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)

We are interested in determining the signaling pathways for 1,25-dihydroxyvitamin D3 (1,25D)-induced differentiation of HL60 leukemic cells. One possible candidate is Raf-1, which is known to signal cell proliferation and neoplastic transformation through MEK, ERK, and downstream targets. It can also participate in the regulation of cell survival and various forms of cell differentiation, though the precise pathways are less well delineated. Here we report that Raf-1 has a role in monocytic differentiation of human myeloid leukemia HL60, which is not mediated by MEK and ERK, but likely by direct interaction with p90RSK. Specifically, we show that Raf-1 and p90RSK are increasingly activated in the later stages of differentiation of HL60 cells, at the same time as activation of MEK and ERK is decreasing. Transfection of a wild-type Raf-1 construct enhances 1,25D-induced differentiation, while antisense Raf-1 or short interfering (si) Raf-1 reduces 1,25D-induced differentiation. In contrast, antisense oligodeoxynucleotides (ODN) and siRNAs to MEK or ERK have no detectable effect on differentiation. In late stage differentiating cells Raf-1 and p90RSK are found as a complex, and inhibition of Raf-1, but not MEK or ERK expression reduces the levels of phosphorylated p90 RSK. These findings support the thesis that Raf-1 signals cell proliferation and cell differentiation through different intermediary proteins.
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PMID:Raf-1 signaling is required for the later stages of 1,25-dihydroxyvitamin D3-induced differentiation of HL60 cells but is not mediated by the MEK/ERK module. 1688 71

Using the mouse Langendorff heart perfusion model, the signaling pathways that regulate cardiac CREB-S133 phosphorylation have been defined. In mouse hearts stimulated with isoproterenol (ISO) (10(-8) M), endothelin-1 (ET-1) (10(-8) M), and phorbol 12-myristate 13-acetate (TPA) (10(-7) M), CREB-S133 phosphorylation was attained only by TPA-treatment. Activation of protein kinase A (PKA) was achieved by ISO. ISO- and ET-1-stimulation activated Ca2+/calmodulin-dependent kinase II (CaMKII). Protein kinase C (PKC) and p90(RSK) were activated with all three stimuli. Inhibition of ERK1/2 with PD98059 (10(-5) M) completely inhibited the activation of p90(RSK), but did not block CREB-S133 phosphorylation in TPA-perfused heart, indicating that PKA, CaMKII, and p90(RSK) do not phosphorylate CREB-S133 in the murine heart. PKC activation is signal specific. Analyses of PKC isoforms suggest that CREB phosphorylation is mediated by PKC epsilon translocating into nucleus only with TPA stimulation. These results, unlike those reported in other tissues, demonstrate that cardiac CREB is not a multi-signal target.
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PMID:Signaling pathways regulating murine cardiac CREB phosphorylation. 1699 75

Hormones and growth factors induce the activation of a number of protein kinases that belong to the AGC subfamily, including isoforms of PKA, protein kinase B (also known as Akt), PKC, S6K p70 (ribosomal S6 kinase), RSK (p90 ribosomal S6 kinase) and MSK (mitogen- and stress-activated protein kinase), which then mediate many of the physiological processes that are regulated by these extracellular agonists. It can be difficult to assess the individual functions of each AGC kinase because their substrate specificities are similar. Here we describe the small molecule BI-D1870, which inhibits RSK1, RSK2, RSK3 and RSK4 in vitro with an IC(50) of 10-30 nM, but does not signi-ficantly inhibit ten other AGC kinase members and over 40 other protein kinases tested at 100-fold higher concentrations. BI-D1870 is cell permeant and prevents the RSK-mediated phorbol ester- and EGF (epidermal growth factor)-induced phosphoryl-ation of glycogen synthase kinase-3beta and LKB1 in human embry-onic kidney 293 cells and Rat-2 cells. In contrast, BI-D1870 does not affect the agonist-triggered phosphorylation of substrates for six other AGC kinases. Moreover, BI-D1870 does not suppress the phorbol ester- or EGF-induced phosphorylation of CREB (cAMP-response-element-binding protein), consistent with the genetic evidence indicating that MSK, and not RSK, isoforms mediate the mitogen-induced phosphorylation of this transcription factor.
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PMID:BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo. 1715 39

