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

---

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

PDK-1 is a protein kinase that is critical for the activation of many downstream protein kinases in the AGC superfamily, through phosphorylation of the activation loop site on these substrates. Cells lacking PDK-1 show decreased activity of these protein kinases, including protein kinase B (PKB) and p70S6K, whereas mTOR activity remains largely unaffected. Here we show, by assessing both association of cellular RNAs with polysomes and by metabolic labeling, that PDK-1-/- embryonic stem (ES) cells exhibit defects in mRNA translation. We identify which mRNAs are most dramatically translationally regulated in cells lacking PDK-1 expression by performing microarray analysis of total and polysomal RNA in these cells. In addition to the decreased translation of many RNAs, a smaller number of RNAs show increased association with polyribosomes in PDK-1-/- ES cells relative to PDK-1+/+ ES cells. We show that PKB activity is a critical downstream component of PDK-1 in mediating translation of cystatin C, RANKL, and Rab11a, whereas mTOR activity is less important for effective translation of these targets.
...
PMID:Translational deregulation in PDK-1-/- embryonic stem cells. 1616 29

Cyclic AMP (cAMP), one of the most important intracellular second messengers, has been reported to inhibit proliferation of human hepatocellular carcinoma (HCC) cells via negatively regulating p42/44 mitogen-activated protein kinase. Here, we reported that cAMP inhibited the proliferation of HCC BEL-7402 cells via a novel mechanism. Forskolin, an activator of adenylate cyclase, inhibited fetal bovine serum (FBS)-stimulated BEL-7402 cell proliferation in a dose- and time-dependent manner, along with the inhibition of FBS-stimulated serine/threoine protein kinase Akt (also known as PKB) phosphorylation which is required for Akt activation and this effect was mimicked by 8-Br cAMP. Forskolin also inhibited Akt phosphorylation stimulated by other growth factors such as IGF-1, epidermal growth factor, and insulin. These inhibitions were found not only in BEL-7402 cells, but also in another HCC cell line SMMC-7721 cells. Myr-Akt (myristolated-Akt), a constitutively active Akt which was relatively resistant to cAMP inhibition, conferred BEL-7402 cells resistance to cAMP treatment. However, overexpression of Myr-Akt alone was not sufficient to stimulate BEL-7402 cell proliferation. cAMP inhibited FBS-stimulated Akt phosphorylation in a cAMP-dependent protein kinase-dependent manner. Further studies demonstrated that cAMP inhibited FBS-induced membrane localization of 3-phosphoinositide-dependent kinase 1 (PDK-1) which is a required process for PDK-1 to phosphorylate Akt, but had no significant effect on phosphoinositide 3-kinase activity. These results indicate that cAMP inhibition of proliferation of HCC cells is mediated by Akt and cAMP inhibits Akt activation via blocking membrane localization of PDK-1.
...
PMID:Cyclic AMP inhibition of proliferation of hepatocellular carcinoma cells is mediated by Akt. 1641 Jul 16

Pyruvate dehydrogenase kinase 2 (PDK2) is a prototypical mitochondrial protein kinase that regulates the activity of the pyruvate dehydrogenase complex. Recent structural studies have established that PDK2 consists of a catalytic core built of the B and K domains and the relatively long amino and carboxyl tails of unknown function. Here, we show that the carboxy-terminal truncation variants of PDK2 display a greatly diminished capacity for phosphorylation of holo-PDC. This effect is due largely to the inability of the transacetylase component of PDC to promote the phosphorylation reaction catalyzed by the truncated PDK2 variants. Furthermore, the truncated forms of PDK2 bind poorly to the lipoyl-bearing domain(s) provided by the transacetylase component. Taken together, these data strongly suggest that the carboxyl tails of PDK isozymes contribute to the lipoyl-bearing domain-binding site of the kinase molecule. We also show that the carboxyl tails derived from isozymes PDK1, PDK3, and PDK4 are capable of supporting the kinase activity of the kinase core derived from PDK2 as well as binding of the respective PDK2 chimeras to the lipoyl-bearing domain. Furthermore, the chimera carrying the carboxyl tail of PDK3 displays a stronger response to the addition of the transacetylase component along with a better binding to the lipoyl-bearing domain, suggesting that, at least in part, the differences in the amino acid sequences of the carboxyl tails account for the differences between PDK isozymes.
...
PMID:The carboxy-terminal tail of pyruvate dehydrogenase kinase 2 is required for the kinase activity. 1621 81

