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)

The Akt signaling pathway is important for survival and growth of cancer cells. In the present paper we show that the Akt signaling pathway is constitutively activated in human T-cell leukemia virus type I (HTLV-I)-infected T-cell lines and in primary adult T-cell leukemia (ATL) cells. Curcumin, a natural compound present in turmeric, has been studied vigorously as a potent chemopreventive agent for cancer therapy because of its inhibitory effect on proliferation and induction of apoptosis in several tumor cell lines. We investigated the effect of curcumin on Akt activity in HTLV-I-infected T-cell lines and primary ATL cells. Phosphorylated PDK1 is an activator of Akt by phosphorylating Akt. Curcumin reduced phosphorylation of PDK1 and inhibited constitutive activation of Akt. Curcumin activated glycogen synthase kinase (GSK)-3beta, a downstream target of Akt kinase, by inhibiting phosphorylation of this protein. Curcumin reduced the expression of cell cycle regulators, cyclin D1 and c-Myc proteins, which are both degraded by activated GSK-3beta. Our results suggest that activation of the Akt signaling pathway plays an important role in ATL cell survival, and that curcumin may have anti-ATL properties mediated, at least in part, by inhibiting Akt activity. We propose that Akt-targeting agents could be useful for the treatment of ATL. In this regard, curcumin is a potentially promising compound for the treatment of ATL.
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PMID:Curcumin targets Akt cell survival signaling pathway in HTLV-I-infected T-cell lines. 2126 53

The eukaryotic translation initiation factor 4B (eIF4B) plays a critical role in recruiting the 40S ribosomal subunit to the mRNA. In response to insulin, eIF4B is phosphorylated on Ser422 by S6K in a rapamycin-sensitive manner. Here we demonstrate that the p90 ribosomal protein S6 kinase (RSK) phosphorylates eIF4B on the same residue. The relative contribution of the RSK and S6K modules to the phosphorylation of eIF4B is growth factor-dependent, and the two phosphorylation events exhibit very different kinetics. The S6K and RSK proteins are members of the AGC protein kinase family, and require PDK1 phosphorylation for activation. Consistent with this requirement, phosphorylation of eIF4B Ser422 is abrogated in PDK1 null embryonic stem cells. Phosphorylation of eIF4B on Ser422 by RSK and S6K is physiologically significant, as it increases the interaction of eIF4B with the eukaryotic translation initiation factor 3.
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PMID:The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity. 1676 66

The serum- and glucocorticoid-inducible kinase-1 (SGK1) is ubiquitously expressed and under genomic control by cell stress (including cell shrinkage) and hormones (including gluco- and mineralocorticoids). Similar to its isoforms SGK2 and SGK3, SGK1 is activated by insulin and growth factors via phosphatidylinositol 3-kinase and the 3-phosphoinositide-dependent kinase PDK1. SGKs activate ion channels (e.g., ENaC, TRPV5, ROMK, Kv1.3, KCNE1/KCNQ1, GluR1, GluR6), carriers (e.g., NHE3, GLUT1, SGLT1, EAAT1-5), and the Na+-K+-ATPase. They regulate the activity of enzymes (e.g., glycogen synthase kinase-3, ubiquitin ligase Nedd4-2, phosphomannose mutase-2) and transcription factors (e.g., forkhead transcription factor FKHRL1, beta-catenin, nuclear factor kappaB). SGKs participate in the regulation of transport, hormone release, neuroexcitability, cell proliferation, and apoptosis. SGK1 contributes to Na+ retention and K+ elimination of the kidney, mineralocorticoid stimulation of salt appetite, glucocorticoid stimulation of intestinal Na+/H+ exchanger and nutrient transport, insulin-dependent salt sensitivity of blood pressure and salt sensitivity of peripheral glucose uptake, memory consolidation, and cardiac repolarization. A common ( approximately 5% prevalence) SGK1 gene variant is associated with increased blood pressure and body weight. SGK1 may thus contribute to metabolic syndrome. SGK1 may further participate in tumor growth, neurodegeneration, fibrosing disease, and the sequelae of ischemia. SGK3 is required for adequate hair growth and maintenance of intestinal nutrient transport and influences locomotive behavior. In conclusion, the SGKs cover a wide variety of physiological functions and may play an active role in a multitude of pathophysiological conditions. There is little doubt that further targets will be identified that are modulated by the SGK isoforms and that further SGK-dependent in vivo physiological functions and pathophysiological conditions will be defined.
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PMID:(Patho)physiological significance of the serum- and glucocorticoid-inducible kinase isoforms. 1701 87

