title: Opposing roles of angiomotin-like-1 and zona occludens-2 on pro-apoptotic function of YAP.
abstract: YAP (Yes-associated protein) oncogene has been found to form a stable complex with members of the Angiomotin (Amot) family of proteins, which bind WW domains of YAP and sequester the protein in the cytoplasm and junctional complexes. The Amot-mediated retention of YAP in the cytoplasm results in the inhibition of its proliferative function. Using apoptotic 'read-out' of YAP in HEK293 cells, we confirmed the molecular mode by which Amot regulates YAP. We showed that a representative member of the Amot family, AmotL1 (Angiomotin-like-1), uses its PPxY motifs to bind WW domains of YAP and inhibit YAP's nuclear translocation and pro-apoptotic function. Recently we also showed that YAP uses its PDZ-binding motif to interact with zona occludens-2 (ZO-2) protein, which promotes YAP's translocation to the nucleus. We also asked if AmotL1, YAP and ZO-2 signal together. We report here that AmotL1 and ZO-2 form a tripartite complex with YAP and regulate its function in HEK293 cells in opposite directions. AmotL1 inhibits pro-apoptotic function of YAP, whereas ZO-2 enhances it. As YAP is a potent oncogene, the identification and characterization of its regulators is important. AmotL1 and ZO-2 are two candidates that could be harnessed to control the oncogenic function of YAP.
authors.affiliation: Laboratory of Signal Transduction and Proteomic Profiling, Weis Center for Research, Geisinger Clinic, Danville, PA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Oka
authors.forename: A P
authors.initials: AP
authors.lastname: Schmitt
authors.forename: M
authors.initials: M
authors.lastname: Sudol
mesh_terms: D000091082:Angiomotins; D017209:Apoptosis; D018797:Cell Cycle Proteins; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000502:physiology*; D009687:Nuclear Proteins / Q000737:chemistry / Q000502:physiology*; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology*; D062827:Zonula Occludens-2 Protein
chemical_list: C510063:AMOTL1 protein, human; D000091082:Angiomotins; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; C569046:TJP2 protein, human; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D062827:Zonula Occludens-2 Protein