ARK5 is a tumor progression-associated factor that is directly phosphorylated by AKT at serine 600 in the regulatory domain, but phosphorylation at the conserved threonine residue on the active T loop has been found to be required for its full activation. In this study, we identified serine/threonine protein kinase NDR2 as a protein kinase that phosphorylates and activates ARK5 during insulin-like growth factor (IGF)-1 signaling. Upon stimulation with IGF-1, NDR2 was found to directly phosphorylate the conserved threonine 211 on the active T loop of ARK5 and to promote cell survival and invasion of colorectal cancer cell lines through ARK5. During IGF-1 signaling, phosphorylation at three residues (threonine 75, serine 282, and threonine 442) was also found to be required for NDR2 activation. Among these three residues, phosphorylation of serine 282 seemed to be the most important for NDR2 activation (the same as for the mouse homologue) because its aspartic acid-converted mutant (NDR2/S282D) induced ARK5-mediated cell survival and invasion activities even in the absence of IGF-1. As in the mouse homologue, threonine 75 in NDR2 was required for interaction with S100B, and binding was in a calcium ion- and phospholipase C-gamma-dependent manner. We also found that PDK-1 plays an important role in NDR2 activation especially in the phosphorylation of threonine 442. Based on the results of this study, we report here that NDR2 is an upstream kinase of ARK5 that plays an essential role in tumor progression through ARK5.
...
PMID:NDR2 acts as the upstream kinase of ARK5 during insulin-like growth factor-1 signaling. 1648 89

Endothelial cells are normally non-motile and quiescent; however, endothelial cells will become permeable and invade and proliferate to form new blood vessels (angiogenesis) in response to wounding, cancer, diabetic retinopathy, age-related macular degeneration, or rheumatoid arthritis. p21-activated kinase (Pak), an effector for the Rho GTPases Rac and Cdc42, is required for angiogenesis and regulates endothelial cell permeability and motility. Although Pak is primarily activated by Rac and Cdc42, there are additional proteins that regulate Pak activity and localization, including three AGC protein kinase family members, Akt-1, PDK-1, and cAMP-dependent protein kinase. We describe phosphorylation and regulation of Pak localization by a fourth AGC kinase family member, cGMP-dependent protein kinase (PKG). Using in vitro mapping, a phosphospecific antibody, co-transfection assays, and untransfected bovine aortic endothelial cells we determined that PKG phosphorylates Pak at serine 21. Phosphorylation was accompanied by changes in proteins associated with Pak. The adaptor protein Nck was released, whereas a novel complex with vasodilator-stimulated phosphoprotein was stimulated. Furthermore Ser-21 phosphorylation of Pak appears to be important for regulation of cell morphology. In both human umbilical vein endothelial cells and HeLa cells, activation of PKG in the presence of Pak stimulated tail retraction and cell polarization. However, in cells expressing S21A mutant Pak1, PKG activation or treatment with a peptide that blocks Nck/Pak binding caused aberrant cell morphology, blocked cell retraction, and mislocalized Pak, producing uropod (tail-like) structures. These data suggest that PKG regulates Pak and that the interaction plays a role in tail retraction.
...
PMID:cGMP-dependent protein kinase phosphorylates p21-activated kinase (Pak) 1, inhibiting Pak/Nck binding and stimulating Pak/vasodilator-stimulated phosphoprotein association. 1649 Jul 84

Phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor-kappa B (NF-kappaB) signaling pathways play a critical role in mediating survival signals. In this study we have investigated how loss of dystrophin (the primary cause of Duchenne muscular dystrophy) modulates the activation of PI3K/Akt and NF-kappaB signaling pathways in skeletal muscle in response to mechanical stimulation. Activation of Akt was significantly higher in diaphragm muscle from dystrophin-deficient mdx mice compared to normal mice at both prenecrotic and necrotic states. Higher activation of Akt was also observed in cultured dystrophin-deficient primary myotubes differentiated in vitro. Application of passive mechanical stretch ex vivo synergistically increased the activation of Akt in diaphragm of mdx mice. Stretch-induced activation of PDK-1 and PI3K were also higher in diaphragm of mdx mice compared to normal mice. Pretreatment of diaphragm with PI3K inhibitor LY294002 blocked the activation of Akt in normal and mdx mice. Higher activation of Akt was associated with increased phosphorylation of its downstream targets glycogen synthase kinase 3beta (GSK3beta), FKHR, and mammalian target of rapamycin (mTOR). Treatment of diaphragm muscle with LY294002 inhibited the stretch-induced activation of IkappaB (IkappaB) kinase (IKK) and NF-kappaB transcription factor in normal and mdx mice. Mechanical stretch also reduced the interaction of HDAC1 with RelA subunit of NF-kappaB in diaphragm muscle. Finally, cellular levels of Bcl-2, cIAP1, and integrin beta1 and activation of integrin linked kinase were higher in diaphragm muscle of mdx mice compared to normal mice. Taken together, our data suggest that loss of dystrophin and/or mechanical stretch results in the up-regulation of P13K/Akt and NF-kappaB signaling pathways in skeletal muscle.
...
PMID:Regulation of phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor-kappa B signaling pathways in dystrophin-deficient skeletal muscle in response to mechanical stretch. 1674 26

Fibroblast growth factor (FGF) signals are transduced through FGF receptors (FGFRs) and FRS2/FRS3- SHP2 (PTPN11)-GRB2 docking protein complex to SOS-RAS-RAF-MAPKK-MAPK signaling cascade and GAB1/GAB2-PI3K-PDK-AKT/aPKC signaling cascade. The RAS approximately MAPK signaling cascade is implicated in cell growth and differentiation, the PI3K approximately AKT signaling cascade in cell survival and cell fate determination, and the PI3K approximately aPKC signaling cascade in cell polarity control. FGF18, FGF20 and SPRY4 are potent targets of the canonical WNT signaling pathway in the gastrointestinal tract. SPRY4 is the FGF signaling inhibitor functioning as negative feedback apparatus for the WNT/FGF-dependent epithelial proliferation. Recombinant FGF7 and FGF20 proteins are applicable for treatment of chemotherapy/radiation-induced mucosal injury, while recombinant FGF2 protein and FGF4 expression vector are applicable for therapeutic angiogenesis. Helicobacter pylori, a causative pathogen for peptic ulcer diseases, chronic atrophic gastritis and gastric cancer, injects bacterial proteins into gastric epithelial cells by using Type IV secretion system, which leads to FGF signaling activation through FGF2 upregulation as well as CagA-dependent SHP2 activation. FGFR2 gene is preferentially amplified and overexpressed in diffuse-type gastric cancer. PD173074 is a small-molecule inhibitor for FGFR, while RO4396686 and SU6668 are small-molecule inhibitors for FGFR and other tyrosine kinases. Cocktail therapy using multiple protein kinase inhibitors could enhance the therapeutic effects for gastrointestinal cancer through the reduction of recurrence associated with somatic mutations of drug-target genes. Single nucleotide polymorphism (SNP) and copy number polymorphism (CNP) of genes encoding FGF signaling molecules will be identified as novel risk factors of gastrointestinal cancer. Personalized prevention and personalized medicine based on the combination of genetic screening and novel therapeutic agents could dramatically improve the prognosis of cancer patients.
...
PMID:FGF signaling network in the gastrointestinal tract (review). 1677 96

To elucidate the role of 3-phosphoinositide-dependent protein kinase-1 (PDK1) in cellular signaling, we constructed and expressed a pseudosubstrate of PDK1, designated as deltaAL-PIF, and characterized its properties in cultured cells. deltaAL-PIF consists of two fused proteins of the protein kinase Cdelta (deltaPKC) activation loop (deltaAL) and PDK1-interacting fragment (PIF). The phosphorylation of deltaAL-PIF was detected with anti-deltaPKC phospho-Thr505-specific antibody and was increased in proportion to the expression level of co-expressed GST-PDK1, indicating that it acts as a pseudosubstrate of PDK1. In cells expressing deltaAL-PIF, basal phosphorylation level at the activation loop of PKBalpha, deltaPKC and gammaPKC was reduced, compared with that in control cells, suggesting that deltaAL-PIF functions as an inhibitory molecule for PDK1. deltaAL-PIF affected the stability, translocation and endogenous activity of PKCs. These effects of deltaAL-PIF on gammaPKC properties were confirmed by investigation using conditioned PDK1 knockout cells. Furthermore, apoptosis frequently occurred in cells expressing deltaAL-PIF for 3 days. These findings revealed that deltaAL-PIF served as an effective pseudosubstrate and an inhibitory molecule for PDK1, suggesting that this molecule can be used as a tool for investigating PDK-mediated cellular functions as well as being applicable for anti-cancer therapy.
...
PMID:Fused protein of deltaPKC activation loop and PDK1-interacting fragment (deltaAL-PIF) functions as a pseudosubstrate and an inhibitory molecule for PDK1 when expressed in cells. 1692 25

