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)

CD33 (Siglec-3) is a marker of myeloid progenitor cells, mature myeloid cells, and most myeloid leukemias. Although its biologic role remains unknown, it has been demonstrated to function as a sialic acid-specific lectin and a cell adhesion molecule. Many of the Siglecs (including CD33) have been reported to be tyrosine phosphorylated in the cytosolic tails under specific stimulation conditions. Here we report that CD33 is also a serine/threonine phosphoprotein, containing at least 2 sites of serine phosphorylation in its cytoplasmic domain, catalyzed by protein kinase C (PKC). Phosphorylation could be augmented by exposure to the protein kinase-activating cytokines interleukin 3, erythropoietin, or granulocyte-macrophage colony-stimulating factor, in a cytokine-dependent cell line, TF-1. The CD33 cytoplasmic tail was phosphorylated by PKC in vitro, in a Ca(++)/lipid-dependent manner. CHOK1 cells stably expressing CD33 with cytoplasmic tails of various length also showed phorbol myristate acetate (PMA)-dependent phosphorylation of CD33. Inhibition of CD33 phosphorylation with pharmacologic agents resulted in an increase of sialic acid-dependent rosette formation. Furthermore, the occupancy of the lectin site affected its basal level of phosphorylation. Rosette formation by COS cells expressing a form of CD33 lacking its cytoplasmic domain was not affected by these same agents. These data indicate that CD33 is a phosphoprotein, that its phosphorylation may be controlled by PKC downstream of cytokine stimulation, and that its phosphorylation is cross-regulated with its lectin activity. Notably, although this is the first example of serine/threonine phosphorylation in the subfamily of CD33-like Siglecs, some of the other members also have putative target sites in their cytoplasmic tails.
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PMID:Role of protein kinase C in the phosphorylation of CD33 (Siglec-3) and its effect on lectin activity. 1196 82

Monocyte chemoattractant protein-1 (MCP-1) plays a crucial role in the migration and activation of leukocytes in both physiological and pathological contexts. In this paper, we report the in vitro effect of MCP-1 on myeloid haematopoiesis. MCP-1-treated murine nonadherent bone marrow cells (NABMCs) were assayed for in vitro proliferation and colony forming ability. It is observed that MCP-1 treatment in vitro caused an enhancement in the proliferation and colony forming ability of the murine NABMCs as compared to the untreated cells. This response was concentration-dependent and most effective at a dose of 100ng/ml MCP-1. In the presence of MCSF (200U/ml), GCSF (200U/ml), GMCSF (200U/ml) or IL-3 (200U/ml), the MCP-1-induced colony forming ability of the NABMCs was significantly augmented, indicating a synergistic effect of MCP-1 with these CSFs. However, irrespective of the CSFs used, MCP-1 stimulated the lineage-restricted differentiation of the murine BMCs into predominantly the granulocytic lineage. NABMCs cultured in medium alone formed minimal colonies. The probable signal transduction mechanism responsible for the MCP-1-induced NABMC proliferation/differentiation was also investigated. The results of the colony forming assay indicate that the protein kinase inhibitors, genistein (10&mgr;g/ml), chelenthryin chloride (10&mgr;M), wortmannin (200nM) and PD98059 (10&mgr;M) significantly blocked the in vitro colony forming ability of the MCP-1-treated NABMCs, while the phosphatase inhibitors, okadaic acid (10nM) and sodium orthovanadate (10&mgr;M) caused an increase in the BMC colony forming ability in response to MCP-1. These data suggests the involvement of the respective protein kinases and phosphatases in the above process. Correlating with this, the role of several signaling molecules likes Lyn, p42/44MAPK, PI3K and STAT5 has also been implicated in the signal cascade of murine NABMC proliferation/differentiation following MCP-1 treatment.
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PMID:Effect of monocyte chemoattractant protein-1 on murine bone marrow cells: proliferation, colony-forming ability and signal transduction pathway involved. 1257 18

