title: Endosomal regulation of contact inhibition through the AMOT:YAP pathway.
abstract: Contact-mediated inhibition of cell proliferation is an essential part of organ growth control; the transcription coactivator Yes-associated protein (YAP) plays a pivotal role in this process. In addition to phosphorylation-dependent regulation of YAP, the integral membrane protein angiomotin (AMOT) and AMOT family members control YAP through direct binding. Here we report that regulation of YAP activity occurs at the endosomal membrane through a dynamic interaction of AMOT with an endosomal integral membrane protein, endotubin (EDTB). EDTB interacts with both AMOT and occludin and preferentially associates with occludin in confluent cells but with AMOT family members in subconfluent cells. EDTB competes with YAP for binding to AMOT proteins in subconfluent cells. Overexpression of the cytoplasmic domain or full-length EDTB induces translocation of YAP to the nucleus, an overgrowth phenotype, and growth in soft agar. This increase in proliferation is dependent upon YAP activity and is complemented by overexpression of p130-AMOT. Furthermore, overexpression of EDTB inhibits the AMOT:YAP interaction. EDTB and AMOT have a greater association in subconfluent cells compared with confluent cells, and this association is regulated at the endosomal membrane. These data provide a link between the trafficking of tight junction proteins through endosomes and contact-inhibition-regulated cell growth.
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Cox
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, CT 06511.
authors.forename: Edward K
authors.initials: EK
authors.lastname: Mandell
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Stewart
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724.
authors.forename: Ruifeng
authors.initials: R
authors.lastname: Lu
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Johnson
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724.
authors.forename: Sarah D
authors.initials: SD
authors.lastname: McCarter
authors.affiliation: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
authors.forename: Andre
authors.initials: A
authors.lastname: Tavares
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724.
authors.forename: Ray
authors.initials: R
authors.lastname: Runyan
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, CT 06511.
authors.forename: Sourav
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724 jeanw@email.arizona.edu.
authors.forename: Jean M
authors.initials: JM
authors.lastname: Wilson
mesh_terms: D000818:Animals; D003260:Contact Inhibition / Q000502:physiology*; D004285:Dogs; D011992:Endosomes / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D015534:Trans-Activators; C427264:endotubin protein, Canis familiaris