Rho differentially regulates the Hippo pathway by modulating the interaction between Amot and Nf2 in the blastocyst

Development. 2017 Nov 1;144(21):3957-3967. doi: 10.1242/dev.157917. Epub 2017 Sep 25.

Abstract

The Hippo pathway modulates the transcriptional activity of Yap to regulate the differentiation of the inner cell mass (ICM) and the trophectoderm (TE) in blastocysts. Yet how Hippo signaling is differentially regulated in ICM and TE cells is poorly understood. Through an inhibitor/activator screen, we have identified Rho as a negative regulator of Hippo in TE cells, and PKA as a positive regulator of Hippo in ICM cells. We further elucidated a novel mechanism by which Rho suppresses Hippo, distinct from the prevailing view that Rho inhibits Hippo signaling through modulating cytoskeleton remodeling and/or cell polarity. Active Rho prevents the phosphorylation of Amot Ser176, thus stabilizing the interaction between Amot and F-actin, and restricting the binding between Amot and Nf2. Moreover, Rho attenuates the interaction between Amot and Nf2 by binding to the coiled-coil domain of Amot. By blocking the association of Nf2 and Amot, Rho suppresses Hippo in TE cells.

Keywords: Amot; Blastocyst; F-actin; Hippo; Mouse; Nf2; Rho.

MeSH terms

  • Actins / metabolism
  • Angiomotins
  • Animals
  • Blastocyst / cytology*
  • Blastocyst / metabolism*
  • Cell Line
  • Cell Membrane / metabolism
  • Cell Polarity
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cytoskeleton / metabolism
  • Ectoderm / cytology
  • Ectoderm / metabolism
  • Female
  • Intercellular Signaling Peptides and Proteins / chemistry
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Mice, Inbred ICR
  • Microfilament Proteins / chemistry
  • Microfilament Proteins / metabolism*
  • Models, Biological
  • Neurofibromin 2 / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein Domains
  • Signal Transduction*
  • rho GTP-Binding Proteins / metabolism*
  • rho-Associated Kinases / metabolism

Substances

  • Actins
  • Amot protein, mouse
  • Angiomotins
  • Intercellular Signaling Peptides and Proteins
  • Microfilament Proteins
  • Neurofibromin 2
  • rho-Associated Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • rho GTP-Binding Proteins