title: Snapshots of a hybrid transcription factor in the Hippo pathway.
abstract: The Hippo pathway plays key roles in animal development. It suppresses tumorigenesis by controlling the transcription of the target genes that are critical for cell proliferation and apoptosis. The transcriptional coactivator YAP is the major downstream effector of the Hippo signaling. Upon extracellular stimulation, a kinase cascade in the Hippo pathway phosphorylates YAP and promotes its cytoplasmic sequestration by 14-3-3 and ubiquitin-dependent degradation. When the Hippo pathway is turned off, YAP (which lacks a DNA-binding domain) is dephosphorylated and translocates to the nucleus, where it associates with the transcription factor TEAD to form a functional heterodimeric transcription factor and to promote the expression of the Hippo-responsive genes. Recently, structures of the YAP-binding domain of TEAD alone or in complex with YAP have revealed the atomic details of the TEAD-YAP interaction. Here, I review these exciting advances, propose a strategy for targeting the TEAD-YAP interaction using small molecules, and suggest potential mechanisms by which phosphorylation and 14-3-3 binding regulate the cytoplasmic retention of YAP.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA. xuelian.luo@utsouthwestern.edu
authors.forename: Xuelian
authors.initials: X
authors.lastname: Luo
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology; D029721:Drosophila Proteins / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000502:physiology*; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry / Q000502:physiology; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction; D000091262:TEA Domain Transcription Factors; D015534:Trans-Activators / Q000737:chemistry / Q000502:physiology; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology*; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D000091262:TEA Domain Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C101205:TEAD2 protein, human; C456659:YY1AP1 protein, human; C503814:Yki protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases