title: Regulation of Hippo signaling by Jun kinase signaling during compensatory cell proliferation and regeneration, and in neoplastic tumors.
abstract: When cells undergo apoptosis, they can stimulate the proliferation of nearby cells, a process referred to as compensatory cell proliferation. The stimulation of proliferation in response to tissue damage or removal is also central to epimorphic regeneration. The Hippo signaling pathway has emerged as an important regulator of growth during normal development and oncogenesis from Drosophila to humans. Here we show that induction of apoptosis in the Drosophila wing imaginal disc stimulates activation of the Hippo pathway transcription factor Yorkie in surviving and nearby cells, and that Yorkie is required for the ability of the wing to regenerate after genetic ablation of the wing primordia. Induction of apoptosis activates Yorkie through the Jun kinase pathway, and direct activation of Jun kinase signaling also promotes Yorkie activation in the wing disc. We also show that depletion of neoplastic tumor suppressor genes, including lethal giant larvae and discs large, or activation of aPKC, activates Yorkie through Jun kinase signaling, and that Jun kinase activation is necessary, but not sufficient, for the disruption of apical-basal polarity associated with loss of lethal giant larvae. Our observations identify Jnk signaling as a modulator of Hippo pathway activity in wing imaginal discs, and implicate Yorkie activation in compensatory cell proliferation and disc regeneration.
authors.affiliation: Howard Hughes Medical Institute, Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Gongping
authors.initials: G
authors.lastname: Sun
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Irvine
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D047908:Intracellular Signaling Peptides and Proteins; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D012038:Regeneration; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D014921:Wings, Animal / Q000166:cytology / Q000502:physiology; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D048670:MAP Kinase Kinase 4; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C503814:Yki protein, Drosophila; C081435:l(2)gl protein, Drosophila; C070350:dlg1 protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases