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. 2009 Mar;16(3):411-20.
doi: 10.1016/j.devcel.2009.01.010.

The FERM-domain Protein Expanded Regulates Hippo Pathway Activity via Direct Interactions With the Transcriptional Activator Yorkie

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The FERM-domain Protein Expanded Regulates Hippo Pathway Activity via Direct Interactions With the Transcriptional Activator Yorkie

Caroline Badouel et al. Dev Cell. .
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Abstract

The Hippo kinase pathway plays a central role in growth regulation and tumor suppression from flies to man. The Hippo/Mst kinase phosphorylates and activates the NDR family kinase Warts/Lats, which phosphorylates and inhibits the transcriptional activator Yorkie/YAP. Current models place the FERM-domain protein Expanded upstream of Hippo kinase in growth control. To understand how Expanded regulates Hippo pathway activity, we used affinity chromatography and mass spectrometry to identify Expanded-binding proteins. Surprisingly we find that Yorkie is the major Expanded-binding protein in Drosophila S2 cells. Expanded binds Yorkie at endogenous levels via WW-domain-PPxY interactions, independently of Yorkie phosphorylation at S168, which is critical for 14-3-3 binding. Expanded relocalizes Yorkie from the nucleus, abrogating its nuclear activity, and it can regulate growth downstream of warts in vivo. These data lead to a new model whereby Expanded functions downstream of Warts, in concert with 14-3-3 proteins to sequester Yorkie in the cytoplasm, inhibiting growth activity of the Hippo pathway.

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