title: Interlocked positive and negative feedback network motifs regulate β-catenin activity in the adherens junction pathway.
abstract: The integrity of epithelial tissue architecture is maintained through adherens junctions that are created through extracellular homotypic protein-protein interactions between cadherin molecules. Cadherins also provide an intracellular scaffold for the formation of a multiprotein complex that contains signaling proteins, including β-catenin. Environmental factors and controlled tissue reorganization disrupt adherens junctions by cleaving the extracellular binding domain and initiating a series of transcriptional events that aim to restore tissue homeostasis. However, it remains unclear how alterations in cell adhesion coordinate transcriptional events, including those mediated by β-catenin in this pathway. Here were used quantitative single-cell and population-level in vitro assays to quantify the endogenous pathway dynamics after the proteolytic disruption of the adherens junctions. Using prior knowledge of isolated elements of the overall network, we interpreted these data using in silico model-based inference to identify the topology of the regulatory network. Collectively the data suggest that the regulatory network contains interlocked network motifs consisting of a positive feedback loop, which is used to restore the integrity of adherens junctions, and a negative feedback loop, which is used to limit β-catenin-induced gene expression.
authors.affiliation: Department of Chemical Engineering and Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506 Department of Immunology, Microbiology, and Cell Biology, West Virginia University, Morgantown, WV 26506 david.klinke@mail.wvu.edu).
authors.forename: David J
authors.initials: DJ
authors.lastname: Klinke
authors.affiliation: Department of Chemical Engineering and Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Horvath
authors.affiliation: Department of Chemical Engineering and Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Cuppett
authors.affiliation: Department of Chemical Engineering and Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506.
authors.forename: Yueting
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Immunology, Microbiology, and Cell Biology, West Virginia University, Morgantown, WV 26506.
authors.forename: Wentao
authors.initials: W
authors.lastname: Deng
authors.affiliation: Department of Immunology, Microbiology, and Cell Biology, West Virginia University, Morgantown, WV 26506.
authors.forename: Rania
authors.initials: R
authors.lastname: Kanj
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism*; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D025461:Feedback, Physiological; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D015534:Trans-Activators / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D015820:Cadherins; D015534:Trans-Activators; D051176:beta Catenin