Epidemiological data suggest that epigallocatechin-3-gallate (EGCG) possesses chemopreventive properties against cancer. In this study, we examined the molecular mechanisms of EGCG in human pancreatic cancer cells. EGCG caused growth arrest at G1 stage of cell cycle through regulation of cyclin D1, cdk4, cdk6, p21/WAF1/CIP1 and p27/KIP1, and induced apoptosis through generation of reactive oxygen species and activation of caspase-3 and caspase-9. EGCG inhibited expressions of Bcl-2 and Bcl-XL and induced expressions of Bax, Bak, Bcl-XS and PUMA. Mouse embryonic fibroblasts (MEFs) derived from Bax and Bak double knockout mice exhibited greater protection against EGCG-induced apoptosis than wild-type or single knockout MEFs. EGCG caused Bax activation in p53 -/- MEFs, suggesting that EGCG can induce apoptosis in the absence of p53. Furthermore, the activities of Ras, Raf-1 and ERK1/2 were inhibited, whereas the activities of MEKK1, JNK1/2 and p38 MAP kinases were induced by EGCG. Inhibition of cRaf-1 or ERK enhanced EGCG-induced apoptosis, whereas inhibition of JNK or p38 MAP kinase inhibited EGCG-induced apoptosis. EGCG inhibited the activation of p90 ribosomal protein S6 kinase, and induced the activation of cJUN. Our results suggest that EGCG induces growth arrest and apoptosis through multiple mechanisms, and can be used for pancreatic cancer prevention.
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PMID:Epigallocatechin-3-gallate inhibits cell cycle and induces apoptosis in pancreatic cancer. 1756 28

AS160 (Akt substrate of 160 kDa) mediates insulin-stimulated GLUT4 (glucose transporter 4) translocation, but is widely expressed in insulin-insensitive tissues lacking GLUT4. Having isolated AS160 by 14-3-3-affinity chromatography, we found that binding of AS160 to 14-3-3 isoforms in HEK (human embryonic kidney)-293 cells was induced by IGF-1 (insulin-like growth factor-1), EGF (epidermal growth factor), PMA and, to a lesser extent, AICAR (5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside). AS160-14-3-3 interactions were stabilized by chemical cross-linking and abolished by dephosphorylation. Eight residues on AS160 (Ser318, Ser341, Thr568, Ser570, Ser588, Thr642, Ser666 and Ser751) were differentially phosphorylated in response to IGF-1, EGF, PMA and AICAR. The binding of 14-3-3 proteins to HA-AS160 (where HA is haemagglutinin) was markedly decreased by mutation of Thr642 and abolished in a Thr642Ala/Ser341Ala double mutant. The AGC (protein kinase A/protein kinase G/protein kinase C-family) kinases RSK1 (p90 ribosomal S6 kinase 1), SGK1 (serum- and glucocorticoid-induced protein kinase 1) and PKB (protein kinase B) displayed distinct signatures of AS160 phosphorylation in vitro: all three kinases phosphorylated Ser318, Ser588 and Thr642; RSK1 also phosphorylated Ser341, Ser751 and to a lesser extent Thr568; and SGK1 phosphorylated Thr568 and Ser751. AMPK (AMP-activated protein kinase) preferentially phosphorylated Ser588, with less phosphorylation of other sites. In cells, the IGF-1-stimulated phosphorylations, and certain EGF-stimulated phosphorylations, were inhibited by PI3K (phosphoinositide 3-kinase) inhibitors, whereas the RSK inhibitor BI-D1870 inhibited the PMA-induced phosphorylations. The expression of LKB1 in HeLa cells and the use of AICAR in HEK-293 cells promoted phosphorylation of Ser588, but only weak Ser341 and Thr642 phosphorylations and binding to 14-3-3s. Paradoxically however, phenformin activated AMPK without promoting AS160 phosphorylation. The IGF-1-induced phosphorylation of the novel phosphorylated Ser666-Pro site was suppressed by AICAR, and by combined mutation of a TOS (mTOR signalling)-like sequence (FEMDI) and rapamycin. Thus, although AS160 is a common target of insulin, IGF-1, EGF, PMA and AICAR, these stimuli induce distinctive patterns of phosphorylation and 14-3-3 binding, mediated by at least four protein kinases.
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PMID:Regulation of multisite phosphorylation and 14-3-3 binding of AS160 in response to IGF-1, EGF, PMA and AICAR. 1761 58

