The Hippo pathway regulates apical-domain size independently of its growth-control function

Abstract

The Hippo pathway, identified in Drosophila and conserved in vertebrates, regulates tissue growth by promoting cell cycle exit and apoptosis. In addition to their well-characterised overproliferation phenotype, adult Drosophila epithelial cells mutant for the kinases Hippo and Warts have hypertrophic apical domains. Here we examine the molecular basis of this apical hypertrophy and its impact on cell proliferation. In the wing imaginal disc epithelium, we observe increased staining for members of the apical polarity complexes aPKC and Crumbs as well as adherens junction components when Hippo activity is compromised, while basolateral markers are not affected. This increase in apical proteins is correlated with a hypertrophy of the apical domain and adherens junctions. The cell surface localisation of the Notch receptor is also increased in mutant clones, opening the possibility that aberrant receptor signalling may participate in overgrowth of hpo-deficient tissue. Interestingly, however, although the polarity determinant Crumbs is required for the accumulation of apical proteins, this does not appear to significantly contribute to the overproliferation defect elicited by loss of Hippo signalling. Therefore, Hippo signalling controls growth and apical domain size by distinct mechanisms.

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

“…The specific biochemical and genetic link between Crb and Ex, but not between Crb and Mer or Crb and Kibra, is consistent with the view that these apical membrane-associated proteins may integrate distinct upstream signals. We also note that like kibra, ex, and mer, transcription of crb is increased in Hippo pathway mutant cells (25). Thus, negative-feedback regulation of upstream regulators appears to be a general feature of this pathway and may provide an important mechanism to maintain a constant level of Hippo signaling activity in vivo.…”

Essential role of the ERK/MAPK pathway in blood-placental barrier formation

“…In the absence of Hippo signaling, YAP1 is not phosphorylated and is translocated to the nucleus, where it participates in the expansion of the apical domain (Genevet et al, 2009;Hamaratoglu et al, 2009). In Drosophila, misexpression of regulators of cell polarity, such as LGL, atypical PKC and Crumbs, was shown to control the Hippo pathway by affecting the localization of Hippo, Rassf and Expanded (Grzeschik et al, 2010).…”

Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus

“…Thus, although the results of both studies attribute to Merlin a role in regulating subcellular trafficking of multiple transmembrane receptors, the underlying mechanisms appear to be divergent. Genetic studies in Drosophila indicate that such trafficking regulation functions through the Hippo signalling pathway [76,77], as receptor accumulation on the surface of imagi- [76,77], as receptor accumulation on the surface of imagi-, as receptor accumulation on the surface of imaginal epithelial cells can similarly be seen when other components of the Hippo pathway are depleted. Importantly, such accumulation depends on Yorkie [77].…”