The Raf/MEK/ERK kinase cascade plays a critical role in transducing growth signals from activated cell surface receptors. Using DeltaMEK1:ER, a conditionally active form of MEK1 which responds to either beta-estradiol or the estrogen receptor antagonist 4 hydroxy-tamoxifen (4HT), we previously documented the ability of this dual specificity protein kinase to abrogate the cytokine-dependency of human (TF-1) and murine (FDC-P1 and FL5.12) hematopoietic cells lines. Here we demonstrate the ability of DeltaMEK1:ER to activate the phosphatidylinositol 3-kinase (PI3K)/Akt/p70 ribosomal S6 kinase (p70(S6K)) pathway and the importance of this pathway in MEK1-mediated prevention of apoptosis. MEK1-responsive cells can be maintained long term in the presence of beta-estradiol, 4HT or IL-3. Removal of hormone led to the rapid cessation of cell proliferation and the induction of apoptosis in a manner similar to cytokine deprivation of the parental cells. Stimulation of DeltaMEK1:ER by 4HT resulted in ERK, PI3K, Akt and p70(S6K) activation. Treatment with PI3K, Akt and p70(S6K) inhibitors prevented MEK-responsive growth. Furthermore, the apoptotic effects of PI3K/Akt/p70(S6K) inhibitors could be enhanced by cotreatment with MEK inhibitors. Use of a PI3K inhibitor and a constitutively active form of Akt, [DeltaAkt(Myr(+))], indicated that activation of PI3K was necessary for MEK1-responsive growth and survival as activation of Akt alone was unable to compensate for the loss of PI3K activity. Cells transduced by MEK or MEK+Akt displayed different sensitivities to signal transduction inhibitors, which targeted these pathways. These results indicate a requirement for the activation of the PI3K pathway during MEK-mediated transformation of certain hematopoietic cells. These experiments provide important clues as to why the identification of mutant signaling pathways may be the Achilles heel of leukemic cell growth. Leukemia treatment targeting multiple signal transduction pathways may be more efficacious than therapy aimed at inhibiting a single pathway.
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PMID:Requirement for the PI3K/Akt pathway in MEK1-mediated growth and prevention of apoptosis: identification of an Achilles heel in leukemia. 1276 69

FDC-P1 hematopoietic cells were conditionally transformed to grow in response to (delta)B Raf:ER, (delta)Raf-1:ER or DA-Raf:ER in which the hormone binding domain of the estrogen receptor (ER) was linked to the N-terminal truncated (delta) Raf genes. When these cells were deprived of IL-3 or beta-estradiol for 24 hrs, they exited the cell cycle and underwent apoptosis. FD/(delta)Raf-1:ER and FD/(delta)A-Raf:ER, but not FD/(delta)B-Raf:ER cells, were readily induced to re-enter the cell cycle after addition of beta-estradiol or IL-3. Deprived FD/(delta)Raf-1:ER, but not FD/(delta)B-Raf:ER cells, expressed activated forms of MEK1 and ERK after beta-estradiol or IL-3 stimulation. Insulin or beta-estradiol alone did not induce FD/(delta)B-Raf:ER cells to re-enter the cell cycle, whereas cell cycle entry was observed upon their co-addition. Apoptosis was prevented in FD/(delta)B-Raf:ER cells when they were cultured in the presence of IL-3 or beta-estradiol, whereas they underwent apoptosis in their absence. Insulin by itself did not prevent apoptosis, however, upon DB-Raf:ER or DRaf-1:ER activation and addition of insulin, more than an additive effect was observed in both lines indicating that these path- ways synergized to prevent apoptosis. Raf isoforms differ in their abilities to control apoptosis and cell cycle progression and B-Raf requires insulin-activated pathways for full antiapoptotic and proliferative activity.
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PMID:B-raf and insulin synergistically prevent apoptosis and induce cell cycle progression in hematopoietic cells. 1471 85

