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)

Many hormones mediate their intracellular actions by triggering signal transduction pathways that alter the phosphorylation state of key regulatory proteins. Protein phosphorylation is a reversible process involving two classes of signaling enzymes: protein kinases, which catalyze the transfer of phosphate from ATP onto substrate proteins, and phosphoprotein phosphatases, which perform the dephosphorylation step. To insure tight control of hormonally initiated phosphorylation events, the activity of multifunctional kinases and phosphatases is precisely regulated and responds to fluctuations in diffusible second messengers such as Ca2+, phospholipid, and cAMP. Another mechanism that contributes to their regulation is to restrict the location of these enzymes to certain subcellular compartments. Subcellular targeting enhances the selectivity of serine/threonine phosphatases and kinases by favoring their accessibility to certain substrate proteins. Compartmentalization is achieved through a "targeting moiety," which is defined as that part of a phosphatase or kinase that directs the catalytic subunit to a certain subcellular environment. The targeting moiety restricts the location of a phosphatase or kinase through association with a "targeting locus." These are often structural membrane proteins, cytoskeletal components, or cellular organelles. Targeting subunits for the type I phosphatase and protein kinase C have been identified; however, the focus of this chapter centers around a family of anchoring proteins, called AKAPs, that localize the type II cAMP-dependent protein kinase (PKA). Structure-function analysis suggest that each anchoring protein binds to the RII dimer through a conserved amphipathic helix region and is tethered to specific subcellular sites via association of a targeting domain with structural proteins or cellular organelles. Peptides patterned after the amphipathic region have been used to probe the functional significance of PKA anchoring inside cells and have begun to be established by that disruption RII/AKAP interaction in vivo has concomitant effects on certain PKA-mediated phosphorylation events. In addition, multivalent binding proteins such as AKAP79 and AKAP250 have been characterized and appear to serve as platforms for the assembly of kinase/phosphatase signaling complexes. Collectively, these studies suggest that the AKAPs represent a growing family of regulatory proteins that provide a molecular architecture that organizes the intracellular location of a single or multiple multifunctional kinase.
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PMID:Anchoring and scaffold proteins for kinases and phosphatases. 923 61

The cardiac L-type Ca2+ channel is a textbook example of an ion channel regulated by protein phosphorylation; however, the molecular events that underlie its regulation remain unknown. Here, we report that in transiently transfected HEK293 cells expressing L-type channels, elevations in cAMP resulted in phosphorylation of the alpha1C and beta2a channel subunits and increases in channel activity. Channel phosphorylation and regulation were facilitated by submembrane targeting of protein kinase A (PKA), through association with an A-kinase anchoring protein called AKAP79. In transfected cells expressing a mutant AKAP79 that is unable to bind PKA, phosphorylation of the alpha1C subunit and regulation of channel activity were not observed. Furthermore, we have demonstrated that the association of an AKAP with PKA was required for beta-adrenergic receptor-mediated regulation of L-type channels in native cardiac myocytes, illustrating that the events observed in the heterologous expression system reflect those occurring in the native system. Mutation of Ser1928 to alanine in the C-terminus of the alpha1C subunit resulted in a complete loss of cAMP-mediated phosphorylation and a loss of channel regulation. Thus, the PKA-mediated regulation of L-type Ca2+ channels is critically dependent on a functional AKAP and phosphorylation of the alpha1C subunit at Ser1928.
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PMID:cAMP-dependent regulation of cardiac L-type Ca2+ channels requires membrane targeting of PKA and phosphorylation of channel subunits. 924 74

Subcellular localization directed by specific A kinase anchoring proteins (AKAPs) is a mechanism for compartmentalization of cAMP-dependent protein kinase (PKA). Using a two-hybrid screen, a novel AKAP was isolated. Because it interacts with both the type I and type II regulatory subunits, it was defined as a dual specific AKAP or D-AKAP1. Here we report the cloning and characterization of another novel cDNA isolated from that screen. This new member of the D-AKAP family, D-AKAP2, also binds both types of regulatory subunits. A message of 5 kb pairs was detected for D-AKAP2 in all embryonic stages and in all adult tissues tested. In brain, skeletal muscle, kidney, and testis, a 10-kb mRNA was identified. In testis, several small mRNAs were observed. Therefore, D-AKAP2 represents a novel family of proteins. cDNA cloning from a mouse testis library identified the full length D-AKAP2. It is composed of 372 amino acids which includes the R binding fragment, residues 333-372, at its C-terminus. Based on coprecipitation assays, the R binding domain interacts with the N-terminal dimerization domain of RIalpha and RIIalpha. A putative RGS domain was identified near the N-terminal region of D-AKAP2. The presence of this domain raises the intriguing possibility that D-AKAP2 may interact with a Galpha protein thus providing a link between the signaling machinery at the plasma membrane and the downstream kinase.
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PMID:D-AKAP2, a novel protein kinase A anchoring protein with a putative RGS domain. 932 83

