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)

The hedgehog gene (hh) of Drosophila melanogaster exerts both short- and long-range effects on cell patterning during development. The product of hedgehog is a secreted protein that apparently acts by triggering an intra-cellular signaling pathway, but little is known about the details of that pathway. The Drosophila gene fused (fu) encodes a serine/threonine-protein kinase that genetic experiments have implicated in signaling initiated by hedgehog. Here we report that the fused protein is phosphorylated during the course of Drosophila embryogenesis, as a result of hedgehog activity. In cell culture, phosphorylation of fused protein occurs in response to the biologically active form of hedgehog and cannot be blocked by activation of protein kinase A, which is thought to be an antagonist of signaling from hedgehog. These results suggest that fused and protein kinase A function downstream of hedgehog but in parallel pathways that eventually converge distal to fused. The reconstruction of signaling from hedgehog in cell culture should provide further access to the mechanisms by which hedgehog acts.
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PMID:Phosphorylation of the fused protein kinase in response to signaling from hedgehog. 863 45

Hedgehog (Hh) signaling plays a significant role in defining the polarity of a variety of tissue types along the anterior/posterior and dorsal/ventral axes in both vertebrate and invertebrate organisms. The pathway through which Hh transduces its signal is still obscure, however, recent data have implicated the cyclic AMP-dependent protein kinase A as a negative regulator of the Hh signal transduction pathway. One of the vertebrate Hh family members, Sonic hedgehog (Shh), can induce ventral neural cell types both in vivo and in vitro; high concentrations induce floor plate and lower concentrations motor neurons. To investigate whether PKA plays an active role in the suppression of ventral neural differentiation, we generated transgenic embryos expressing a dominant negative form of PKA (dnPKA) in primarily dorsal aspects of the mouse CNS. Similar to our earlier results with Shh, we observed the induction of floor plate and motor neuron markers in embryos expressing the dominant negative PKA transgene and the loss of dorsal gene expression at rostral levels. Thus suppression of PKA activity is sufficient to activate targets of the Shh signaling pathway in the vertebrate CNS suggesting that induction of ventral cell types occurs via the antagonistic action of Shh on PKA activity. Two mammalian target genes that are strongly expressed in ectopic dorsal locations in response to dnPKA are Ptc and Gli. As both of these are targets of Drosophila Hh signaling, our data point to an evolutionary conservation in both the mechanisms of signaling and the effectors of the signaling pathway.
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PMID:Antagonizing cAMP-dependent protein kinase A in the dorsal CNS activates a conserved Sonic hedgehog signaling pathway. 878 61

The zebrafish hedgehog (hh) family members tiggy-winkle hedgehog (twhh) and sonic hedgehog (shh) are involved in patterning the ventral CNS and proximal eye. Using a dominant negative protein kinase A regulatory subunit mutant, we show that these hh activities are mediated by protein kinase A. The effects of dominant negative protein kinase A on pax2 expression appear to be cell nonautonomous, suggesting that cells can respond to regulation of hh signaling by modulating an additional cell-cell signaling pathway. We also investigate the potential involvement of cyclops in the hh signaling pathway and conclude that although cyclops mutant cells can respond to hh signaling, neither hh nor dominant negative protein kinase A rescues the phenotypes associated with cyclops.
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PMID:Inhibition of protein kinase A phenocopies ectopic expression of hedgehog in the CNS of wild-type and cyclops mutant embryos. 881 20

