Signaling through the Hippo (named for the protein Hpo in flies, which is called Mst in vertebrates) pathway suppresses cell growth by triggering phosphorylation of the transcriptional coactivator Yorkie (Yki, Yap in vertebrates) by the kinase Warts (Wts, Lats in vertebrates), thus excluding Yki from the nucleus, where it promotes expression of genes that stimulate proliferation and inhibit apoptosis. Reddy et al. report that epidermal growth factor receptor (EGFR) signaling through the Ras-mitogen–activated protein kinase (MAPK) pathway activated Yki by inhibiting Hpo signaling. In the fruit fly Drosophila melanogaster, expression of a constitutively active form of EGFR in eye discs promoted glial proliferation, and knockdown of Yki by RNA interference (RNAi) prevented this. Conversely, RNAi-mediated knockdown of EGFR inhibited glial proliferation, which was partially suppressed by expressing an activated form of Yki in glia. In wing discs, expression of constitutively active EGFR also promoted Yki-dependent epithelial cell proliferation, nuclear localization of Yki, and expression of a Yki target gene. Experiments with constitutively active proteins and RNAi constructs expressed in imaginal discs and brain indicated that EGFR signaled through the guanosine triphosphatase Ras, the kinase Raf, and the extracellular signal–regulated kinase (ERK) Rolled. Activation of Yki through the EGFR-Ras-MAPK pathway required the LIM domain protein Ajuba (Jub), which binds to Wts and to Salvador (Sav), a protein that interacts with Wts to promote phosphorylation of Wts by Hpo. EGFR-Ras-MAPK signaling stimulated phosphorylation of Jub and increased the amount of Jub that was associated with Wts and Sav in extracts from cultured fly cells, consistent with a model in which Jub acts downstream of EGFR-Ras-MAPK signaling to inhibit Wts activity toward Yki. Experiments in human glial and kidney cell lines indicated that this mechanism of crosstalk between the EGFR and Hippo pathways is likely conserved. The EGFR and Hippo pathways have important and opposing effects on cell growth, and both have been linked to various cancers. The mode of crosstalk identified in this report suggests that one of the ways in which EGFR signaling can promote oncogenesis is by inhibiting the tumor-suppressing Hippo pathway.
B. V. V. G. Reddy, K. D. Irvine, Regulation of Hippo signaling by EGFR-MAPK signaling through Ajuba family proteins. Dev. Cell 24, 459–471 (2013). [PubMed]