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Filling out the Hippo pathway

Nature Reviews Molecular Cell Biology volume 8, pages 613–621 (2007)Cite this article

Key Points

  • Studies in Drosophila melanogaster have delineated a novel signalling pathway, the Hippo pathway, which has an important role in restraining cell proliferation and promoting apoptosis in differentiating epithelia. Although this pathway is currently poorly characterized in mammals, several components of the Hippo pathway appear to function as tumour suppressors.

  • The protein Fat, originally discovered in D. melanogaster as the founding member of a subfamily of genes called protocadherins, has been newly identified as an upstream regulator of the Hippo pathway. The data suggest that Fat increases Hippo activity by two mechanisms: it modulates Hippo activity through phosphorylation and stabilizes the Warts protein (a central kinase of the Hippo signal transduction pathway).

  • Two recent reports have identified a new transcriptional target downstream of the Hippo pathway in D. melanogaster that can promote tissue growth and inhibit apoptosis: the microRNA bantam. However, it remains unclear how bantam promotes cell proliferation and whether the mechanism(s) is conserved in mammals.

  • In flies and mammals, Hippo signalling promotes apoptosis in response to irradiation. Recent work in D. melanogaster suggests that p53 is responsible for the activation of Hippo following irradiation, and that members of the Ras association family can temper this response.

  • Loss of Hippo signalling allows cells in the developing fly to outcompete and eliminate neighbouring wild-type cells. This phenomenon is known as supercompetition. The mechanism(s) that enables Hippo-mutant cells to act as 'supercompetitors' remains unclear.

  • Two unresolved questions pertaining to the Hippo pathway are: do extracellular ligands regulate Hippo activity by binding to Fat? And does the supercompetition phenotype of Hippo mutants contribute to mammalian tumorigenesis?

Abstract

How cell numbers are controlled during organ development is a problem that is still in need of answers. Recent studies in Drosophila melanogaster have delineated a novel signalling pathway, the Hippo pathway, which has an important role in restraining cell proliferation and promoting apoptosis in differentiating epithelial cells. Much like cancer cells, cells that contain mutations for components of the Hippo pathway proliferate inappropriately and have a competitive edge in genetically mosaic tissues. Although poorly characterized in mammals, several components of the Hippo pathway seem to be tumour suppressors in humans.

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Figure 1: The Hippo signalling pathway.
Figure 2: Warts and Fat mutant phenotypes.
Figure 3: Regulation of Hippo signalling.
Figure 4: Inactivation of Hippo signalling promotes cell competition.

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Authors and Affiliations

  1. Department of Biology, University of Puget Sound, 1500 North Warner Street, Tacoma, 98416, Washington, USA

    Leslie J. Saucedo

  2. Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, 98109, Washington, USA

    Leslie J. Saucedo & Bruce A. Edgar

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Glossary

FERM domain

An amino-acid homology domain that was first identified in the Band 4.1 family of proteins (4.1, ezrin, radixin and moesin). This domain typically localizes to cell surfaces and crosslinks the actin cytoskeleton with the plasma membrane.

Protocadherin

A member of the largest subgroup of the cadherin family. Protocadherins have extensive extracellular domains and cytoplasmic domains that vary widely from each other and from the domains of classic cadherins.

Adherens junction

An adhesive junction that is commonly found between epithelial cells. It is maintained by extracellular interactions of cadherin proteins and intracellular interactions with the actin cytoskeleton.

Desmosomal junction

An adhesive junction between epithelial cells that is located basally to adherens junctions. It is maintained by extracellular interactions of cadherin proteins that are anchored intracellularly to intermediate filaments.

Unconventional myosin

A member of a class of motor proteins that interact with the actin cytoskeleton and have been shown to direct intracellular vesicle transport and to contribute to neurosensory function.

Interommatidial cell

One of a single layer of pigment cells that surround each ommatidia in the adult eye of Drosophila melanogaster. These cells are produced in excess before being reduced by apoptosis during insect development.

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Saucedo, L., Edgar, B. Filling out the Hippo pathway. Nat Rev Mol Cell Biol 8, 613–621 (2007). https://doi.org/10.1038/nrm2221

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