title: Hippo pathway-independent restriction of TAZ and YAP by angiomotin.
abstract: The Hippo pathway restricts the activity of transcriptional co-activators TAZ and YAP by phosphorylating them for cytoplasmic sequestration or degradation. In this report, we describe an independent mechanism for the cell to restrict the activity of TAZ and YAP through interaction with angiomotin (Amot) and angiomotin-like 1 (AmotL1). Amot and AmotL1 were robustly co-immunoprecipitated with FLAG-tagged TAZ, and their interaction is dependent on the WW domain of TAZ and the PPXY motif in the N terminus of Amot. Amot and AmotL1 also interact with YAP via the first WW domain of YAP. Overexpression of Amot and AmotL1 caused cytoplasmic retention of TAZ and suppressed its transcriptional outcome such as the expression of CTGF and Cyr61. Hippo refractory TAZ mutant (S89A) is also negatively regulated by Amot and AmotL1. HEK293 cells express the highest level of Amot and AmotL1 among nine cell lines examined, and silencing the expression of endogenous Amot increased the expression of CTGF and Cyr61 either at basal levels or upon overexpression of exogenous S89A. These results reveal a novel mechanism to restrict the activity of TAZ and YAP through physical interaction with Amot and AmotL1.
authors.affiliation: Cancer and Developmental Cell Biology Division, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673.
authors.forename: Siew Wee
authors.initials: SW
authors.lastname: Chan
authors.forename: Chun Jye
authors.initials: CJ
authors.lastname: Lim
authors.forename: Yaan Fun
authors.initials: YF
authors.lastname: Chong
authors.forename: Ajaybabu V
authors.initials: AV
authors.lastname: Pobbati
authors.forename: Caixia
authors.initials: C
authors.lastname: Huang
authors.forename: Wanjin
authors.initials: W
authors.lastname: Hong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000091082:Angiomotins; D002455:Cell Division / Q000502:physiology; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000502:physiology; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D000091102:YAP-Signaling Proteins
chemical_list: C423985:AMOT protein, human; C510063:AMOTL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000091082:Angiomotins; C526317:CCN2 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D055513:Connective Tissue Growth Factor