title: Drosophila Costal1 mutations are alleles of protein kinase A that modulate hedgehog signaling.
abstract: Hedgehog (Hh) signaling is crucial for the development of many tissues, and altered Hh signal transduction can result in cancer. The Drosophila Costal1 (Cos1) and costal2 (cos2) genes have been implicated in Hh signaling. cos2 encodes a kinesin-related molecule, one component of a cytoplasmic complex of Hh signal transducers. Mutations in Cos1 enhance loss-of-function cos2 mutations, but the molecular nature of Cos1 has been unknown. We found that previously identified alleles of Cos1 actually map to two separate loci. Four alleles of Cos1 appear to be dominant-negative mutations of a catalytic subunit of protein kinase A (pka-C1) and the fifth allele, Cos1(A1), is a gain-of-function allele of the PKA regulatory subunit pka-RII. PKA-RII protein levels are higher in Cos1(A1) mutants than in wild type. Overexpression of wild-type pka-RII phenocopies Cos1 mutants. PKA activity is aberrant in Cos1(A1) mutants. PKA-RII is uniformly overproduced in the wing imaginal disc in Cos1(A1) mutants, but only certain cells respond by activating the transcription factor Ci and Hh target gene transcription. This work shows that overexpression of a wild-type regulatory subunit of PKA is sufficient to activate Hh target gene transcription.
authors.affiliation: Program in Cancer Biology, Department of Developmental Biology, Howard Hughes Medical Institute, Stanford University School of Medicine, California 94305-5439, USA.
authors.forename: Lara S
authors.initials: LS
authors.lastname: Collier
authors.forename: Kaye
authors.initials: K
authors.lastname: Suyama
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Anderson
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Scott
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics*; D017931:DNA Primers; D004330:Drosophila / Q000201:enzymology / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics*; D053823:Hedgehog Proteins; D016547:Kinesins / Q000235:genetics*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011995:Recombination, Genetic; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014921:Wings, Animal / Q000033:anatomy & histology
chemical_list: D017931:DNA Primers; D029721:Drosophila Proteins; D053823:Hedgehog Proteins; C107452:cos protein, Drosophila; C077245:hh protein, Drosophila; D017868:Cyclic AMP-Dependent Protein Kinases; D016547:Kinesins