title: Polarity-dependent distribution of angiomotin localizes Hippo signaling in preimplantation embryos.
abstract: BACKGROUND
  In preimplantation mouse embryos, the first cell fate specification to the trophectoderm or inner cell mass occurs by the early blastocyst stage. The cell fate is controlled by cell position-dependent Hippo signaling, although the mechanisms underlying position-dependent Hippo signaling are unknown.
  
  
  RESULTS
  We show that a combination of cell polarity and cell-cell adhesion establishes position-dependent Hippo signaling, where the outer and inner cells are polar and nonpolar, respectively. The junction-associated proteins angiomotin (Amot) and angiomotin-like 2 (Amotl2) are essential for Hippo pathway activation and appropriate cell fate specification. In the nonpolar inner cells, Amot localizes to adherens junctions (AJs), and cell-cell adhesion activates the Hippo pathway. In the outer cells, the cell polarity sequesters Amot from basolateral AJs to apical domains, thereby suppressing Hippo signaling. The N-terminal domain of Amot is required for actin binding, Nf2/Merlin-mediated association with the E-cadherin complex, and interaction with Lats protein kinase. In AJs, S176 in the N-terminal domain of Amot is phosphorylated by Lats, which inhibits the actin-binding activity, thereby stabilizing the Amot-Lats interaction to activate the Hippo pathway.
  
  
  CONCLUSIONS
  We propose that the phosphorylation of S176 in Amot is a critical step for activation of the Hippo pathway in AJs and that cell polarity disconnects the Hippo pathway from cell-cell adhesion by sequestering Amot from AJs. This mechanism converts positional information into differential Hippo signaling, thereby leading to differential cell fates.
authors.affiliation: Department of Cell Fate Control, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Hirate
authors.forename: Shino
authors.initials: S
authors.lastname: Hirahara
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Inoue
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suzuki
authors.forename: Vernadeth B
authors.initials: VB
authors.lastname: Alarcon
authors.forename: Kazunori
authors.initials: K
authors.lastname: Akimoto
authors.forename: Takaaki
authors.initials: T
authors.lastname: Hirai
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hara
authors.forename: Makoto
authors.initials: M
authors.lastname: Adachi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Chida
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ohno
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Marikawa
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nakao
authors.forename: Akihiko
authors.initials: A
authors.lastname: Shimono
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sasaki
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D000091082:Angiomotins; D000818:Animals; D001755:Blastocyst / Q000378:metabolism*; D002448:Cell Adhesion; D016764:Cell Polarity; D018507:Gene Expression Regulation, Developmental; D000090683:Hippo Signaling Pathway; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C511047:Amot protein, mouse; D000091082:Angiomotins; D036341:Intercellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D025521:Tumor Suppressor Proteins; C490501:Lats1 protein, mouse; C522633:LATS2 protein, mouse; D017346:Protein Serine-Threonine Kinases