title: Drosophila Src-family kinases function with Csk to regulate cell proliferation and apoptosis.
abstract: Elevated Src protein levels and activity are associated with the development and progression of a variety of cancers. The consequences of deregulated Src activity have been studied extensively in cell culture; however, the effects of this deregulation in vivo, as well as the mechanisms of Src-induced tumorigenesis, remain poorly understood. In this study, the effect of expressing wild-type and constitutively active Drosophila Src-family kinases (SFKs) in the developing eye was examined. Overexpression of either wild-type Drosophila SFK (Src64 and Src42) is sufficient to induce ectopic proliferation in G1/G0-arrested, uncommitted cells in eye imaginal discs. In addition, both kinases trigger apoptosis in vivo, in a dosage-dependent manner. Constitutively active mutants are hypermorphic as they trigger proliferation and death more potently than their wild-type counterparts. Moreover, SFK-induced proliferation and apoptosis are largely independent events, as blocking ectopic proliferation does not block cell death. Further, DCsk (the Drosophila homolog of the C-terminal Src kinase) phosphorylates and interacts genetically with the wild-type SFKs, but not with the constitutively active mutants in which a conserved C-terminal tyrosine was mutated to phenylalanine, providing the first in vivo evidence that Csk regulates SFKs during development through phosphorylation of their C-terminal tyrosine.
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, PO Box 9812, New Haven, CT 06536-0812, USA.
authors.forename: Laura G
authors.initials: LG
authors.lastname: Pedraza
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Stewart
authors.forename: Da-Ming
authors.initials: DM
authors.lastname: Li
authors.forename: Tian
authors.initials: T
authors.lastname: Xu
mesh_terms: D000818:Animals; D017209:Apoptosis; D000081247:CSK Tyrosine-Protein Kinase; D002455:Cell Division / Q000235:genetics* / Q000502:physiology; D003001:Cloning, Molecular; D004330:Drosophila / Q000201:enzymology / Q000235:genetics*; D029721:Drosophila Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D005123:Eye / Q000196:embryology / Q000648:ultrastructure; D005982:Glutathione Transferase / Q000378:metabolism; D007814:Larva; D008565:Membrane Proteins / Q000378:metabolism*; D008855:Microscopy, Electron, Scanning; D009154:Mutation; D010750:Phosphoproteins / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D005982:Glutathione Transferase; D000081247:CSK Tyrosine-Protein Kinase; C000609101:Csk protein, Drosophila; D019061:src-Family Kinases