Zyxin-Siah2-Lats2 Axis Mediates Cooperation Between Hippo and TGF-β Signalling Pathways

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Apr 1

PMID 27030211

Citations 60

Authors

Biao Ma

Hongcheng Cheng

Ruize Gao

Chenglong Mu

Ling Chen

Shian Wu

Quan Chen

Yushan Zhu

Affiliations

Soon will be listed here.

Abstract

The evolutionarily conserved Hippo pathway is a regulator that controls organ size, cell growth and tissue homeostasis. Upstream signals of the Hippo pathway have been widely studied, but how microenvironmental factors coordinately regulate this pathway remains unclear. In this study, we identify LIM domain protein Zyxin, as a scaffold protein, that in response to hypoxia and TGF-β stimuli, forms a ternary complex with Lats2 and Siah2 and stabilizes their interaction. This interaction facilitates Lats2 ubiquitination and degradation, Yap dephosphorylation and subsequently activation. We show that Zyxin is required for TGF-β and hypoxia-induced Lats2 downregulation and deactivation of Hippo signalling in MDA-MB-231 cells. Depletion of Zyxin impairs the capability of cell migration, proliferation and tumourigenesis in a xenograft model. Zyxin is upregulated in human breast cancer and positively correlates with histological stages and metastasis. Our study demonstrates that Zyxin-Lats2-Siah2 axis may serve as a potential therapeutic target in cancer treatment.

Citing Articles

Research progress of the Hippo signaling pathway in renal cell carcinoma.

Yang Y, Gan X, Zhang W, Zhu B, Huangfu Z, Shi X Asian J Urol. 2024; 11(4):511-520.

PMID: 39534002 PMC: 11551326. DOI: 10.1016/j.ajur.2024.02.005.

Prognostic signature and immunotherapeutic relevance of Focal adhesion signaling pathway-related genes in osteosarcoma.

Wu Z, Wang Z, Hua Z, Ji Y, Ye Q, Zhang H Heliyon. 2024; 10(21):e38523.

PMID: 39524888 PMC: 11550747. DOI: 10.1016/j.heliyon.2024.e38523.

TBK1-Zyxin signaling controls tumor-associated macrophage recruitment to mitigate antitumor immunity.

Zhou R, Wang M, Li X, Liu Y, Yao Y, Wang A EMBO J. 2024; 43(21):4984-5017.

PMID: 39304793 PMC: 11535546. DOI: 10.1038/s44318-024-00244-9.

Decreased expression of p53 is associated with down expression of zyxin in breast cancer.

Rostampour R, Bahremand K, Mohammadi H, Roghani S, Shakiba E, Goodarzi M Health Sci Rep. 2024; 7(8):e2288.

PMID: 39100715 PMC: 11294437. DOI: 10.1002/hsr2.2288.

Leveraging biotin-based proximity labeling to identify cellular factors governing early alphaherpesvirus infection.

Quan J, Fan Q, Simons L, Smukowski S, Pegg C, Longnecker R mBio. 2024; 15(8):e0144524.

PMID: 38953638 PMC: 11323796. DOI: 10.1128/mbio.01445-24.

References

Zhao B, Ye X, Yu J, Li L, Li W, Li S . TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 2008; 22(14):1962-71. PMC: 2492741. DOI: 10.1101/gad.1664408. View

Massague J . TGFbeta in Cancer. Cell. 2008; 134(2):215-30. PMC: 3512574. DOI: 10.1016/j.cell.2008.07.001. View

Mori M, Nakagami H, Koibuchi N, Miura K, Takami Y, Koriyama H . Zyxin mediates actin fiber reorganization in epithelial-mesenchymal transition and contributes to endocardial morphogenesis. Mol Biol Cell. 2009; 20(13):3115-24. PMC: 2704162. DOI: 10.1091/mbc.e09-01-0046. View

Pardali K, Moustakas A . Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta. 2006; 1775(1):21-62. DOI: 10.1016/j.bbcan.2006.06.004. View

Saucedo L, Edgar B . Filling out the Hippo pathway. Nat Rev Mol Cell Biol. 2007; 8(8):613-21. DOI: 10.1038/nrm2221. View

Hugo H, Ackland M, Blick T, Lawrence M, Clements J, Williams E . Epithelial--mesenchymal and mesenchymal--epithelial transitions in carcinoma progression. J Cell Physiol. 2007; 213(2):374-83. DOI: 10.1002/jcp.21223. View

Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford S . Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007; 130(6):1120-33. PMC: 2666353. DOI: 10.1016/j.cell.2007.07.019. View

Zhao B, Wei X, Li W, Udan R, Yang Q, Kim J . Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 2007; 21(21):2747-61. PMC: 2045129. DOI: 10.1101/gad.1602907. View

Nieto M . Epithelial-Mesenchymal Transitions in development and disease: old views and new perspectives. Int J Dev Biol. 2009; 53(8-10):1541-7. DOI: 10.1387/ijdb.072410mn. View

10.

Zhang J, Ji J, Yu M, Overholtzer M, Smolen G, Wang R . YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nat Cell Biol. 2009; 11(12):1444-50. PMC: 2819909. DOI: 10.1038/ncb1993. View

11.

Sperry R, Bishop N, Bramwell J, Brodeur M, Carter M, Fowler B . Zyxin controls migration in epithelial-mesenchymal transition by mediating actin-membrane linkages at cell-cell junctions. J Cell Physiol. 2009; 222(3):612-24. DOI: 10.1002/jcp.21977. View

12.

Zhao B, Li L, Tumaneng K, Wang C, Guan K . A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes Dev. 2010; 24(1):72-85. PMC: 2802193. DOI: 10.1101/gad.1843810. View

13.

Pan D . The hippo signaling pathway in development and cancer. Dev Cell. 2010; 19(4):491-505. PMC: 3124840. DOI: 10.1016/j.devcel.2010.09.011. View

14.

Varelas X, Samavarchi-Tehrani P, Narimatsu M, Weiss A, Cockburn K, Larsen B . The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-β-SMAD pathway. Dev Cell. 2010; 19(6):831-44. DOI: 10.1016/j.devcel.2010.11.012. View

15.

Xiao L, Chen Y, Ji M, Dong J . KIBRA regulates Hippo signaling activity via interactions with large tumor suppressor kinases. J Biol Chem. 2011; 286(10):7788-7796. PMC: 3048666. DOI: 10.1074/jbc.M110.173468. View

16.

Garcia Fernandez B, Gaspar P, Bras-Pereira C, Jezowska B, Rebelo S, Janody F . Actin-Capping Protein and the Hippo pathway regulate F-actin and tissue growth in Drosophila. Development. 2011; 138(11):2337-46. DOI: 10.1242/dev.063545. View

17.

Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M . Role of YAP/TAZ in mechanotransduction. Nature. 2011; 474(7350):179-83. DOI: 10.1038/nature10137. View

18.

Rauskolb C, Pan G, Reddy B, Oh H, Irvine K . Zyxin links fat signaling to the hippo pathway. PLoS Biol. 2011; 9(6):e1000624. PMC: 3110180. DOI: 10.1371/journal.pbio.1000624. View

19.

Zhao B, Tumaneng K, Guan K . The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat Cell Biol. 2011; 13(8):877-83. PMC: 3987945. DOI: 10.1038/ncb2303. View

20.

Zhao B, Li L, Wang L, Wang C, Yu J, Guan K . Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes Dev. 2012; 26(1):54-68. PMC: 3258966. DOI: 10.1101/gad.173435.111. View