PTH binding to its receptor activates protein kinase A (PKA), protein kinase C (PKC), and calcium signaling to induce transcription of primary response genes in osteoblasts. Adenovirus E4 promoter-binding protein/nuclear factor regulated by IL-3 (E4BP4/NFIL3), a transcriptional repressor, is a PTH-induced primary response gene in primary mouse osteoblasts (MOBs). Here we investigate the signaling pathway(s) that lead to PTH induction of E4bp4 mRNA expression. Ten and 100 nm PTH induced maximum E4bp4 expression in MOBs. Forskolin (FSK), an adenylate cyclase inducer, 8-bromo-cAMP, a cAMP analog, and phorbol myristate acetate, a PKC activator, increased E4bp4 mRNA levels, whereas ionomycin, a calcium ionophore, had no effect. Pretreatment of cells with 30 microm H89, a PKA inhibitor, strongly inhibited PTH- and FSK-induced E4bp4 expression. In contrast, overnight pretreatment with 1 microm phorbol myristate acetate to down-regulate PKC signaling did not alter PTH and FSK effects. Moreover, PTH (3-34) that does not activate cAMP signaling did not increase E4bp4 expression. Prostaglandin E(2), which signals through cAMP, increased E4bp4 mRNA at all doses, whereas prostaglandin F(2alpha) that primarily activates PKC and calcium signaling, induced E4bp4 only at high doses and fluprostenol that only activates PKC and calcium signaling, had no effect. Finally, 80 microg/kg PTH (1-34) ip injection induced E4bp4 mRNA expression at 1 h in mice. In contrast, 80 microg/kg PTH (3-34) had no effect. Our data suggest that PTH-induced E4bp4 mRNA expression is mediated primarily through cAMP-PKA signaling in vitro and in vivo. In conjunction with our previous report, we hypothesize that E4bp4 attenuates transcription of osteoblastic genes possessing E4bp4 promoter binding sites.
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PMID:Parathyroid hormone induces E4bp4 messenger ribonucleic acid expression primarily through cyclic adenosine 3',5'-monophosphate signaling in osteoblasts. 1508 29

The Raf-1 serine/threonine kinase is a key protein that is implicated in the transmission of many growth and cell survival signals. In the present study we demonstrate that apoptosis of hematopoietic cells induced by IL-3-deprivation is associated with the cleavage of Raf-1, resulting in the separation of the N-terminal regulatory domain and the C-terminal kinase domain. Raf-1 cleavage specifically occurs upon triggering of the mitochondrial death pathway, and coincides with the activation of specific caspases. Moreover, Bcl-2 overexpression or treatment with the caspase inhibitor z-VAD.fmk completely prevented Raf-1 cleavage, whereas caspase inhibition by treatment of cells with Ac-DEVD.fmk or z-IETD.fmk, or CrmA overexpression had no effect. Furthermore, in vitro cleavage studies indicate that caspase-9, which is the apical protease in the mitochondrial death pathway, is able to cleave Raf-1 at position D279. Cell fractionation studies showed that the Raf-1 C-terminal fragment that is generated upon IL-3 withdrawal is localized predominantly to the mitochondria. In addition, constitutive expression of this C-terminal Raf-1 fragment fused to a mitochondrial targeting sequence in Ba/F3 pre-B cells significantly delays apoptosis induced by IL-3 withdrawal. These results suggest an important role for caspase-9 mediated cleavage of Raf-1 in the negative feedback regulation of hematopoietic cell apoptosis induced by growth factor withdrawal.
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PMID:Apoptosis of hematopoietic cells induced by growth factor withdrawal is associated with caspase-9 mediated cleavage of Raf-1. 1567 27

Caveolin-1 (Cav-1) has been suggested to function as a negative regulator of mitogen-stimulated proliferation and the Ras-p42/44 ERK (MAP kinase) pathway in a variety of cell types. However, the molecular basis of this suppression has not been clarified. Spred/Sprouty family proteins are also negative regulators of the ERK pathway by interacting with Raf-1. The Spred/Sprouty family proteins contain a cysteine-rich (CR) domain at the C-terminus, which is thought to be palmitoylated like Cav-1 and necessary for membrane anchoring. In this study, we demonstrated that Spred-1 localized in cholesterol-rich membrane raft/caveola fractions and interacted with Cav-1. To clarify the biological effect of Cav-1/Spred-1 interaction, we used hematopoietic cells that lacked expression of caveolins but expressed Spred-1. Forced expression of Cav-1 suppressed SCF- and IL-3-induced proliferation and ERK activation. Furthermore, forced expression of exogenous Spred-1 in Cav-1-expressing cells further suppressed proliferation and ERK activation. These data suggest that Spred-1 inhibits ERK activation in collaboration with Cav-1.
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PMID:The Sprouty-related protein, Spred-1, localizes in a lipid raft/caveola and inhibits ERK activation in collaboration with caveolin-1. 1611 97

