Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Members of the hedgehog gene family encode a novel class of secreted proteins and are expressed in embryonic cells known to possess important signalling activities in organisms as diverse as flies and chickens. Proteins of the hedgehog family act in these different developmental contexts as both permissive and instructive signals. How this signalling activity is transduced is (as yet) poorly understood, but recent studies point to the involvement of protein kinase A in both Drosophila and vertebrates.
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PMID:Signalling by hedgehog family proteins in Drosophila and vertebrate development. 758 Jan 42

Midbrain dopaminergic neurons, whose loss in adults results in Parkinson's disease, can be specified during embryonic development by a contact-dependent signal from floor plate cells. Here we show that the amino-terminal product of Sonic hedgehog autoproteolysis (SHH-N), an inductive signal expressed by floor plate cells, can induce dopaminergic neurons in vitro. We show further that manipulations to increase the activity of cyclic AMP-dependent protein kinase A, which is known to antagonize hedgehog signaling, can block dopaminergic neuron induction by floor plate cells. Our results and those of other studies indicate that SHH-N can function in a dose-dependent manner to induce different cell types within the neural tube. Our results also provide the basis for a potential cell transplantation therapy for Parkinson's disease.
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PMID:Induction of midbrain dopaminergic neurons by Sonic hedgehog. 761 28

In the developing Drosophila compound eye, a wave of pattern formation and cell-type determination sweeps across the presumptive eye epithelium. This 'morphogenetic furrow' coordinates the epithelial cells' division cycle, shape and gene expression to produce evenly spaced neural cell clusters that will eventually form the adult ommatidia. As these clusters develop, they rotate inwards to face the eye's equator and establish tissue polarity. We have found that wingless is strongly expressed in the dorsal margin of the presumptive eye field, ahead of the morphogenetic furrow. We have shown that inactivation of Wingless results in the induction of an ectopic furrow that proceeds ventrally from the dorsal margin. This ectopic furrow is normal in most respects, however the clusters formed by it fail to rotate, and we propose a two-vector model to account for normal rotation and tissue polarity in the retina. A second consequence of this inactivation of Wingless is that the dorsal head is largely deleted. We have also found that patched loss-of-function mosaic clones induce circular ectopic morphogenetic furrows (consistent with the observations of other workers with the hedgehog, and PKA genes). We use such patched induced furrows to test the two-vector model for cluster rotation and tissue polarity.
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PMID:Wingless and patched are negative regulators of the morphogenetic furrow and can affect tissue polarity in the developing Drosophila compound eye. 767 95

A long-range signal encoded by the Sonic hedgehog (Shh) gene has been implicated as the ventral patterning influence from the notochord that induces sclerotome and represses dermomyotome in somite differentiation. Long-range effects of hedgehog (hh) signaling have been suggested to result either from local induction of a secondary diffusible signal or from the direct action of the highly diffusible carboxy-terminal product of HH autoproteolytic cleavage. Here we provide evidence that the long-range somite patterning effects of SHH are instead mediated by a direct action of the amino-terminal cleavage product. We also show that pharmacological manipulations to increase the activity of cyclic AMP-dependent protein kinase A can selectively antagonize the effects of the amino-terminal cleavage product. Our results support the operation of a single evolutionarily conserved signaling pathway for both local and direct long-range inductive actions of HH family members.
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PMID:Long-range sclerotome induction by sonic hedgehog: direct role of the amino-terminal cleavage product and modulation by the cyclic AMP signaling pathway. 773 97

The earliest physical sign of differentiation in the Drosophila retina is the passage of the morphogenetic furrow across the epithelium of the eye disc. Secreted factors encoded by hedgehog (hh) and decapentaplegic (dpp) have been implicated in propagation of the furrow and the subsequent initiation of photoreceptor differentiation. The morphogenetic furrow initiates at the posterior edge of the third larval instar eye imaginal disc. Its continued progression towards the anterior is believed to depend upon secretion of Hh protein by the differentiating clusters of photoreceptors that emerge posterior to the moving furrow. This progression is marked by the initiation of expression of the transforming growth factor-beta homologue Dpp in cells entering the furrow anteriorly, and loss of dpp expression in cells emerging posteriorly. Although the transmembrane protein encoded by the patched gene has been genetically implicated as the Hh receptor, the intercellular signalling pathways involved in these inductive processes remain uncharacterized. 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. 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. Our results indicate that Pka-C1 lies in a signalling pathway that controls the orderly temporal progression of differentiation across the eye imaginal disc.
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PMID:Regulation of furrow progression in the Drosophila eye by cAMP-dependent protein kinase A. 785 37

