The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded

Abstract

The Hippo signaling pathway regulates organ size and tissue homeostasis from Drosophila to mammals. At the core of the Hippo pathway is a kinase cascade extending from the Hippo (Hpo) tumor suppressor to the Yorkie (Yki) oncoprotein. The Hippo kinase cascade, in turn, is regulated by apical membrane-associated proteins such as the FERM domain proteins Merlin and Expanded (Ex), and the WW- and C2-domain protein Kibra. How these apical proteins are themselves regulated remains poorly understood. Here, we identify the transmembrane protein Crumbs (Crb), a determinant of epithelial apical-basal polarity in Drosophila embryos, as an upstream component of the Hippo pathway in imaginal disk growth control. Loss of Crb leads to tissue overgrowth and target gene expression characteristic of defective Hippo signaling. Crb directly binds to Ex through its juxtamembrane FERM-binding motif (FBM). Loss of Crb or mutation of its FBM leads to mislocalization of Ex to basolateral domain of imaginal disk epithelial cells. These results shed light on the mechanism of Ex regulation and provide a molecular link between apical-basal polarity and tissue growth. Furthermore, our studies implicate Crb as a putative cell surface receptor for Hippo signaling by uncovering a transmembrane protein that directly binds to an apical component of the Hippo pathway.

Regulation of leg size and shape: Involvement of the Dachsous‐fat signaling pathway

“…et al, 2010. Furthermore, as an upstream component of Ex, the transmembrane protein Crumbs (Crb), a determinant of epithelial apical-basal polarity in Drosophila embryos, was also identified (Ling et al, 2010). These new factors are likely to function as apical components of the WrsHpo signaling pathway.…”

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

“…A number of cell polarity and cell adhesion proteins were also found to regulate the Hippo pathway. These include the Scribble (Scrib)-Discs large (Dlg)-Lethal giant larvae (Lgl) complex, atypical protein kinase C (aPKC), Crumbs (Crb) , and Echinoid (Ed) (Chen et al, 2010a;Grzeschik et al, 2010;Ling et al, 2010;Robinson et al, 2010;Yue et al, 2012), indicating a role of cell polarity and cell adhesion in Hippo pathway regulation. Furthermore, two studies identified Tao-1, a STE20 family protein kinase as a positive regulator of the Hippo pathway, possibly by directly phosphorylating and activating the Hpo kinase (Boggiano et al, 2011;Poon et al, 2011).…”

Snapshots of a hybrid transcription factor in the Hippo pathway

“…The Ex-Mer-Kibra complex or subcomplexes may activate Hpo-Sav through direct interactions. The atypical cadherin Fat (Ft) and the apical transmembrane protein Crumbs (Crb) function as tumor suppressors and have been implicated as potential cell surface receptors for Hippo signaling (Grzeschik et al, 2010;Ling et al, 2010;Robinson et al, 2010). Crb and Ex directly bind to each other, linking a transmembrane protein to an apical component of the Hippo pathway.…”