title: Drosophila actin-Capping Protein limits JNK activation by the Src proto-oncogene.
abstract: The Src family kinases c-Src, and its downstream effectors, the Rho family of small GTPases RhoA and Jun N-terminal kinase (JNK) have a significant role in tumorigenesis. In this report, using the Drosophila wing disc epithelium as a model system, we demonstrate that the actin-Capping Protein (CP) αβ heterodimer, which regulates actin filament (F-actin) polymerization, limits Src-induced apoptosis or tissue overgrowth by restricting JNK activation. We show that overexpressing Src64B drives JNK-independent loss of epithelial integrity and JNK-dependent apoptosis via Btk29A, p120ctn and Rho1. However, when cells are kept alive with the Caspase inhibitor P35, JNK acts as a potent inducer of proliferation via activation of the Yorkie oncogene. Reducing CP levels direct apoptosis of overgrowing Src64B-overexpressing tissues. Conversely, overexpressing capping protein inhibits Src64B and Rho1, but not Rac1-induced JNK signaling. CP requires the actin-binding domain of the α-subunit to limit Src64B-induced apoptosis, arguing that the control of F-actin mediates this effect. In turn, JNK directs F-actin accumulation. Moreover, overexpressing capping protein also prevents apoptosis induced by ectopic JNK expression. Our data are consistent with a model in which the control of F-actin by CP limits Src-induced apoptosis or tissue overgrowth by acting downstream of Btk29A, p120ctn and Rho1, but upstream of JNK. In turn, JNK may counteract the effect of CP on F-actin, providing a positive feedback, which amplifies JNK activation. We propose that cytoskeletal changes triggered by misregulation of F-actin modulators may have a significant role in Src-mediated malignant phenotypes during the early stages of cellular transformation.
authors: Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors: B G
authors: BG
authors: Fernández
authors: Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors: B
authors: B
authors: Jezowska
authors: Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors: F
authors: F
authors: Janody
mesh_terms: D051344:Actin Capping Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D051177:Catenins / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D060227:Imaginal Discs / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D009154:Mutation; D055503:Protein Multimerization; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D014921:Wings, Animal / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000095002:Delta Catenin
chemical_list: D051344:Actin Capping Proteins; D000199:Actins; D051177:Catenins; D029721:Drosophila Proteins; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D049452:Green Fluorescent Proteins; D011505:Protein-Tyrosine Kinases; C474449:Btk29A protein, Drosophila; C075699:Src64B protein, Drosophila; D048031:JNK Mitogen-Activated Protein Kinases; C511153:Rho1 protein, Drosophila; D020741:rho GTP-Binding Proteins; D000095002:Delta Catenin
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