Arabidopsis PDK1 activity is regulated by binding to the lipid phosphatidic acid (PA) resulting in activation of the oxidative stress-response protein kinase OXI1/AGC2-1. Thus there is an inferred link between lipid signaling and oxidative stress signaling modules. Among a panel of hormones and stresses tested, we found that, in addition to PA, the fungal elicitor xylanase activated PDK1, suggesting that PDK1 has a role in plant pathogen defense mechanisms. The downstream OXI1 was activated by additional stress factors, including PA, H(2)O(2), and partially by xylanase. We have isolated an interacting partner of OXI1, a Ser/Thr kinase (PTI1-2), which is downstream of OXI1. Its sequence closely resembles the tomato Pti kinase, which has been implicated in the hypersensitive response, a localized programmed cell death that occurs at the site of pathogen infection. PTI1-2 is activated by the same stresses/elicitors as OXI1 and additionally flagellin. We have used RNA interference to knock out the expression of PDK1 and OXI1 and to study the effects on PTI1-2 activity. We show that specific lipid signaling pathways converge on PTI1-2 via the PDK1-OXI1 axis, whereas H(2)O(2) and flagellin signals to OXI1-PTI1-2 via a PDK1-independent pathway. PTI1-2 represents a new downstream component that integrates diverse lipid and reactive oxygen stress signals and functions closely with OXI1.
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PMID:The Arabidopsis protein kinase PTI1-2 is activated by convergent phosphatidic acid and oxidative stress signaling pathways downstream of PDK1 and OXI1. 1704 Sep 18

Due to the numerous kinases in the cell, many with overlapping substrates, it is difficult to find novel substrates for a specific kinase. To identify novel substrates of cAMP-dependent protein kinase (PKA), the PKA catalytic subunit was engineered to accept bulky N(6)-substituted ATP analogs, using a chemical genetics approach initially pioneered with v-Src (1). Methionine 120 was mutated to glycine in the ATP-binding pocket of the catalytic subunit. To express the stable mutant C-subunit in Escherichia coli required co-expression with PDK1. This mutant protein was active and fully phosphorylated on Thr(197) and Ser(338). Based on its kinetic properties, the engineered C-subunit preferred N(6)(benzyl)-ATP and N(6)(phenethyl)-ATP over other ATP analogs, but still retained a 30 microm K(m) for ATP. This mutant recombinant C-subunit was used to identify three novel PKA substrates. One protein, a novel mitochondrial ChChd protein, ChChd3, was identified, suggesting that PKA may regulate mitochondria proteins.
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PMID:Identification of ChChd3 as a novel substrate of the cAMP-dependent protein kinase (PKA) using an analog-sensitive catalytic subunit. 1724 5

In recent years, the phosphoinositide-3-kinase/Akt cell survival signaling pathway has been increasingly researched in the field of stroke. Akt activity is suggested to be upregulated by phosphorylation through the activation of receptor tyrosine kinases by growth factors. Although the upstream signaling components phosphoinositide-dependent protein kinase (PDK)1 and integrinlinked kinase enhance the activity of Akt, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) decreases it. Upon activation, Akt phosphorylates an array of molecules, including glycogen synthase kinase3beta (GSK3beta), forkhead homolog in rhabdomyosarcoma (FKHR), and Bcl-2-associated death protein, thereby blocking mitochondrial cytochrome c release and caspase activity. Generally, the level of Akt phosphorylation at site Ser 473 (P-Akt) transiently increases after focal ischemia, whereas the levels of phosphorylation of PTEN, PDK1, forkhead transcription factor, and GSK3beta decrease. Numerous compounds (such as growth factors, estrogen, free radical scavengers, and other neuroprotectants) reduce ischemic damage, possibly by upregulating P-Akt. However, preconditioning and hypothermia block ischemic damage by inhibiting an increase of P-Akt. Inhibition of the Akt pathway blocks the protective effect of preconditioning and hypothermia, suggesting the Akt pathway contributes to their protective effects and that the P-Akt level does not represent its true kinase activity. Together, attenuation of the Akt pathway dysfunction contributes to neuronal survival after stroke.
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PMID:Phosphoinositide-3-kinase/akt survival signal pathways are implicated in neuronal survival after stroke. 1730 56

HTS screening identified 1 with micromolar inhibitory activity against PDK1. Optimization of 1 afforded 4i (BX-517) which has single-digit nanomolar activity against PDK1 and excellent selectivity against PKA.
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PMID:Indolinone based phosphoinositide-dependent kinase-1 (PDK1) inhibitors. Part 1: design, synthesis and biological activity. 1753 83

