title: Angiomotins link F-actin architecture to Hippo pathway signaling.
abstract: The Hippo pathway regulates the transcriptional coactivator YAP to control cell proliferation, organ size, and stem cell maintenance. Multiple factors, such as substrate stiffness, cell density, and G protein-coupled receptor signaling, regulate YAP through their effects on the F-actin cytoskeleton, although the mechanism is not known. Here we show that angiomotin proteins (AMOT130, AMOTL1, and AMOTL2) connect F-actin architecture to YAP regulation. First, we show that angiomotins are required to relocalize YAP to the cytoplasm in response to various manipulations that perturb the actin cytoskeleton. Second, angiomotins associate with F-actin through a conserved F-actin-binding domain, and mutants defective for F-actin binding show enhanced ability to retain YAP in the cytoplasm. Third, F-actin and YAP compete for binding to AMOT130, explaining how F-actin inhibits AMOT130-mediated cytoplasmic retention of YAP. Furthermore, we find that LATS can synergize with F-actin perturbations by phosphorylating free AMOT130 to keep it from associating with F-actin. Together these results uncover a mechanism for how F-actin levels modulate YAP localization, allowing cells to make developmental and proliferative decisions based on diverse inputs that regulate actin architecture.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology and Program in Cell Dynamics, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mana-Capelli
authors.affiliation: Department of Biochemistry and Molecular Pharmacology and Program in Cell Dynamics, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Murugan
authors.initials: M
authors.lastname: Paramasivam
authors.affiliation: Department of Biochemistry and Molecular Pharmacology and Program in Cell Dynamics, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Shubham
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Department of Biochemistry and Molecular Pharmacology and Program in Cell Dynamics, University of Massachusetts Medical School, Worcester, MA 01605 dannel.mccollum@umassmed.edu.
authors.forename: Dannel
authors.initials: D
authors.lastname: McCollum
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors*; D000091082:Angiomotins; D001665:Binding Sites / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002460:Cell Line; D057809:HEK293 Cells; D006367:HeLa Cells; D000090683:Hippo Signaling Pathway; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008840:Microfilament Proteins; D010750:Phosphoproteins / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: C423985:AMOT protein, human; C510063:AMOTL1 protein, human; C508566:AMOTL2 protein, human; D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D000091082:Angiomotins; D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C406449:LATS2 protein, human; D017346:Protein Serine-Threonine Kinases