title: Amot130 adapts atrophin-1 interacting protein 4 to inhibit yes-associated protein signaling and cell growth.
abstract: The adaptor protein Amot130 scaffolds components of the Hippo pathway to promote the inhibition of cell growth. This study describes how Amot130 through binding and activating the ubiquitin ligase AIP4/Itch achieves these effects. AIP4 is found to bind and ubiquitinate Amot130 at residue Lys-481. This both stabilizes Amot130 and promotes its residence at the plasma membrane. Furthermore, Amot130 is shown to scaffold a complex containing overexpressed AIP4 and the transcriptional co-activator Yes-associated protein (YAP). Consequently, Amot130 promotes the ubiquitination of YAP by AIP4 and prevents AIP4 from binding to large tumor suppressor 1. Amot130 is found to reduce YAP stability. Importantly, Amot130 inhibition of YAP dependent transcription is reversed by AIP4 silencing, whereas Amot130 and AIP4 expression interdependently suppress cell growth. Thus, Amot130 repurposes AIP4 from its previously described role in degrading large tumor suppressor 1 to the inhibition of YAP and cell growth.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Adler
authors.forename: Brigitte L
authors.initials: BL
authors.lastname: Heller
authors.forename: Lauren R
authors.initials: LR
authors.lastname: Bringman
authors.forename: William P
authors.initials: WP
authors.lastname: Ranahan
authors.forename: Ross R
authors.initials: RR
authors.lastname: Cocklin
authors.forename: Mark G
authors.initials: MG
authors.lastname: Goebl
authors.forename: Misook
authors.initials: M
authors.lastname: Oh
authors.forename: Hyun-Suk
authors.initials: HS
authors.lastname: Lim
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ingham
authors.forename: Clark D
authors.initials: CD
authors.lastname: Wells
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000091082:Angiomotins; D049109:Cell Proliferation; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: C423985:AMOT protein, human; D048868:Adaptor Proteins, Signal Transducing; D000091082:Angiomotins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: AIP4; Amot; Angiomotin; Cell Growth; Protein Complexes; Protein Turnover; Ubiquitin Ligase; Ubiquitination; WW Domain; YAP
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