The Cell Adhesion Molecule Echinoid Functions as a Tumor Suppressor and Upstream Regulator of the Hippo Signaling Pathway

The Hippo (Hpo) signaling pathway controls tissue growth and organ size in species ranging from Drosophila to mammals and is deregulated ina wide range of human cancers. The core pathway consists of the Hpo/Warts (Wts) kinase cassette that phosphorylates and inactivates the transcriptional coactivator Yorkie (Yki). Here, we report that Echinoid (Ed), an immunoglobulin domain-containing cell adhesion molecule, acts as an upstream regulator of the Hpo pathway. Loss of Ed compromises Yki phosphorylation, resulting in elevated Yki activity that increases Hpo target gene expression and drives tissue overgrowth. Ed physically interacts with and stabilizes the Hpo-binding partner Salvador (Sav) at adherens junctions. Ed/Sav interaction is promoted by cell-cell contact and requires dimerization of Ed cytoplasmic domain. Overexpression of Sav or dimerized Ed cytoplasmic domain suppressed loss-of-Ed phenotypes. We propose that Ed may link cell-cell contact to Hpo signaling through binding and stabilizing Sav, thus modulating the Hpo kinase activity. The Hippo signaling pathway mediates contact inhibition of cell proliferation, but how cell adhesion controls Hippo signaling was unknown. Tao etal. now find that the homophilic cell adhesion molecule Echinoid (a Drosophila nectin) binds and stabilizes the Hippo pathway scaffold Salvador, activating signaling, preferentially during homotypic adhesion.