The genes decapentaplegic (dpp) and wingless (wg), which encode secreted factors of the TGF-beta and Wnt families, respectively, are required for the proper development of the imaginal discs. The expression of these genes must be finely regulated since their ectopic expression induces overgrowth and pattern alterations in wings and legs. Genes like patched (ptc) and costal-2 (cos-2), and the gene encoding the catalytic subunit of the protein kinase A gene (pkA) are required to restrict dpp and wg expression in their proper positions. We show here that some mutations in the cubitus interruptus (ci) gene also show ectopic dpp expression in the wing disc. We have also analyzed the functional hierarchy between these genes and the gene fused (fu), in the activation of dpp by the hedgehog (hh) signal. fu is required to transmit the hh signal in imaginal discs, since fu mutations rescue the phenotype due to the ectopic hh expression or to the lack of ptc activity. fu is also required for the activation of engrailed (en) caused when hh is ectopically activated in the wing disc. By contrast, fu mutations do not rescue the phenotypic consequences of the abnormal ci, cos-2 or pkA activity. Although fu, cos-2 and ci probably form part of the same pathway that controls dpp expression, pkA probably controls dpp transcription by a different pathway.
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PMID:The fu gene discriminates between pathways to control dpp expression in Drosophila imaginal discs. 886 Oct 96

We have investigated the anterior and posterior compartmental organization of the genital imaginal disc. Unlike the thoracic discs, the genital disc is a compound disc consisting of three primordia--the female genital, male genital, and anal primordia. Here we provide evidence that each primordium is divided into anterior and posterior compartments. Genes that are known to be expressed in compartment-specific manners in other discs (engrailed, hedgehog, patched, decapentaplegic, wingless and cubitus interruptus) are expressed in analogous patterns in each primordium of the genital disc. Specifically, engrailed and cubitus interruptus are expressed in complementary domains, while patched, decapentaplegic and wingless are expressed along the border between the two domains. Mitotic clones induced at the beginning of the second larval instar do not cross the boundary between the engrailed-expressing and cubitus interruptus-expressing domains, indicating that these domains are true genetic compartments. Furthermore, we examined the phenotypes of mutant clones of the cAMP-dependent protein kinase A and engrailed-invected, genes that are known to play compartment-specific functions in other discs. These experiments demonstrate that the anterior/posterior patterning functions of these genes are conserved in the genital disc. The adult clonal phenotypes of protein kinase A and engrailed-invected mutants also provide a more detailed map of the adult genitalia and analia with respect to the anterior/posterior compartmental subdivision. Our results lead us to propose a new model to describe the anterior and posterior compartmental organization of the genital disc.
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PMID:Compartmental organization of the Drosophila genital imaginal discs. 900 81

Many of the same genes needed for proper eye and limb development in vertebrates, such as hairy, hedgehog, patched and cyclic AMP-dependent protein kinase A, are responsible for patterning Drosophila imaginal discs, the tissues that will give rise to the adult cuticle structures. This is well demonstrated in the control of morphogenetic furrow movement and differentiation in the eye imaginal disc. We report that ultraspiracle, the gene encoding the Drosophila cognate of the Retinoid X Receptor, is required for normal morphogenetic furrow movement and ommatidial cluster formation. Examination of the expression of genes involved in regulating the furrow suggests that ultraspiracle defines a novel regulatory pathway in eye differentiation.
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PMID:A role for ultraspiracle, the Drosophila RXR, in morphogenetic furrow movement and photoreceptor cluster formation. 921 92

In vertebrates, pattern formation in the eye, central nervous system, somites, and limb depends on hedgehog activity, but a general target gene controlled by hedgehog in all these signaling centers has remained largely elusive. The medaka fish gene spalt encodes a zinc-finger transcription factor, which is expressed in all known hedgehog signaling centers of the embryo and in the organizer region at the midbrain-hindbrain boundary. We show that the spalt expression domains expand in response to ectopic hedgehog activity and narrow in the presence of protein kinase A activity, an antagonist of hedgehog signaling, indicating that spalt is a hedgehog target gene. Our results also suggest a signaling mechanism for anterior-posterior patterning of the vertebrate brain that controls spalt expression at the midbrain-hindbrain boundary in a protein kinase A dependent manner likely to involve an unknown member of the hedgehog family.
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PMID:Medaka spalt acts as a target gene of hedgehog signaling. 927 55