A-kinase anchor protein 75 (AKAP75) binds regulatory subunits (RIIalpha and RIIbeta) of type II protein kinase A (PKAII) isoforms and targets the resulting complexes to sites in the cytoskeleton that abut the plasma membrane [1-7]. Co-localization of AKAP75-PKAII with adenylate cyclase and PKA substrate/effector proteins in cytoskeleton and plasma membrane effects a physical and functional integration of up-stream and downstream signaling proteins, thereby ensuring efficient propagation of signals carried by locally generated cyclic AMP (cAMP) [4-9]. An important, but previously untested, prediction of the AKAP model is that efficient, cyclic nucleotide-dependent liberation of diffusible PKA catalytic subunits from cytoskeleton-bound AKAP75-PKAII complexes will also enhance signaling to distal organelles, such as the nucleus. We tested this idea by suing HEK-A75 cells, in which PKAII isoforms are immobilized in cortical cytoskeleton by AKAP75. Abilities of HEK-A75 and control cells (with cytoplasmically dispersed PKAII isoforms) to respond to increases in cAMP content were compared. Cells with anchored PKAII exhibited a threefold higher level of nuclear catalytic subunit content and 4-10-fold greater increments in phosphorylation of a regulatory serine residue in cAMP response element binding protein (CREB) and in phosphoCREB-stimulated transcription of the c-fos gene. Each effect occurred more rapidly in cells containing targeted AKAP75-PKAII complexes. Thus, anchoring of PKAII in actin cortical cytoskeleton increases the rate, magnitude and sensitivity of cAMP signaling to the nucleus.
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PMID:A-kinase anchor protein 75 increases the rate and magnitude of cAMP signaling to the nucleus. 938 44

In the present study, we have used the two-electrode voltage-clamp and patch-clamp techniques to study the effects of forskolin and cAMP on the ROMK1 channels, which are believed to be the native K+ secretory channels in the kidney. Addition of 1 microM forskolin or 100 microM 8-bromo-cAMP, within 10 min, has no significant effect on the current of ROMK1 channels expressed in Xenopus oocytes. In contrast, application of 1 microM forskolin, within 3 min, significantly increased whole-cell K+ current by 35%, when ROMK1 channels were coexpressed with the A kinase anchoring protein AKAP79, which was cloned from neuronal tissue. Two lines of evidence indicate that the effect of forskolin is mediated by a cAMP-dependent pathway: (i) Addition of 100 microM 8-bromo-cAMP mimics the effect of forskolin and (ii) the effect of forskolin and cAMP is not additive. That AKAP is required for the effect of cAMP is further supported by experiments in which addition of ATP (100 microM) and cAMP (100 microM) restored the activity of run-down ROMK1 channels in inside-out patches in oocytes that coexpressed ROMK1 and AKAP79 but not in those that expressed ROMK1 alone. Moreover, when we used RII, the regulatory subunit of type II protein kinase A, in an overlay assay, we identified a RII-binding protein in membranes obtained from the kidney cortex but not in membranes from oocytes. This suggests that the insensitivity of ROMK1 channels to forskolin and cAMP is due to the absence of AKAPs. We conclude that AKAP may be a critical component that mediates the effect of protein kinase A on the ROMK channels in the kidney.
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PMID:The A kinase anchoring protein is required for mediating the effect of protein kinase A on ROMK1 channels. 970 37

Distinct A Kinase Anchor Proteins (AKAPs) immobilize and concentrate protein kinase A II (PKAII) isoforms at specific intracellular locations. AKAP121 binds and targets PKAIIalpha to the cytoplasmic surface of mitochondria. Mechanisms that control expression of this mitochondrial AKAP are unknown. We have cloned cDNA for rat AKAP121 and show that AKAP121 protein expression is regulated by thyroid stimulating hormone (TSH) and cAMP. Differentiated thyroid cells (TL5) accumulate AKAP121 upon incubation with TSH or a cAMP analog. Levels of total and newly synthesized AKAP121 mRNA also increased after treatment. AKAP121 mRNA accumulated in the presence of cycloheximide, suggesting that transcription of the anchor protein gene is directly controlled by cAMP and PKA. AKAP121 is induced with similar kinetics when an unrelated, spermatocyte-derived cell line (GC-2) is incubated with 8-chlorophenylthio-cAMP. Thus, AKAP121 concentration may be controlled by hormones that activate adenylate cyclase. This mode of regulation could provide a general mechanism for (a) enhancing the sensitivity of distal organelles to cAMP and (b) shifting the focus of cAMP-mediated signaling from cytoplasm to organelles.
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PMID:Expression of a kinase anchor protein 121 is regulated by hormones in thyroid and testicular germ cells. 972 70

