Studies of the Hippo Signaling Pathway

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2012-08-13

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Abstract

How multicellular organisms control their growth to reach proper organ size during development is a fascinating question. Recent studies, initially from Drosophila, have identified the Hpo tumor suppressor pathway as a crucial mechanism that controls tissue growth by inhibiting cell growth, proliferation and survival. Deregulation of the Hpo pathway has been implicated in various human cancers.

Central to the Hpo pathway is a kinase cassette consisting of four tumor suppressor proteins, the Ste20-like kinase Hpo, the WW domain-containing protein Salvador (Sav), the NDR family kinase Warts (Wts) and the Mob family protein Mats. The kinase activities of Hpo and Wts are facilitated by their regulatory proteins Sav and Mats, respectively. Activated Hpo/Sav complex phosphorylates and activates the Wts/Mats complex, which in turn phosphorylates and inactivates the transcriptional coactivator Yorkie (Yki). Phosphorylation of Yki restricts its nuclear localization through recruiting 14-3-3. When the activity of the Hpo/Wts kinase cassette is compromised, Yki forms complexes with transcription factors including Scalloped (Sd) and translocates to the nucleus to activate Hpo pathway target genes, including cyclin E, diap1, and the microRNA bantam that regulate cell growth, proliferation and survival.

To identify novel components of the Hpo signaling pathway, I carried out a genetic modifier screen in which flies carrying GMR-Gal4 and UAS-Yki were crossed to a collection of transgenic RNAi lines from Vienna Drosophila RNAi center (VDRC) and Bloomington stock center, and looked for enhancers or suppressors of the overgrown eye phenotype caused by Yki overexpression. Through this screen, I have found that Echinoid (Ed), an immunoglobulin domain-containing cell adhesion molecule, acts as an upstream regulator of the Hpo pathway. Loss of Ed compromises Yki phosphorylation, resulting in elevated Yki activity that drives Hpo target gene expression and tissue overgrowth. Ed physically interacts with and stabilizes the Hpo-binding partner Sav at adherens junctions. Ed/Sav interaction is promoted by cell-cell contact and requires dimerization of Ed cytoplasmic domain. Overexpression of Sav or dimerized Ed cytoplasmic domain suppressed loss-of-Ed phenotypes. I propose that Ed may link cell-cell contact to Hpo signaling through binding and stabilizing Sav, thus modulating the Hpo kinase activity. Furthermore, the Cul4/WDR40A complex has also been identified as a genetic modifier for the Hippo signaling pathway. However, the exact mechanism by which this complex regulates the Hippo signaling pathway need to be further addressed. [Keywords: hippo pathway, echinoid, Salvado, cell adhesion, cell contact]

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