Reduced protein kinase A (PKA) activity in anterior imaginal disc cells leads to cell-autonomous induction of decapentaplegic (dpp), wingless (wg), and patched (ptc) transcription that is independent of hedgehog (hh) gene activity. The resulting nonautonomous adult wing and leg pattern duplications are largely due to induced dpp and wg expression and resemble phenotypes elicited by ectopic hh expression. Inhibition of PKA in anterior cells close to the posterior compartment can substitute for hh activity to promote growth of imaginal discs, whereas overexpression of PKA can counteract transcriptional induction of ptc by hh in these cells. PKA therefore appears to be an integral component of the mechanism by which hh regulates the expression of key patterning molecules in imaginal discs.
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PMID:Function of protein kinase A in hedgehog signal transduction and Drosophila imaginal disc development. 786 63

The Drosophila hedgehog (hh) gene encodes a secreted protein involved in organizing growth and patterning in many developmental processes. Hh appears to act by inducing the localized expression of at least two other signaling molecules, decapentaplegic (dpp) and wingless (wg), which then govern cell proliferation and patterning in surrounding tissue. Here, we demonstrate that cyclic AMP (cAMP)-dependent protein kinase A (PKA) is essential during limb development to prevent inappropriate dpp and wg expression. We also show that a constitutively active form of PKA can prevent inappropriate dpp and wg expression, but does not interfere with their normal induction by hh. We propose that the basal activity of PKA imposes a block on the transcription of dpp and wg and that hh exerts its organizing influence by alleviating this block.
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PMID:Protein kinase A and hedgehog signaling in Drosophila limb development. 786 64

The membrane protein, Patched, plays a critical role in patterning embryonic and imaginal tissues in Drosophila. patched constitutively inactivates the transcription of target genes such as wingless, decapentaplegic, and patched itself. The secreted protein, Hedgehog, induces transcription of target genes by opposing the Patched signaling pathway. Using the Gal4 UAS system we have overexpressed patched in wing imaginal discs and found that high Patched levels, expressed in either normal or ectopic patterns, result in loss of wing vein patterning in both compartments centering at the anterior/posterior border. In addition, patched inhibits the formation of the mechanosensory neurons, the campaniform sensilla, in the wing blade. The patched wing vein phenotype is modulated by mutations in hedgehog and cubitus interruptus (ci). Patched overexpression inhibits transcription of patched and decapentaplegic and post-transcriptionally decreases the amount of Ci protein at the anterior/posterior boundary. In hedgehogMrt wing discs, which express ectopic hedgehog, Ci levels are correspondingly elevated, suggesting that hedgehog relieves patched repression of Ci accumulation. Protein kinase A also regulates Ci; protein kinase A mutant clones in the anterior compartment have increased levels of Ci protein. Thus patched influences wing disc patterning by decreasing Ci protein levels and inactivating hedgehog target genes in the anterior compartment.
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PMID:patched overexpression alters wing disc size and pattern: transcriptional and post-transcriptional effects on hedgehog targets. 857 16

Midline signaling by Hedgehog (Hh) family members has been implicated in patterning the vertebrate embryo. We have explored the potential regulatory role of cAMP-dependent protein kinase A (PKA) in these events. Zebrafish embryos injected with RNAs encoding Sonic hedgehog (Shh), Indian hedgehog (Ihh), or a dominant-negative regulatory subunit of PKA, PKI, have equivalent phenotypes. These include the expansion of proximal fates in the eye, ventral fates in the brain, and adaxial fates in somites and head mesenchyme. Moreover, ectopic expression of PKI partially rescues somite and optic stalk defects in no tail and cyclops mutants that lack midline structures that normally synthesize Shh. Conversely, all cell types promoted by ectopic expression of hhs and PKI are suppressed in embryos injected with RNA encoding a constitutively active catalytic subunit of PKA (PKA*). These results, together with epistasis studies on the block of ectopic Hh signaling by PKA*, indicate that PKA acts in target cells as a common negative regulator of Hedgehog signaling.
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PMID:Protein kinase A is a common negative regulator of Hedgehog signaling in the vertebrate embryo. 859 93

In Drosophila, it has been shown that protein kinase A and hedgehog have antagonistic actions during the formation of imaginal disks. In vertebrate skin, sonic hedgehog is expressed specifically in the feather bud epithelia. using an in vitro explant culture model we showed that dibutyryl cAMP, a protein kinase A (PKA) activator, suppresses the expression of Sonic hedgehog, (Shh) and continuous feather growth. The results suggest that Shh and PKA also have antagonistic action during vertebrate skin morphogenesis.
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PMID:cAMP, an activator of protein kinase A, suppresses the expression of sonic hedgehog. 861 4


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