IL-3 is a potent priming cytokine for human basophils, inducing an increase of mediator release after stimulation. The mechanism of IL-3 priming of the basophil response to FcepsilonRI aggregating stimuli remains unknown. We explored the regulation of several elements of IgE-mediated signaling by a short priming with IL-3. Early signaling events such as phosphorylation of Syk, Shc, linker for activation of T cells, and the calcium signal were not statistically affected by acute IL-3 priming. Downstream in the signaling cascade, a point of up-regulation was found at the level of Raf-1-Mek-Erk. Although the phosphorylation of Raf-1 was not changed by IL-3 priming, IL-3-primed anti-IgE-stimulated basophils showed a strong synergism for Mek and Erk phosphorylation when compared with either IL-3 or anti-IgE alone; pre-exposure to IL-3 induced a final 13-fold average increase over anti-IgE-induced Erk phosphorylation (6-fold above the sum of anti-IgE and IL-3 alone). The kinetics, dose response, and pharmacologic characteristics of the IL-3 priming of stimulus-induced Erk phosphorylation support the involvement of a yet unknown mechanism that is independent of IL-3-induced Erk and PI3K activation. This type of preactivation can be mimicked by incubation with the Ser-Thr kinase inhibitors, Ro-81-3220, or bisindoylmaleimide II.
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PMID:Acute IL-3 priming up-regulates the stimulus-induced Raf-1-Mek-Erk cascade independently of IL-3-induced activation of Erk. 1611 88

Aggregation of the type 1 Fc-epsilon receptors (Fc-epsilon-RI) on mast cells initiates a network of biochemical processes culminating in secretion of both granule-stored and de novo-synthesized inflammatory mediators. A strict control of this response is obviously a necessity; nevertheless, this regulation is hardly characterized. Here we report that a prototype inhibitory receptor, the mast cell function-associated antigen (MAFA), selectively regulates the Fc-epsilon-RI stimulus-response coupling network and the subsequent de novo production and secretion of inflammatory mediators. Specifically, MAFA suppresses the PLC-gamma2-[Ca2+]i, Raf-1-Erk1/2, and PKC-p38 coupling pathways, while the Fyn-Gab2-mediated activation of PKB and Jnk is essentially unaffected. Hence, the activities of several transcription/nuclear factors for inflammatory mediators (NF-kappaB, NFAT) are markedly reduced, while those of others (Jun, Fos, Fra, p90rsk) are unaltered. This results in a selective inhibition of gene transcription of cytokines including IL-1beta, IL-4, IL-8, and IL-10, while that of TNF-alpha, MCP-1, IL-3, IL-5, or IL-13 remains unaffected. Taken together, these results illustrate the capacity of an immunoreceptor tyrosine-based inhibitory motif-containing receptor to cause tight and specific control of the production and secretion of inflammatory mediators by mast cells.
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PMID:Selective inhibition of the Fc epsilon RI-induced de novo synthesis of mediators by an inhibitory receptor. 3070 14

We investigated the role of glycogen synthase kinase-3 (GSK-3), which is inactivated by AKT, for its role in the regulation of apoptosis. Upon IL-3 withdrawal, protein levels of MCL-1 decreased but were sustained by pharmacological inhibition of GSK-3, which prevented cytochrome c release and apoptosis. MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). S159 phosphorylation of MCL-1 was induced by IL-3 withdrawal or PI3K inhibition and prevented by AKT or inhibition of GSK-3, and it led to increased ubiquitinylation and degradation of MCL-1. A phosphorylation-site mutant (MCL-1(S159A)), expressed in IL-3-dependent cells, showed enhanced stability upon IL-3 withdrawal and conferred increased protection from apoptosis compared to wild-type MCL-1. The results demonstrate that the control of MCL-1 stability by GSK-3 is an important mechanism for the regulation of apoptosis by growth factors, PI3K, and AKT.
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PMID:Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. 1654 40


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