Vitamin A and its metabolite retinoic acid (RA) are essential elements for normal lung development and the differentiation of lung epithelial cells. We previously showed that RA rapidly activated cyclic AMP response element-binding protein (CREB) in a nonclassical manner in normal human tracheobronchial epithelial (NHTBE) cells. In the present study, we further demonstrated that this nonclassical signaling of RA on the activation of CREB plays a critical role in regulating the expression of airway epithelial cell differentiation markers, the MUC2, MUC5AC, and MUC5B genes. We found that RA rapidly activates the protein kinase Calpha isozyme and transmits the activation signal to CREB via the Raf/MEK/extracellular signal-regulated kinase/p90 ribosomal S6 kinase (RSK) pathway. Activated RSK translocated from the cytoplasm to the nucleus, where it phosphorylates CREB. Activated CREB then binds to a cis-acting replication element motif on the promoter (at nucleotides [nt] -878 to -871) of the MUC5AC gene. The depletion of CREB using small interfering RNA abolished not only the RA-induced MUC5AC but also RA-induced MUC2 and MUC5B. Taken together, our findings demonstrate that CREB activation via this nonclassical RA signaling pathway may play an important role in regulating the expression of mucin genes and mediating the early biological effects of RA during normal mucous differentiation in NHTBE cells.
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PMID:Regulation of mucin gene expression by CREB via a nonclassical retinoic acid signaling pathway. 1764 88

5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) is a commonly used pharmacological agent to study physiological effects which are similar to those of exercise. However, signal transduction pathways by which AICAR elicits downstream effects in liver are poorly understood. We report here that AICAR not only activated AMPK but also phosphorylated/deactivated glycogen synthase kinase-3 alpha/beta (GSK-3alpha/beta) and dephophorylated/activated glycogen synthase (GS) in a time-dependent manner in human hepatoma HepG2 cells. The signal connection between AICAR and GSK-3 is indirect and involves activation of Raf-1/MEK/p42/44(MAPK)/p90(RSK) signaling cascade as pharmacologic inhibition of MEK significantly reduced phosphorylation/deactivation of GSK-3 and consequent dephosphorylation/activation of GS. Moreover, silencing the expression of p90(RSK), a substrate of p42/44(MAPK), attenuated AICAR-dependent GSK-3 phosphorylation, implicating this kinase as a key mediator of AICAR signaling to GSK-3. Furthermore, consistent with the involvement of Raf-1 kinase cascade, AICAR-induced low-density lipoprotein (LDL) receptor expression in a p42/44(MAPK)-dependent manner. Finally, AICAR requires AMPK-alpha2-dependent and -independent pathways to activate Raf-1 kinase cascade as suppression of AMPKalpha2 activity, and not of AMPKalpha1, partially blocked AICAR-dependent p42/44(MAPK) activation and GSK-3 phosphorylation/deactivation. Collectively, these results highlight Raf-1 signaling cascade as the critical mediator of AICAR action on glucose and lipid metabolism in HepG2 cells.
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PMID:AICAR positively regulate glycogen synthase activity and LDL receptor expression through Raf-1/MEK/p42/44MAPK/p90RSK/GSK-3 signaling cascade. 1794 90

