Regulation of Hippo Signalling by P38 Signalling

Overview

Journal J Mol Cell Biol

Publisher Oxford University Press

Specialty Molecular Biology

Date 2016 Jul 13

PMID 27402810

Citations 21

Authors

Dashun Huang

Xiaojiao Li

Li Sun

Ping Huang

Hao Ying

Hui Wang

Jiarui Wu

Haiyun Song

Affiliations

Soon will be listed here.

Abstract

The Hippo signalling pathway has a crucial role in growth control during development, and its dysregulation contributes to tumorigenesis. Recent studies uncover multiple upstream regulatory inputs into Hippo signalling, which affects phosphorylation of the transcriptional coactivator Yki/YAP/TAZ by Wts/Lats. Here we identify the p38 mitogen-activated protein kinase (MAPK) pathway as a new upstream branch of the Hippo pathway. In Drosophila, overexpression of MAPKK gene licorne (lic), or MAPKKK gene Mekk1, promotes Yki activity and induces Hippo target gene expression. Loss-of-function studies show that lic regulates Hippo signalling in ovary follicle cells and in the wing disc. Epistasis analysis indicates that Mekk1 and lic affect Hippo signalling via p38b and wts We further demonstrate that the Mekk1-Lic-p38b cascade inhibits Hippo signalling by promoting F-actin accumulation and Jub phosphorylation. In addition, p38 signalling modulates actin filaments and Hippo signalling in parallel to small GTPases Ras, Rac1, and Rho1. Lastly, we show that p38 signalling regulates Hippo signalling in mammalian cell lines. The Lic homologue MKK3 promotes nuclear localization of YAP via the actin cytoskeleton. Upregulation or downregulation of the p38 pathway regulates YAP-mediated transcription. Our work thus reveals a conserved crosstalk between the p38 MAPK pathway and the Hippo pathway in growth regulation.

Citing Articles

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References

Cully M, Genevet A, Warne P, Treins C, Liu T, Bastien J . A role for p38 stress-activated protein kinase in regulation of cell growth via TORC1. Mol Cell Biol. 2009; 30(2):481-95. PMC: 2798466. DOI: 10.1128/MCB.00688-09. View

Robinson B, Huang J, Hong Y, Moberg K . Crumbs regulates Salvador/Warts/Hippo signaling in Drosophila via the FERM-domain protein Expanded. Curr Biol. 2010; 20(7):582-90. PMC: 2855393. DOI: 10.1016/j.cub.2010.03.019. View

Zheng Y, Wang W, Liu B, Deng H, Uster E, Pan D . Identification of Happyhour/MAP4K as Alternative Hpo/Mst-like Kinases in the Hippo Kinase Cascade. Dev Cell. 2015; 34(6):642-55. PMC: 4589524. DOI: 10.1016/j.devcel.2015.08.014. View

Pantalacci S, Tapon N, Leopold P . The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Nat Cell Biol. 2003; 5(10):921-7. DOI: 10.1038/ncb1051. View

Reddy B, Irvine K . Regulation of Hippo signaling by EGFR-MAPK signaling through Ajuba family proteins. Dev Cell. 2013; 24(5):459-71. PMC: 3624988. DOI: 10.1016/j.devcel.2013.01.020. View

Das Thakur M, Feng Y, Jagannathan R, Seppa M, Skeath J, Longmore G . Ajuba LIM proteins are negative regulators of the Hippo signaling pathway. Curr Biol. 2010; 20(7):657-62. PMC: 2855397. DOI: 10.1016/j.cub.2010.02.035. View

Fernandez B, Jezowska B, Janody F . Drosophila actin-Capping Protein limits JNK activation by the Src proto-oncogene. Oncogene. 2013; 33(16):2027-39. DOI: 10.1038/onc.2013.155. View

Chen H, Wang C, Wang T, Liaw G, Hsu T, Lin T . The Hippo pathway controls polar cell fate through Notch signaling during Drosophila oogenesis. Dev Biol. 2011; 357(2):370-9. DOI: 10.1016/j.ydbio.2011.07.003. View

Inoue H, Tateno M, Takaesu G, Ninomiya-Tsuji J, Irie K, Nishida Y . A Drosophila MAPKKK, D-MEKK1, mediates stress responses through activation of p38 MAPK. EMBO J. 2001; 20(19):5421-30. PMC: 125648. DOI: 10.1093/emboj/20.19.5421. View

10.

Sansores-Garcia L, Bossuyt W, Wada K, Yonemura S, Tao C, Sasaki H . Modulating F-actin organization induces organ growth by affecting the Hippo pathway. EMBO J. 2011; 30(12):2325-35. PMC: 3116287. DOI: 10.1038/emboj.2011.157. View

11.

Lai Z, Wei X, Shimizu T, Ramos E, Rohrbaugh M, Nikolaidis N . Control of cell proliferation and apoptosis by mob as tumor suppressor, mats. Cell. 2005; 120(5):675-85. DOI: 10.1016/j.cell.2004.12.036. View

12.

Polesello C, Tapon N . Salvador-warts-hippo signaling promotes Drosophila posterior follicle cell maturation downstream of notch. Curr Biol. 2007; 17(21):1864-70. DOI: 10.1016/j.cub.2007.09.049. View

13.

Schertel C, Huang D, Bjorklund M, Bischof J, Yin D, Li R . Systematic screening of a Drosophila ORF library in vivo uncovers Wnt/Wg pathway components. Dev Cell. 2013; 25(2):207-19. DOI: 10.1016/j.devcel.2013.02.019. View

14.

Regue L, Mou F, Avruch J . G protein-coupled receptors engage the mammalian Hippo pathway through F-actin: F-Actin, assembled in response to Galpha12/13 induced RhoA-GTP, promotes dephosphorylation and activation of the YAP oncogene. Bioessays. 2013; 35(5):430-5. PMC: 4092039. DOI: 10.1002/bies.201200163. View

15.

Hamaratoglu F, Willecke M, Kango-Singh M, Nolo R, Hyun E, Tao C . The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat Cell Biol. 2005; 8(1):27-36. DOI: 10.1038/ncb1339. View

16.

Wu S, Huang J, Dong J, Pan D . hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell. 2003; 114(4):445-56. DOI: 10.1016/s0092-8674(03)00549-x. View

17.

Yin D, Huang P, Wu J, Song H . Drosophila protein phosphatase V regulates lipid homeostasis via the AMPK pathway. J Mol Cell Biol. 2013; 6(1):100-2. DOI: 10.1093/jmcb/mjt050. View

18.

Koul H, Pal M, Koul S . Role of p38 MAP Kinase Signal Transduction in Solid Tumors. Genes Cancer. 2013; 4(9-10):342-59. PMC: 3863344. DOI: 10.1177/1947601913507951. View

19.

Meignin C, Alvarez-Garcia I, Davis I, Palacios I . The salvador-warts-hippo pathway is required for epithelial proliferation and axis specification in Drosophila. Curr Biol. 2007; 17(21):1871-8. PMC: 3432442. DOI: 10.1016/j.cub.2007.09.062. View

20.

Chen J, Xie C, Tian L, Hong L, Wu X, Han J . Participation of the p38 pathway in Drosophila host defense against pathogenic bacteria and fungi. Proc Natl Acad Sci U S A. 2010; 107(48):20774-9. PMC: 2996427. DOI: 10.1073/pnas.1009223107. View