AKT is a potent antiapoptotic kinase, but its role in the cardioprotective actions of alpha(1)-adrenergic receptors (ARs) remains uncertain, because alpha(1)-ARs typically induce little-to-no AKT activation in most cardiomyocyte models. This study identifies a prominent alpha(1)-AR-dependent AKT activation pathway that is under tonic inhibitory control by novel protein kinase Cs (nPKCs) in neonatal rat cardiomyocyte cultures. We also implicate Pyk2, Pyk2 complex formation with PDK-1 and paxillin, and increased PDK-1-Y373/376 phosphorylation as the mechanism that links alpha(1)-AR activation to increased AKT phosphorylation. nPKCs (which are prominent alpha(1)-AR effectors) interfere with this alpha(1)-AR-dependent AKT activation by blocking Pyk2/PDK-1/paxillin complex formation and PDK-1-Y373/376 phosphorylation. Additional studies used an adenoviral-mediated overexpression strategy to show that Pyk2 exerts dual controls on antiapoptotic PDK-1/AKT and proapoptotic c-Jun N-terminal kinase (JNK) pathways. Although the high nPKC activity of most cardiomyocyte models favors Pyk2 signaling to JNK (and cardiac apoptosis), the cardioprotective actions of Pyk2 through the PDK-1/AKT pathway are exposed when PKC or JNK activation is prevented. Collectively, these studies identify JNK and AKT as functionally distinct downstream components of the alpha(1)-AR/Pyk2 signaling pathway. We also implicate nPKCs as molecular switches that control the balance of signaling via proapoptotic JNK and antiapoptotic PDK-1/AKT pathways, exposing a novel mechanism for nPKC-dependent regulation of cardiac hypertrophy and failure.
...
PMID:Alpha1-adrenergic receptors activate AKT via a Pyk2/PDK-1 pathway that is tonically inhibited by novel protein kinase C isoforms in cardiomyocytes. 1711 May 96

Pyruvate dehydrogenase kinase isoenzyme 4 (PDK4) cDNA was cloned from the brain of greater horseshoe bat (Rhinolophus ferrumequinum). The deduced amino acid sequence shares strong homology with these PDK4 of other mammals. Moreover, we partially cloned homologues of dual-specificity tyrosine-phosphorylated and regulated protein kinase 1A (DYRK1A), and forkhead box protein O1A (FOXO1A) from greater horseshoe bat. Among five different tissues tested, PDK4 mRNA was highly expressed in the heart, white adipose tissue and muscle, but weakly expressed in the brain and liver, while DYRK1A and FOXO1A were expressed in all five tissues. Moreover, the transcript levels of PDK4, DYRK1A, and FOXO1A were measured in the heart, white adipose tissue and muscle of hibernating and arousal greater horseshoe bats by Northern blot and real time PCR. The results showed that transcript level of PDK4 was significantly higher in white adipose tissue. Expression level of DYRK1A was significantly higher in hibernating state in white adipose tissue, and expression level of FOXO1A was significantly higher in muscle in aroused state. These results suggest that up-regulation of the transcript levels of PDK4 during hibernation were not regulated via DYRK1A and FOXO1A in white adipose tissue and muscle, and the possible presence of another isoenzyme of PDK which is responsible for the tissue-specific regulation of Pyruvate dehydrogenase complex (PDC) activity in the bat heart during hibernation.
...
PMID:Cloning and expression of PDK4, FOXO1A and DYRK1A from the hibernating greater horseshoe bat (Rhinolophus ferrumequinum). 1714 Aug 34


<< Previous 1 2 3 4 5 6 7 Next >>

---