUMO pathway is essential for nuclear integrity and chromosome segregation in mice. Dev Cell. 2005;9:769–79. https://doi.org/10.1016/j.devcel.2005.10.007

    Article  CAS  PubMed  Google Scholar 

  21. Yu EY, Coleman R, Schultz N, Fang M, Lange PH, Shendure J, et al. Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat Med. 2016;22:369–78. https://doi.org/10.1038/nm.4053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Li W, Cooper J, Zhou L, Yang CY, Erdjument-Bromage H, Zagzag D. Merlin/NF2 loss-driven tumorigenesis linked to CRL4(DCAF1)-mediated inhibition of the hippo pathway kinases Lats1 and 2 in the nucleus. Cancer Cell. 2014;26:48–60. https://doi.org/10.1016/j.ccr.2014.05.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pefani DE, Latusek R, Pires I, Grawenda AM, Yee KS, Hamilton G, et al. RASSF1A-LATS1 signalling stabilizes replication forks by restricting CDK2-mediated phosphorylation of BRCA2. Nat Cell Biol. 2014;16:962–71. https://doi.org/10.1038/ncb3035. 1-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kim M, Kim M, Park SJ, Lee C, Lim DS. Role of Angiomotin-like 2 mono-ubiquitination on YAP inhibition. EMBO Rep. 2016;17:64–78. https://doi.org/10.15252/embr.201540809

    Article  CAS  PubMed  Google Scholar 

  25. Si Y, Ji X, Cao X, Dai X, Xu L, Zhao H, et al. Src inhibits the hippo tumor suppressor pathway through tyrosine phosphorylation of Lats1. Cancer Res. 2017;77:4868–80. https://doi.org/10.1158/0008-5472.CAN-17-0391

    Article  CAS  PubMed  Google Scholar 

  26. Zhang Q, Du X, He Q, Shi W, Mei L, Qv M, et al. T851I mutation of human large tumor suppressor 1 disrupts its kinase activity and tumor-suppressor functions. Life Sci. 2021;264:118655 https://doi.org/10.1016/j.lfs.2020.118655

    Article  CAS  PubMed  Google Scholar 

  27. Yang X, Li DM, Chen W, Xu T. Human homologue of Drosophila lats, LATS1, negatively regulate growth by inducing G(2)/M arrest or apoptosis. Oncogene. 2001;20:6516–23. https://doi.org/10.1038/sj.onc.1204817

    Article  CAS  PubMed  Google Scholar 

  28. Lapi E, Di Agostino SD, Donzelli S, Gal H, Domany E, Rechavi G, et al. PML, YAP, and p73 are components of a proapoptotic autoregulatory feedback loop. Mol Cell. 2008;32:803–14. https://doi.org/10.1016/j.molcel.2008.11.019

    Article  CAS  PubMed  Google Scholar 

  29. Yan Y, Ollila S, Wong IP, Vallenius T, Palvimo JJ, et al. SUMOylation of AMPKα1 by PIAS4 specifically regulates mTORC1 signalling. Nat Commun. 2015;6:8979 https://doi.org/10.1038/ncomms9979

    Article  CAS  PubMed  Google Scholar 

  30. Rubio T, Vernia S, Sanz P. Sumoylation of AMPKb2 subunit enhances AMPactivated protein kinase activity. Mol Biol Cell. 2013;24:1801–11. https://doi.org/10.1091/mbc.E12-11-0806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ritho J, Arold ST, Yeh ET. A critical SUMO1 modification of LKB1 regulates AMPK activity during energy stress. Cell Rep. 2015;12:734–42. https://doi.org/10.1016/j.celrep.2015.07.002

    Article  CAS  PubMed  Google Scholar 

  32. Wang XD, Gong Y, Chen ZL, Gong BN, Xie JJ, Zhong CQ. TCR- induced sumoylation of the kinase PKC-q controls T cell synapse organization and T cell activation. Nat Immunol. 2015;16:1195–203. https://doi.org/10.1038/ni.3259

    Article  CAS  PubMed  Google Scholar 

  33. Li R, Wei J, Jiang C, Liu DM, Deng L, Zhang K, et al. Akt SUMOylation regulates cell proliferation and tumorigenesis. Cancer Res. 2013;73:5742–53. https://doi.org/10.1158/0008-5472.CAN-13-0538

    Article  CAS  PubMed  Google Scholar 

  34. Aukrust I, Bjorkhaug L, Negahdar M, Molnes J, Johansson BB, Müller Y, et al. SUMOylation of pancreatic glucokinase regulates its cellular stability and activity. J Biol Chem. 2013;288:5951–62. https://doi.org/10.1074/jbc.M112.393769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tao W, Zhang S, Turenchalk GS, Stewart RA, St John MA, Chen W, et al. Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity. Nat Genet. 1999;21:177–81. https://doi.org/10.1038/5960

