Modulation of the Hippo pathway and organ growth by RNA processing proteins

Jana Mach, Mardelle Atkins, Kathleen M. Gajewski, Violaine Mottier-Pavie, Leticia Sansores-Garcia, Jun Xie, Robert Andrew Mills, Weronika Kowalczyk, Leen Van Huffel, Gordon Mills, Georg Halder

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

The Hippo tumor-suppressor pathway regulates organ growth, cell proliferation, and stem cell biology. Defects in Hippo signaling and hyperactivation of its downstream effectors-Yorkie (Yki) in Drosophila and YAP/TAZ in mammals-result in progenitor cell expansion and overgrowth of multiple organs and contribute to cancer development. Deciphering the mechanisms that regulate the activity of the Hippo pathway is key to understanding its function and for therapeutic targeting. However, although the Hippo kinase cascade and several other upstream inputs have been identified, the mechanisms that regulate Yki/YAP/TAZ activity are still incompletely understood. To identify new regulators of Yki activity, we screened in Drosophila for suppressors of tissue overgrowth and Yki activation caused by overexpression of atypical protein kinase C (aPKC), a member of the apical cell polarity complex. In this screen, we identified mutations in the heterogeneous nuclear ribonucleoprotein Hrb27C that strongly suppressed the tissue defects induced by ectopic expression of aPKC. Hrb27C was required for aPKC-induced tissue growth and Yki target gene expression but did not affect general gene expression. Genetic and biochemical experiments showed that Hrb27C affects Yki phosphorylation. Other RNA-binding proteins known to interact with Hrb27C for mRNA transport in oocytes were also required for normal Yki activity, although they suppressed Yki output. Based on the known functions of Hrb27C, we conclude that Hrb27C-mediated control of mRNA splicing, localization, or translation is essential for coordinated activity of the Hippo pathway.

Original languageEnglish (US)
Pages (from-to)10684-10689
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number42
DOIs
StatePublished - Oct 16 2018
Externally publishedYes

Keywords

  • APKC
  • Hippo pathway
  • HNRNP
  • Hrb27C
  • RNA-binding proteins

ASJC Scopus subject areas

  • General

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  • Cite this

    Mach, J., Atkins, M., Gajewski, K. M., Mottier-Pavie, V., Sansores-Garcia, L., Xie, J., Mills, R. A., Kowalczyk, W., Van Huffel, L., Mills, G., & Halder, G. (2018). Modulation of the Hippo pathway and organ growth by RNA processing proteins. Proceedings of the National Academy of Sciences of the United States of America, 115(42), 10684-10689. https://doi.org/10.1073/pnas.1807325115