Compartmentalization of signalling molecules through association with anchoring proteins ensures specificity in signal transduction by placing enzymes close to their appropriate effectors and substrates. For example, 'A-kinase anchoring proteins' (AKAPs) bind to the regulatory subunit of cAMP-dependent protein kinase (PKA) to direct the kinase to discrete intracellular locations. Recently, functional studies aimed at disrupting AKAP-PKA complexes have demonstrated a role for anchored PKA in various cellular processes, including gene transcription, hormone-mediated insulin secretion and ion-channel modulation. By binding to additional signalling molecules, AKAPs might function to coordinate multiple components of signal-transduction pathways.
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PMID:AKAPs: from structure to function. 1035 67

Sequence analysis of cosmid clones was instrumental to identify three genes in the region flanking the Fugu rubripes NF1 gene in the 3' direction: the AKAP84 gene (A-kinase anchor protein 84), the WSB1 gene (WD-40-repeat protein with a SOCS box) and the BAW gene of yet unknown function located between the AKAP84 and the WSB1 genes. The human homologues of these genes are not located in the immediate vicinity of the NF1 gene at 17q11.2. Although synteny of the NF1, AKAP84, BAW and WSB1 genes is conserved between Fugu and human, the gene order is not conserved, and more than a simple inversion would have been necessary to explain the difference in gene order. The mammalian homologue of the Fugu BAW gene or protein has not yet been characterized. As deduced from the respective cDNAs, the Fugu AKAP84, WSB1 and BAW proteins vary concerning the overall degree of similarity to their mammalian counterparts. Whereas the overall similarity of AKAP84 between Fugu and mouse is low, three regions of known functional importance show considerable conservation. These are the N-terminal anchoring domain mediating the insertion of AKAP84 in the outer mitochondrial membrane, the binding site of the regulatory subunit (RI or RII) of protein kinase A, and the C-terminal domain present in the alternatively spliced isoform AKAP121 with an hnRNP K homology domain involved in RNA binding. A higher overall similarity of deduced protein sequences between Fugu and mouse was observed comparing the BAW gene products (74.1%) and the WSB1 proteins (77.2%).
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PMID:Characterization of three genes, AKAP84, BAW and WSB1, located 3' to the neurofibromatosis type 1 locus in Fugu rubripes. 1041 27

A cDNA of a tentative A-kinase anchoring protein, presumably coupled with heterotrimeric GTP binding protein alpha 13 subunit (G alpha 13), was cloned from a human heart cDNA library. It was approximately 650 bases and its mRNA was expressed in the heart. Homology search of DNA sequences revealed that it was a novel cDNA with 84% homology with the partial sequence of rabbit cDNA of AKAP 120 without a stop codon. 3'-Rapid Amplification of cDNA Ends (3'-RACE) and yeast functional assay were performed to determine the 3'-end of the cDNA and ribosomal frameshifting was suggested as a translational mechanism. Here we report that a protein encoded by the cDNA may be involved in intracellular signal transduction via the G alpha 13 and PKA in hearts.
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PMID:A novel A-kinase anchoring protein in the heart interacts with G alpha 13. 1042 Aug 81

Activation of D1-like dopamine (DA) receptors reduces peak Na(+) current in acutely isolated hippocampal neurons via a modulatory mechanism involving phosphorylation of the Na(+) channel alpha subunit by cAMP-dependent protein kinase (PKA). Peak Na(+) current is reduced 20-50% in the presence of the D1 agonist SKF 81297 or the PKA activator Sp-5,6-dichloro-l-beta-d-ribofuranosyl benzimidazole-3',5'-cyclic monophosphorothionate (cBIMPS). Co-immunoprecipitation experiments show that Na(+) channels are associated with PKA and A-kinase-anchoring protein 15 (AKAP-15), and immunocytochemical labeling reveals their co-localization in the cell bodies and proximal dendrites of hippocampal pyramidal neurons. Anchoring of PKA near the channel by an AKAP, which binds the RII alpha regulatory subunit, is necessary for Na(+) channel modulation in acutely dissociated hippocampal pyramidal neurons. Intracellular dialysis with the anchoring inhibitor peptides Ht31 from a human thyroid AKAP and AP2 from AKAP-15 eliminated the modulation of the Na(+) channel by the D1-agonist SKF 81297 and the PKA activator cBIMPS. In contrast, dialysis with the inactive proline-substituted control peptides Ht31-P and AP2-P had little effect on the D1 and PKA modulation. Therefore, we conclude that modulation of the Na(+) channel by activation of D1-like DA receptors requires targeted localization of PKA near the channel to achieve phosphorylation of the alpha subunit and to modify the functional properties of the channel.
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PMID:Dopaminergic modulation of voltage-gated Na+ current in rat hippocampal neurons requires anchoring of cAMP-dependent protein kinase. 1046 Feb 75


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