Disruption of the Cdc42/Par6/aPKC or Dlg/Scrib/Lgl Polarity Complex Promotes Epithelial Proliferation via Overlapping Mechanisms

• Published in: PloS one Vol. 11; no. 7; p. e0159881
• Main Authors: Schimizzi, Gregory V, Maher, Meghan T, Loza, Andrew J, Longmore, Gregory D
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25-07-2016; Public Library of Science (PLoS)
• Subjects: Actin; Adaptor Proteins, Signal Transducing - metabolism; Analysis; Animals; Apoptosis; Biology; Biology and Life Sciences; Cancer; Carcinoma; cdc42 GTP-Binding Protein - metabolism; Cdc42 protein; Cell adhesion & migration; Cell division; Cell growth; Cell Proliferation; Contractility; Cortex; Disruption; Drosophila; Drosophila melanogaster; Drosophila Proteins - metabolism; Epithelial Cells - metabolism; Epithelium; Epithelium - metabolism; Gene expression; Insects; JNK protein; Kinases; MAP Kinase Signaling System; Medicine; Medicine and Health Sciences; Mitogen-Activated Protein Kinases - metabolism; Moesin; Morphogenesis; Multiprotein Complexes - metabolism; Myosin; Myosins - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Physiology; Polarity; Polarity (Biology); Protein Binding; Protein Kinase C - metabolism; Proteins; Research and Analysis Methods; rho GTP-Binding Proteins - metabolism; rho-Associated Kinases - metabolism; Signaling; Suppressors; Trends; Tumor necrosis factor; Tumor Suppressor Proteins - metabolism; Viruses; South Korea; United States > US; Missouri
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0159881

The establishment and maintenance of apical-basal polarity is a defining characteristic and essential feature of functioning epithelia. Apical-basal polarity (ABP) proteins are also tumor suppressors that are targeted for disruption by oncogenic viruses and are commonly mutated in human carcinomas. Disruption of these ABP proteins is an early event in cancer development that results in increased proliferation and epithelial disorganization through means not fully characterized. Using the proliferating Drosophila melanogaster wing disc epithelium, we demonstrate that disruption of the junctional vs. basal polarity complexes results in increased epithelial proliferation via distinct downstream signaling pathways. Disruption of the basal polarity complex results in JNK-dependent proliferation, while disruption of the junctional complex primarily results in p38-dependent proliferation. Surprisingly, the Rho-Rok-Myosin contractility apparatus appears to play opposite roles in the regulation of the proliferative phenotype based on which polarity complex is disrupted. In contrast, non-autonomous Tumor Necrosis Factor (TNF) signaling appears to suppress the proliferation that results from apical-basal polarity disruption, regardless of which complex is disrupted. Finally we demonstrate that disruption of the junctional polarity complex activates JNK via the Rho-Rok-Myosin contractility apparatus independent of the cortical actin regulator, Moesin.