    Article  CAS  PubMed  Google Scholar 

  36. Tang F, Gao R, Jeevan-Raj B, Wyss CB, Kalathur RKR, Piscuoglio S, et al. LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function. Nat Commun 2019;10:5755 https://doi.org/10.1038/s41467-019-13591-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rabellino A, Andreani C, Scaglioni PP. The role of PIAS SUMO E3-ligases in cancer. Cancer Res. 2017;77:1542–7. https://doi.org/10.1158/0008-5472.CAN-16-2958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Severgnini M, Sherman J, Sehgal A, Jayaprakash NK, Aubin J, Wang G, et al. A rapid two-step method for isolation of functional primary mouse hepatocytes: cell characterization and asialoglycoprotein receptor based assay development. Cytotechnology. 2012;64:187–95. https://doi.org/10.1007/s10616-011-9407-0

    Article  CAS  PubMed  Google Scholar 

  39. Liu NH, Mei L, Fan XY, Tang C, Ji X, Hu XH, et al. Phosphodiesterase 5/protein kinase G signal governs stemness of prostate cancer stem cells through Hippo pathway. Cancer Lett. 2016;378:38–50. https://doi.org/10.1016/j.canlet.2016.05.010

    Article  CAS  PubMed  Google Scholar 

  40. Wu X, Tu X, Joeng KS, Hilton MJ, Williams DA, Long F. Rac1 activation controls nuclear localization of beta-catenin during canonical Wnt signaling. Cell. 2008;133:340–53. https://doi.org/10.1016/j.cell.2008.01.052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Eswar N, Eramian D, Webb B, Shen MY, Sali A. Protein structure modeling with MODELLER. Methods Mol Biol. 2008;426:145–59. https://doi.org/10.1007/978-1-60327-058-8_8

    Article  CAS  PubMed  Google Scholar 

  42. Webb B, Sali A. Comparative protein structure modeling using MODELLER. Curr Protoc Protein Sci. 2016;86:2.9.1–2.9.37. https://doi.org/10.1002/cpps.20

    Article  Google Scholar 

  43. He X, Lai Q, Chen C, Li N, Sun F, Huang W, et al. Both conditional ablation and overexpression of E2 SUMO-conjugating enzyme (UBC9) in mouse pancreatic beta cells result in impaired beta cell function. Diabetologia. 2018;61:881–95. https://doi.org/10.1007/s00125-017-4523-9

    Article  CAS  PubMed  Google Scholar 

  44. Liao X, Cui H, Wang F. Establishment of a transgenic mouse model of corneal dystrophy overexpressing human BIGH3. Int J Mol Med. 2013;32:1110–4. https://doi.org/10.3892/ijmm.2013.1480

    Article  CAS  PubMed  Google Scholar 

  45. Zhang H, Pu WJ, Tian XY, Huang XZ, He LJ, Liu QZ, et al. Genetic lineage tracing identifies endocardial origin of liver vasculature. Nat Genet. 2016;48:537–43. https://doi.org/10.1038/ng.3536

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by 973 Programme (No. 2018YFC1004404) and National Natural Science Foundation of China (Nos. 31871395, 31801207, 81741043, 31571493). We thank Dr. Bin Zhao from Zhejiang University Life Science Institute for constructs and Dr. Congyi Wang from Tongji Hospital of Huazhong University of Science and Technology for Ubc9flox/flox founder mice.

Author information

Author notes

  1. These authors contributed equally: Liu Mei, Meiyu Qv

Authors and Affiliations

  1. Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China

    Liu Mei, Meiyu Qv, Qiangqiang He, Yana Xu, Qin Zhang, Wei Shi, Ziyi Yan, Chengyun Xu, Chao Tang, Musaddique Hussain & Ximei Wu

  2. Department of Biochemistry and Biophysics, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA

    Liu Mei

  3. Department of Orthopaedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Meiyu Qv, Yana Xu, Chao Tang, Musaddique Hussain & Ximei Wu

  4. Department of Physiology, College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China

    Hangyang Bao

  5. Department of Biology and Genetics, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA

    Wei Shi

  6. Department of Pharmacology, Zhejiang University City College, Hangzhou, China

    Qianlei Ren & Ling-Hui Zeng

Authors
  1. Liu Mei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Meiyu Qv
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hangyang Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qiangqiang He
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yana Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wei Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qianlei Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ziyi Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chengyun Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Chao Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Musaddique Hussain
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ling-Hui Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Ximei Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ling-Hui Zeng or Ximei Wu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mei, L., Qv, M., Bao, H. et al. SUMOylation activates large tumour suppressor 1 to maintain the tissue homeostasis during Hippo signalling. Oncogene 40, 5357–5366 (2021). https://doi.org/10.1038/s41388-021-01937-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-021-01937-9

This article is cited by

Search

Advanced search

Quick links