Phosphoinoisitide dependent kinase l (PDK1) is proposed to phosphorylate a key threonine residue within the catalytic domain of the protein kinase C (PKC) superfamily that controls the stability and catalytic competence of these kinases. Hence, in PDK1-null embryonic stem cells intracellular levels of PKCalpha, PKCbeta1, PKCgamma, and PKCepsilon are strikingly reduced. Although PDK1-null cells have reduced endogenous PKC levels they are not completely devoid of PKCs and the integrity of downstream PKC effector pathways in the absence of PDK1 has not been determined. In the present report, the PDK1 requirement for controlling the phosphorylation and activity of a well characterised substrate for PKCs, the serine kinase protein kinase D, has been examined. The data show that in embryonic stem cells and thymocytes loss of PDK1 does not prevent PKC-mediated phosphorylation and activation of protein kinase D. These results reveal that loss of PDK1 does not functionally inactivate all PKC-mediated signal transduction.
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PMID:Phosphoinositide-dependent protein kinase-1 (PDK1)-independent activation of the protein kinase C substrate, protein kinase D. 1761 9

In order to clarify the effect of dehydroepiandrosterone (DHEA) on improvement of insulin resistance, we examined the effects of overexpression of wild-type protein kinase C-zeta (wt-PKCzeta)/3-phosphoinositide-dependent protein kinase-1 (wt-PDK1) and kinase-inactive PKCzeta/PDK1 (DeltaPKCzeta/DeltaPDK1) on DHEA-induced [(3)H]2-deoxyglucose (DOG) uptake using the electroporation method in rat adipocytes. Overexpression of wt-PKCzeta and wt-PDK1 significantly increased in DHEA-induced [(3)H]2-DOG uptake. Wortmannin completely suppressed DHEA-induced [(3)H]2-DOG uptake in wt-PKCzeta- and wt-PDK1-transfected adipocytes. Overexpression of neither DeltaPKCzeta nor DeltaPDK1 increased DHEA-induced [(3)H]2-DOG uptake. Otsuka Long-Evans fatty rats (OLETF), animal models of type 2 diabetes, and Long-Evans Tokushima rats (LETO) as control, were treated with 0.4% DHEA for 2 weeks. Insulin-induced [(3)H]2-DOG uptakes, activations of PI 3-kinase and PKCzeta of adipocytes were significantly increased in DHEA-treated OLETF rats. Moreover, plasma glucose levels in OLETF rats after treatment with DHEA for 2 weeks were significantly lower than treatment without DHEA, but not in LETO rats. These results indicate that DHEA treatment may improve glucose tolerance through a PI 3-kinase-PKCzeta pathway and downregulates adiposity in OLETF rats.
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PMID:Effect of dehydroepiandrosterone on insulin sensitivity in Otsuka Long-Evans Tokushima-fatty rats. 1782 64

A cAMP-induced protein tyrosine phosphorylation and flagellar hyperactivation are controlled via complicated signaling cascades in mammalian spermatozoa. For instance, these events seem to be regulated positively by the PKA-mediated signaling and negatively by the PI3K/PDK1-mediated signaling. In this article, we have shown molecular changes of PKA and PDK1 in cAMP analog (cBiMPS)-treated boar spermatozoa in order to disclose possible roles of these kinases in protein tyrosine phosphorylation and hyperactivation. Ejaculated spermatozoa were incubated with cBiMPS, and then they were used for biochemical analyses of sperm kinases by Western blotting and indirect immunofluorescence and for assessment of flagellar movement. The first 30-min incubation with cBiMPS highly activated PKA of the principal piece to the accompaniment of autophosphorylation on Thr-197 of catalytic subunits. However, protein tyrosine phosphorylation and hyperactivation were fully induced in the sperm samples after the 180-min incubation. A potentially active form of PDK1 (54/55-kDa phospho-PDK1) was detected in the principal piece of the spermatozoa during the 90-min incubation. Another potentially active form (59-kDa phospho-PDK1) gradually increased during the same incubation period. However, the PDK1 suddenly became inactive by the dephosphorylation after the 180-min incubation, namely coincidently with full induction of protein tyrosine phosphorylation and hyperactivation. Additionally, existence of PI3K-dependently suppressing mechanisms for protein tyrosine phosphorylation was confirmed in the principal piece by pharmacological experiments with LY294002 and biochemical analyses with anti-PI3K p85 antibodies. These findings suggest that dephosphorylation of PDK1 may be a molecular switch for enhancement of protein tyrosine phosphorylation and flagellar hyperactivation in boar spermatozoa.
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PMID:Changes of PKA and PDK1 in the principal piece of boar spermatozoa treated with a cell-permeable cAMP analog to induce flagellar hyperactivation. 1821 79


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