POSH regulates Hippo signaling through ubiquitin-mediated expanded degradation

Xianjue Ma; Xiaowei Guo; Helena E Richardson; Tian Xu; Lei Xue

doi:10.1073/pnas.1715165115

POSH regulates Hippo signaling through ubiquitin-mediated expanded degradation

Proc Natl Acad Sci U S A. 2018 Feb 27;115(9):2150-2155. doi: 10.1073/pnas.1715165115. Epub 2018 Feb 12.

Authors

Xianjue Ma^{1

2

3}, Xiaowei Guo⁴, Helena E Richardson⁵, Tian Xu^{2

3}, Lei Xue^{1

6}

Affiliations

¹ Institute of Intervention Vessel, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, 200092 Shanghai, China; [email protected] [email protected].
² Department of Genetics, Yale University School of Medicine, New Haven, CT 06519.
³ Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06519.
⁴ Institute of Intervention Vessel, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, 200092 Shanghai, China.
⁵ Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
⁶ Center of Intervention Radiology, Zhuhai People's Hospital, 519000 Zhuhai, China.

Abstract

The Hippo signaling pathway is a master regulator of organ growth, tissue homeostasis, and tumorigenesis. The activity of the Hippo pathway is controlled by various upstream components, including Expanded (Ex), but the precise molecular mechanism of how Ex is regulated remains poorly understood. Here we identify Plenty of SH3s (POSH), an E3 ubiquitin ligase, as a key component of Hippo signaling in DrosophilaPOSH overexpression synergizes with loss of Kibra to induce overgrowth and up-regulation of Hippo pathway target genes. Furthermore, knockdown of POSH impedes dextran sulfate sodium-induced Yorkie-dependent intestinal stem cell renewal, suggesting a physiological role of POSH in modulating Hippo signaling. Mechanistically, POSH binds to the C-terminal of Ex and is essential for the Crumbs-induced ubiquitination and degradation of Ex. Our findings establish POSH as a crucial regulator that integrates the signal from the cell surface to negatively regulate Ex-mediated Hippo activation in Drosophila.

Keywords: Drosophila; Expanded; Hippo signaling; POSH; intestine stem cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Cytoskeletal Proteins / genetics
Cytoskeletal Proteins / metabolism*
Dextran Sulfate
Drosophila Proteins / genetics
Drosophila Proteins / metabolism*
Drosophila melanogaster / genetics
Drosophila melanogaster / metabolism*
Gene Deletion
Genome
Intestines / drug effects
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
Protein Binding
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Proteolysis
Signal Transduction
Stem Cells / drug effects
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism
Ubiquitin / metabolism*

Substances

Carrier Proteins
Cytoskeletal Proteins
Drosophila Proteins
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Nerve Tissue Proteins
POSH protein, Drosophila
Tumor Suppressor Proteins
Ubiquitin
ex protein, Drosophila
kibra protein, Drosophila
Dextran Sulfate
Protein Serine-Threonine Kinases
hpo protein, Drosophila

Grants and funding

HHMI/Howard Hughes Medical Institute/United States