RRC ID 28602
Author Hirate Y, Hirahara S, Inoue K, Suzuki A, Alarcon VB, Akimoto K, Hirai T, Hara T, Adachi M, Chida K, Ohno S, Marikawa Y, Nakao K, Shimono A, Sasaki H.
Title Polarity-dependent distribution of angiomotin localizes Hippo signaling in preimplantation embryos.
Journal Curr Biol
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.
Volume 23(13)
Pages 1181-94
Published 2013-7-8
DOI 10.1016/j.cub.2013.05.014
PII S0960-9822(13)00577-0
PMID 23791731
PMC PMC3742369
MeSH Adherens Junctions / metabolism Animals Blastocyst / metabolism* Cell Adhesion Cell Polarity* Gene Expression Regulation, Developmental* Intercellular Signaling Peptides and Proteins / genetics* Intercellular Signaling Peptides and Proteins / metabolism Mice Microfilament Proteins / genetics* Microfilament Proteins / metabolism Phosphorylation Polymerase Chain Reaction Protein-Serine-Threonine Kinases / genetics* Protein-Serine-Threonine Kinases / metabolism Signal Transduction* Tumor Suppressor Proteins / metabolism
IF 9.601
Times Cited 190
DNA material pcDNA3.1-pA83-aPKC lambda KD (RDB012202) HA-Amot130/pcDNA3.1-pA83 (RDB012203) HA-Amot80/pcDNA3.1-pA83 (RDB012204) HA-Amot130-delta CC/pcDNA3.1-pA83 (RDB012205) HA-Amot130-m5/pcDNA3.1-pA83 (RDB012206) HA-Amot130-delta PDZbd/pcDNA3.1-pA83 (RDB012207) HA-Amot130-S176A/pcDNA3.1-pA83 (RDB012208) HA-Amot130-S176E/pcDNA3.1-pA83 (RDB012209) HA-Merlin/pCAG-pA83 (RDB012210) HA-Amot-delta(45-100)/pcDNA3.1-pA83 (RDB012211) HA-Amot-delta(101-141)/pcDNA3.1-pA83 (RDB012212) pCMV/SV-Flag-Lats2 (RDB012213) pCMV/SV-Flag-Lats2-KD (RDB012214) Ecad-Flag/pCAG (RDB012215) E-Cadherin-delta C-Flag/pCAG (RDB012216)