Disease relevance of Pka-C1

• In addition, we found that edema factor, a potent adenylate cyclase, inhibits the hh pathway during wing development, consistent with the known role of cAMP-dependent PKA in suppressing the Hedgehog response [1].
• We demonstrate that, as in Drosophila, vertebrate smoothened is essential for hedgehog signaling, and functions upstream of protein kinase A. Further analysis of neural tube defects revealed the absence of lateral floor plate and secondary motoneurons, but the presence of medial floor plate and primary motoneurons in smoothened mutant embryos [2].
• Drosophila melanogaster deficient in protein kinase A manifests behavior-specific arrhythmia but normal clock function [3].

Psychiatry related information on Pka-C1

• A role for cAMP signaling in circadian processes is also suggested by an analysis of DC0 mutants, which have severe kinase deficits and display arrhythmic locomotor activity [4].

High impact information on Pka-C1

• A new study suggests that manipulating the expression of a Drosophila melanogaster neurofibromatosis-1 ortholog affects organismal lifespan through protein kinase A-mediated regulation of mitochondrial respiration and reactive oxygen species production [5].
• Ci-155 proteolysis depends on phosphorylation at three sites by Protein Kinase A (PKA) [6].
• In Drosophila, Ci action as transcriptional repressor or activator is contingent upon Hedgehog-regulated, PKA-dependent proteolytic processing [7].
• Function of protein kinase A in hedgehog signal transduction and Drosophila imaginal disc development [8].
• Using genetic mosaics, we show that in the anterior compartment of appendage discs and anterior to the morphogenetic furrow in the eye disc, cells that lack cAMP-dependent protein kinase (PKA) activity ectopically express dpp [9].

Biological context of Pka-C1

• Here we show that the catalytic subunit of cyclic AMP-dependent protein kinase A (Pka-C1) is required for the correct spatial regulation of dpp expression during eye development [10].
• AMI is restored when a DCO transgene is expressed in mushroom bodies, structures important for olfactory memory formation [11].
• Here we examine Hh target gene expression caused by mutant forms of PKA regulatory (PKAr) and catalytic (PKAc) subunits and by the PKAc inhibitor PKI(1-31) [12].
• However, most Drosophila NF1 mutant phenotypes, including an overall growth deficiency, are not readily modified by manipulating Ras signaling strength, but are rescued by increasing signaling through the cAMP-dependent protein kinase A pathway [13].
• An A-kinase anchoring protein is required for protein kinase A regulatory subunit localization and morphology of actin structures during oogenesis in Drosophila [14].

Anatomical context of Pka-C1

• Loss of Pka-C1 function is sufficient to produce an ectopic morphogenetic wave marked by premature ectopic photoreceptor differentiation and non-autonomous propagation of dpp expression [10].
• We describe mutation affecting Protein Kinase A (PKA) that act in the germ line to disrupt both microtubule distribution and RNA localization along this axis [15].
• We found that ectopic expression of Hedgehogs or inhibition of protein kinase A in zebrafish embryos induces slow muscle precursors throughout the somite but muscle pioneer cells only in the middle of the somite [16].
• In this report we demonstrate, by two different methods, that reduction or elimination of protein kinase A activity had no effect on phenotypes generated by activation of Gs alpha pathways in Drosophila wing epithelial cells [17].
• Induction of ectopic motor neurons by neurogeninl requires coexpression of a dominant negative regulatory subunit of protein kinase A, an intracellular transducer of hedgehog signals [18].

Associations of Pka-C1 with chemical compounds

• In addition, we demonstrate that, in cell culture, the mutation of any one of the three serine-containing PKA sites abolishes the proteolytic processing of CI [19].
• Furthermore, our studies predict the existence of feedback inhibition through protein kinase A on the InsP(3) receptor by increased levels of 20-hydroxyecdysone [20].
• The enhancement of Slob kinase activity by PKAc pretreatment is eliminated when serine 54 in Slob is mutated to alanine (S54A) [21].

Physical interactions of Pka-C1

• Genetic evidence for a protein kinase A/cubitus interruptus complex that facilitates processing of cubitus interruptus in Drosophila [12].
• Furthermore, the catalytically inactive PKAc mutant does bind to dSlo but does not modulate channel activity [22].

Regulatory relationships of Pka-C1

• High signaling is initiated when cooperating Smoothened cytoplasmic tails activate Costal and Fused, driving the regulatory complex to its high state [23].
• The regulatory subunit of a cGMP-regulated protein kinase A of Trypanosoma brucei [24].
• More recent experiments indicate functions in calcium- and cAMP-mediated signaling and it has been proposed that protein kinase A-mediated phosphorylation activates Rap in vivo [25].

Other interactions of Pka-C1

• We present a model where low signaling is initiated when a Costal inhibitory site on the Smoothened cytoplasmic tail shifts the regulatory complex to its low state [23].
• The mutant PKAr*, defective in binding cAMP, is shown to activate Hh target genes solely through its ability to bind and inhibit endogenous PKAc [12].
• Here we present evidence that removing activity of the gene encoding cyclic AMP-dependent protein kinase A (pka) is functionally equivalent to removing ptc activity or to providing cells with the Hh signal [26].
• Ci is phosphorylated by GSK3 after a primed phosphorylation by protein kinase A (PKA), and mutating GSK3-phosphorylation sites in Ci blocks its processing and prevents the production of the repressor form [27].
• The ratio of these forms, which is regulated positively by hh signaling and negatively by PKA activity, determines the on/off status of hh target gene expression [19].

Analytical, diagnostic and therapeutic context of Pka-C1

• RNA in situ hybridization and immunohistochemistry show that DCO is preferentially expressed in the mushroom bodies [28].
• Immunoprecipitation of TbRSU coprecipitates a protein kinase activity with the characteristics of protein kinase A: it phosphorylates a protein kinase specific substrate, and it is strongly inhibited by a synthetic protein kinase inhibitor peptide [24].
• The usefulness of this coculture system in studying presynaptic secretion mechanisms is illustrated by a series of studies on the cAMP pathway mutations, dunce (dnc) and PKA-RI, which disrupt a cAMP-specific phosphodiesterase and the regulatory subunit of cAMP-dependent protein kinase A, respectively [29].

References