title: Regulation of Hippo signalling by p38 signalling.
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.
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science & Technology of China, 96 Jin Zhai Road, Hefei 230031, China Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China Key Laboratory of Food Safety Risk Assessment, Ministry of Health, 37 Guang Qu Road, Beijing 100021, China.
authors.forename: Dashun
authors.initials: D
authors.lastname: Huang
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China Key Laboratory of Food Safety Risk Assessment, Ministry of Health, 37 Guang Qu Road, Beijing 100021, China.
authors.forename: Xiaojiao
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China Key Laboratory of Food Safety Risk Assessment, Ministry of Health, 37 Guang Qu Road, Beijing 100021, China.
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China Key Laboratory of Food Safety Risk Assessment, Ministry of Health, 37 Guang Qu Road, Beijing 100021, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Huang
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China Key Laboratory of Food Safety Risk Assessment, Ministry of Health, 37 Guang Qu Road, Beijing 100021, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Ying
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China Key Laboratory of Food Safety Risk Assessment, Ministry of Health, 37 Guang Qu Road, Beijing 100021, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science & Technology of China, 96 Jin Zhai Road, Hefei 230031, China wujr@sibs.ac.cn hysong@sibs.ac.cn.
authors.forename: Jiarui
authors.initials: J
authors.lastname: Wu
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China Key Laboratory of Food Safety Risk Assessment, Ministry of Health, 37 Guang Qu Road, Beijing 100021, China wujr@sibs.ac.cn hysong@sibs.ac.cn.
authors.forename: Haiyun
authors.initials: H
authors.lastname: Song
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D004843:Epistasis, Genetic; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008322:Mammals; D006080:Ovarian Follicle / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014921:Wings, Animal / Q000166:cytology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099317:Hippo Kinases
chemical_list: D000199:Actins; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases
keywords: F-actin; Hippo signalling; p38 signalling