Editors' ChoiceDevelopmental Biology

Kibra Is a Pez Dispenser

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Science Signaling  13 Mar 2012:
Vol. 5, Issue 215, pp. ec80
DOI: 10.1126/scisignal.2003032

The Hippo pathway limits cell size and proliferation and has been implicated in midgut homeostasis in flies and intestinal regeneration in mammals. Activation of the kinase Hippo leads to phosphorylation of the transcriptional coactivator Yorkie (Yki), which prevents Yki from translocating to the nucleus, where it stimulates expression of genes required for proliferation. Activation of Hippo requires the FERM (band 4.1, ezrin, radixin, moesin) domain proteins Merlin (Mer) and Expanded (Ex), which bind to the scaffolding protein Kibra. Using affinity purification–mass spectrometry and various biochemical assays, Poernbacher et al. identified Pez as an additional binding partner for Kibra. Pez mutant flies were smaller than wild-type (WT) flies and exhibited signs of starvation. Although the midgut epithelia of Pez mutant larvae were normal, the adult midgut exhibited hyperplasia, with increased numbers of mitotic cells and of intestinal stem cells (ISCs) and their multipotent descendants. Under conditions of intestinal stress, Yki promotes the production of cytokines that trigger proliferation of ISCs. Signaling through these proliferative pathways and expression of a Yki transcriptional target were increased in the midguts of Pez mutants as compared with those of WT flies. Removing one copy of yki rescued the body size and midgut hypertrophy in Pez mutants. Expressing Pez specifically in enterocytes rescued the midgut defects of Pez mutants and prevented increased ISC proliferation in response to the cell-damaging agent bleomycin. Likewise, knocking down yki or overexpressing hippo in enterocytes partially rescued Pez midgut defects, implying that Pez promotes Hippo signaling in enterocytes to restrict proliferation of ISCs. The FERM domain of Pez was required for its activity, and the interaction of Pez with Kibra required Kibra’s first WW domain, which is also required for Kibra binding to Mer and Ex, and a proline-rich domain in Pez. There are two Pez homologs in mammals, and previous reports indicate that Hippo signaling restricts proliferation in mammalian intestinal epithelia in the absence of regenerative cues. Therefore, Pez may represent a conserved tissue-specific Hippo signaling component that limits intestinal cell proliferation.

I. Poernbacher, R. Baumgartner, S. K. Marada, K. Edwards, H. Stocker, Drosophila Pez acts in Hippo signaling to restrict intestinal stem cell proliferation. Curr. Biol. 22, 389–396 (2012). [PubMed]

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