Waardenburg syndrome (WS) is an inherited sensorineural deafness condition in humans caused by melanocyte deficiencies in the inner ear and forelock. Mutation of microphthalmia-associated transcription factor (MITF) is known to produce WS type IIA whereas mutations of either endothelin (EDN) or its receptor endothelin receptor B (EDNRB) produce WS type IV. However, a link between MITF haploinsufficiency and EDN signaling has not yet been established. Here we demonstrate mechanistic connections between EDN and MITF and their functional importance in melanocytes. Addition of EDN to cultured human melanocytes stimulated the phosphorylation of MITF in an EDNRB-dependent manner, which was completely abolished by mitogen-activated protein kinase kinase inhibition. The expression of melanocyte-specific MITF mRNA transcripts was markedly augmented after incubation with EDN1 and was followed by increased expression of MITF protein. Up-regulated expression of MITF was found to be mediated via both the mitogen-activated protein kinase-p90 ribosomal S6 kinase-cAMP response element-binding protein (CREB) and cAMP-protein kinase A-CREB pathways. In addition, EDNRB expression itself was seen to be dependent on MITF. The functional importance of these connections is illustrated by the ability of EDN to stimulate expression of melanocytic pigmentation and proliferation markers in an MITF-dependent fashion. Collectively these data provide mechanistic and epistatic links between MITF and EDN/EDNRB, critical melanocytic survival factors and WS genes.
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PMID:Epistatic connections between microphthalmia-associated transcription factor and endothelin signaling in Waardenburg syndrome and other pigmentary disorders. 1803 26

Haloperidol, a classical antipsychotic drug, affects the extracellular signal-regulated kinase (ERK) pathway in the brain. However, findings are inconsistent and the mechanism by which haloperidol regulates ERK is poorly understood. Therefore, we examined the ERK pathway and the related protein phosphatase 2A (PP2A) in detail after haloperidol administration. Haloperidol (0.5 and 1 mg/kg) induced biphasic changes in the phosphorylation level of mitogen-activated protein kinase kinase (MEK), ERK, and p90 ribosomal S6 kinase (p90RSK) without changing Raf-1 phosphorylation. Fifteen minutes after haloperidol administration, MEK-ERK-p90RSK phosphorylation increased, whilst PP2A activity decreased. At 60 min, the reverse was observed and the binding of PP2A to MEK and ERK increased. Higher dosages of haloperidol (2 and 4 mg/kg), affected neither MEK-ERK-p90RSK phosphorylation nor PP2A activity. Accordingly, PP2A regulates acute dose- and time-dependent changes in MEK-ERK-p90RSK phosphorylation after haloperidol treatment. These findings suggest the involvement of a dephosphorylating mechanism in the acute action of haloperidol.
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PMID:Haloperidol regulates the phosphorylation level of the MEK-ERK-p90RSK signal pathway via protein phosphatase 2A in the rat frontal cortex. 1827 21

PDK1 activates a group of kinases, including protein kinase B (PKB)/Akt, p70 ribosomal S6 kinase (S6K), and serum and glucocorticoid-induced protein kinase (SGK), that mediate many of the effects of insulin as well as other agonists. PDK1 interacts with phosphoinositides through a pleckstrin homology (PH) domain. To study the role of this interaction, we generated knock-in mice expressing a mutant of PDK1 incapable of binding phosphoinositides. The knock-in mice are significantly small, insulin resistant, and hyperinsulinemic. Activation of PKB is markedly reduced in knock-in mice as a result of lower phosphorylation of PKB at Thr308, the residue phosphorylated by PDK1. This results in the inhibition of the downstream mTOR complex 1 and S6K1 signaling pathways. In contrast, activation of SGK1 or p90 ribosomal S6 kinase or stimulation of S6K1 induced by feeding is unaffected by the PDK1 PH domain mutation. These observations establish the importance of the PDK1-phosphoinositide interaction in enabling PKB to be efficiently activated with an animal model. Our findings reveal how reduced activation of PKB isoforms impinges on downstream signaling pathways, causing diminution of size as well as insulin resistance.
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PMID:Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance. 1834 57


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