Regulation of Hippo Signaling by EGFR-MAPK Signaling through Ajuba Family Proteins

• Published in: Developmental cell Vol. 24; no. 5; pp. 459 - 471
• Main Authors: Reddy, B.V.V.G., Irvine, Kenneth D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.03.2013
• Subjects: Animals; Blotting, Western; carcinogenesis; cell proliferation; Drosophila; Drosophila melanogaster - chemistry; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - antagonists & inhibitors; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; epistasis; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Immunoprecipitation; LIM Domain Proteins - genetics; LIM Domain Proteins - metabolism; linkage (genetics); mammals; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; phosphorylation; ras Proteins - genetics; ras Proteins - metabolism; Real-Time Polymerase Chain Reaction; Receptors, Invertebrate Peptide - antagonists & inhibitors; Receptors, Invertebrate Peptide - genetics; Receptors, Invertebrate Peptide - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Signal Transduction; Trans-Activators - antagonists & inhibitors; Trans-Activators - genetics; Trans-Activators - metabolism; transcription factors; warts; YAP-Signaling Proteins
• ISSN: 1534-5807; 1878-1551; 1878-1551
• DOI: 10.1016/j.devcel.2013.01.020

EGFR and Hippo signaling pathways both control growth and, when dysregulated, contribute to tumorigenesis. We find that EGFR activates the Hippo pathway transcription factor Yorkie and demonstrate that Yorkie is required for the influence of EGFR on cell proliferation in Drosophila. EGFR regulates Yorkie through the influence of its Ras-MAPK branch on the Ajuba LIM protein Jub. Jub is epistatic to EGFR and Ras for Yorkie regulation, Jub is subject to MAPK-dependent phosphorylation, and EGFR-Ras-MAPK signaling enhances Jub binding to the Yorkie kinase Warts and the adaptor protein Salvador. An EGFR-Hippo pathway link is conserved in mammals, as activation of EGFR or RAS activates the Yorkie homolog YAP, and EGFR-RAS-MAPK signaling promotes phosphorylation of the Ajuba family protein WTIP and also enhances WTIP binding to the Warts and Salvador homologs LATS and WW45. Our observations implicate the Hippo pathway in EGFR-mediated tumorigenesis and identify a molecular link between these pathways. ► EGFR-Ras-MAPK signaling regulates Yki/YAP activity ► EGFR regulation of Drosophila Yki requires the Ajuba LIM protein Jub ► ERK phosphorylates the Ajuba family proteins Jub and WTIP ► ERK promotes binding of Jub and WTIP to Warts/LATS and Salvador/WW45 Reddy et al. show that the EGFR/MAPK pathway controls cell proliferation via phosphorylation of Ajuba family LIM proteins. Phosphorylated Ajuba proteins bind to Hippo pathway components, derepressing the transcriptional coactivator Yorkie/YAP. EGFR growth-regulatory effects depend on this direct link to Ajuba proteins and Yorkie/YAP in flies and mammalian cells.