Zebrafish neurogenin1 encodes a basic helix-loop-helix protein which shares structural and functional characteristics with proneural genes of Drosophila melanogaster. neurogenin1 is expressed in the early neural plate in domains comprising more cells than the primary neurons known to develop from these regions and its expression is modulated by Delta/Notch signalling, suggesting that it is a target of lateral inhibition. Misexpression of neurogenin1 in the embryo results in development of ectopic neurons. Markers for different neuronal subtypes are not ectopically expressed in the same patterns in neurogenin1-injected embryos suggesting that the final identity of the ectopically induced neurons is modulated by local cues. 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. Moreover, the pattern of endogenous neurogenin1 expression in the neural plate is expanded in response to elevated levels of Hedgehog (Hh) signalling or abolished as a result of inhibition of Hh signalling. Together these data suggest that Hh signals regulate neurogenin1 expression and subsequently modulate the type of neurons produced by Neurogenin1 activity.
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PMID:The activity of neurogenin1 is controlled by local cues in the zebrafish embryo. 940 73

Cubitus interruptus (Ci) is a transcriptional factor that is positively regulated by the hedgehog (hh) signaling pathway. Recent work has shown that a 75-kDa proteolytic product of the full-length CI protein translocates to the nucleus and represses the transcription of CI target genes. In cells that receive the hh signal, the proteolysis of CI is inhibited and the full-length protein can activate the hh target genes. Because protein kinase A (PKA) inhibits the expression of the hh target genes in developing embryos and discs and the loss of PKA activity results in elevated levels of full-length CI protein, PKA might be involved directly in the regulation of CI proteolysis. Here we demonstrate that the PKA pathway antagonizes the hh pathway by phosphorylating CI. We show that the PKA-mediated phosphorylation of CI promotes its proteolysis from the full-length active form to the 75-kDa repressor form. The PKA catalytic subunit increases the proteolytic processing of CI and the PKA inhibitor, PKI, blocks the processing. In addition, cells do not process the CI protein to the 75-kDa repressor when all of the PKA sites in CI are mutated. Mutant CI proteins that cannot be phosphorylated by PKA have increased transcriptional activity compared with wild-type CI. In addition, exogenous PKA can increase further the transcriptional activity of the CI mutant, suggesting that PKA has a second positive, indirect effect on CI activity. In summary, we show that the modulation of the hh signaling pathway by PKA occurs directly at the level of CI phosphorylation.
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PMID:Protein kinase A directly regulates the activity and proteolysis of cubitus interruptus. 948 88

The axial structures, the notochord and the neural tube, play an essential role in the dorsoventral patterning of somites and in the differentiation of their many cell lineages. Here, we investigated the role of the axial structures in the mediolateral patterning of the somite by using a newly identified murine homeobox gene, Nkx-3.1, as a medial somitic marker in explant in vitro assays. Nkx-3.1 is dynamically expressed during somitogenesis only in the youngest, most newly-formed somites at the caudal end of the embryo. We found that the expression of Nkx-3.1 in pre-somitic tissue explants is induced by the notochord and maintained in newly-differentiated somites by the notochord and both ventral and dorsal parts of the neural tube. We showed that Sonic hedgehog (Shh) is one of the signaling molecules that can reproduce the effect of the axial structures by exposing explants to either COS cells transfected with a Shh expression construct or to recombinant SHH. Shh could induce and maintain Nkx-3.1 expression in pre-somitic mesoderm and young somites but not in more mature, differentiated ones. The effects of Shh on Nkr-3.1 expression were antagonized by a forskolin-induced increase in the activity of cyclic AMP-dependent protein kinase A. Additionally, we confirmed that the expression of the earliest expressed murine myogenic marker, myf 5, is also regulated by the axial structures but that Shh by itself is not capable of inducing or maintaining it. We suggest that the establishment of somitic medial and lateral compartments and the early events in myogenesis are governed by a combination of positive and inhibitory signals derived from the neighboring structures, as has previously been proposed for the dorsoventral patterning of somites.
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PMID:Mediolateral patterning of somites: multiple axial signals, including Sonic hedgehog, regulate Nkx-3.1 expression. 951 22


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