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)

For deciphering the cyclic guanosine monophosphate (cGMP) signaling pathway, we employed chemical proteomics to identify the novel target molecules of cGMP. We used cGMP that was immobilized onto agarose beads with linkers directed at three different positions of cGMP. We performed a pull-down assay using the beads as baits on tissue lysates and identified 9 proteins by MALDI-TOF (Matrix-Assisted Laser Desorption/Ionization Time-of-Flight) mass spectrometry. Some of the identified proteins were previously known cGMP targets, including cGMP-dependent protein kinase and cGMP-stimulated phosphodiesterase. Surprisingly, some of the coprecipitated proteins were never formerly reported to associate with the cGMP signaling pathway. The competition binding assays showed that the interactions are not by nonspecific binding to either the linker or bead itself, but by specific binding to cGMP. Furthermore, we observed that the interactions are highly specific to cGMP against other nucleotides, such as cyclic adenosine monophosphate (cAMP) and 5\'-GMP, which are structurally similar to cGMP. As one of the identified targets, MAPK1 was confirmed by immunoblotting with an anti-MAPK1 antibody. For further proof, we observed that the membrane-permeable cGMP (8-bromo cyclic GMP) stimulated mitogen-activated protein kinase 1 signaling in the treated cells. Our present study suggests that chemical proteomics can be a very useful and powerful technique for identifying the target proteins of small bioactive molecules.
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PMID:Identification of novel target proteins of cyclic GMP signaling pathways using chemical proteomics. 1278 86

Cross talk between the phosphatidylinositol 3-kinase (PI3-K) and mitogen-activating protein kinase (MAPK)1/2 signaling cascades in response to aldosterone-induced K-RasA was investigated in renal A6 epithelial cells. In addition, the contribution of these signaling pathways to aldosterone-stimulated Na(+) transport was investigated. Aldosterone increased active K-RasA levels in A6 cells resulting in activation of downstream effectors in both the MAPK1/2 and PI3-K cascades with K-RasA directly interacting with the catalytic p110 subunit of PI3-K in a steroid-dependent manner. Aldosterone-stimulated PI3-K signaling impinged on the MAPK1/2 cascade at the level of Akt-mediated phosphorylation of c-Raf at an established negative regulatory site. Aldosterone also increased Sgk levels as well as stimulated phosphorylation of this kinase in a PI3-K- and K-RasA-dependent manner. Blockade of MAPK1/2 signaling had little effect on Na(+) transport. Conversely, inhibition of PI3-K markedly suppressed transport. Likewise, suppression of K-RasA induction decreased transport. However, Na(+) transport was subsequently stimulated under these conditions with the PLA(2) inhibitor aristolochic acid, an established positive modulator of Na(+) transport, suggesting that K-RasA signaling through PI3-K does not directly affect epithelial sodium channel (ENaC) levels but the activity of this channel. Consistent with this possibility, activity of ENaC reconstituted in Chinese hamster ovary cells was increased by coexpression of constitutively active PI3-K. The current study demonstrates that aldosterone increases Na(+) transport, in part, by stimulating PI3-K signaling and that during aldosterone actions, there is both signaling convergence between the two aldosterone-induced proteins, K-RasA and Sgk, as well as cross talk between the PI3-K and MAPK1/2 cascades with the prior but not latter cascade enhancing ENaC activity.
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PMID:Regulation of Na+ transport by aldosterone: signaling convergence and cross talk between the PI3-K and MAPK1/2 cascades. 1503 43

The canonical mitogen-activated protein kinase (MAPK) signal cascade was previously suggested to be atypical in the malaria parasite. This raises queries on the existence of alternative mediators of plasmodial MAPK pathways. This study describes, Pfnek3, a malarial protein kinase belonging to the NIMA (Never in Mitosis, Aspergillus) family. Endogenous Pfnek3 is expressed during late asexual to gametocyte stages and lacks some classical protein kinase sequence motifs. Moreover, Pfnek3 is phylogenetically distant from mammalian NIMA-kinases. Recombinant Pfnek3 was able to phosphorylate and stimulate a malarial MAPK (Pfmap2). Contrastingly, this was not observed with two other kinases, Pfmap1 and human MAPK1, suggesting that the Pfnek3-Pfmap2 interaction may be specific for Pfmap2 regulation. In summary, our data reveal a malarial NIMA-kinase with the potential to regulate a MAPK. Possessing biochemical properties divergent from classical mammalian NIMA-kinases, Pfnek3 could potentially be an attractive target for parasite-selective anti-malarials.
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PMID:Pfnek3: an atypical activator of a MAP kinase in Plasmodium falciparum. 1706 92

In mammals, IGFs are important for the proliferation and steroidogenesis of ovarian cells. Metformin is an insulin sensitizer molecule used for the treatment of the infertility of women with polycystic ovary syndrome. It is, however, unclear whether metformin acts on ovarian cells. Adenosine 5' monophosphate-activated protein kinase (AMPK) is involved in metformin action in various cell types. We investigated the effects of metformin on bovine granulosa cell steroidogenesis in response to IGF1 and FSH, and studied AMPK in bovine ovaries. In granulosa cells from small follicles, metformin (10 mM) reduced production of both progesterone and estradiol and decreased the abundance of HSD3B, CYP11A1, and STAR proteins in presence or absence of FSH (10(-8) M) and IGF1 (10(-8) M). In cows, the different subunits of AMPK are expressed in various ovarian cells including granulosa and theca cells, corpus luteum, and oocytes. In bovine granulosa cells from small follicles, metformin, like AICAR (1 mM) a pharmaceutical activator of AMPK, increased phosphorylation of both Thr172 of AMPK alpha and Ser 79 of ACACA (Acetyl-CoA Carboxylase). Both metformin and AICAR treatment reduced progesterone and estradiol secretion in presence or absence of FSH and IGF1. Metformin decreased phosphorylation levels of MAPK3/MAPK1 and MAPK14 in a dose- and time-dependent manner. The adenovirus-mediated production of dominant negative AMPK abolished the effects of metformin on secretion of progesterone and estradiol and on MAPK3/MAPK1 phosphorylation but not on MAPK14 phosphorylation. Thus, in bovine granulosa cells, metformin decreases steroidogenesis and MAPK3/MAPK1 phosphorylation through AMPK activation.
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PMID:Effects of metformin on bovine granulosa cells steroidogenesis: possible involvement of adenosine 5' monophosphate-activated protein kinase (AMPK). 1712 42

Alterations in the intracellular signal transduction pathway in primary afferents may contribute to pain hypersensitivity. Recently, we have reported that the phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) occurs in primary afferent neurons in response to noxious stimulation of the peripheral tissue, i.e., activity-dependent activation of ERK1/2 and p38 MAPK in dorsal root ganglion (DRG) neurons. In the present study, we investigated the phosphorylation of ERK5, also known as big MAPK1, in the DRG by noxious stimulation using immunohistochemistry. Capsaicin injection induced phosphorylated ERK5 (p-ERK5) in small-to-medium diameter sensory neurons with a peak at 2 min after capsaicin injection. Furthermore, we examined the p-ERK5 labeling in the DRG after noxious heat and cold stimuli and found a stimulus intensity-dependent increase in the number of activated neurons. Most of these p-ERK5-immunoreactive neurons were small- and medium-sized neurons, which coexpressed transient receptor potential (TRP) ion channel TRPV1 and TRPA1 after noxious heat and cold stimuli, respectively. In contrast, there was no change in ERK5 phosphorylation in the spinal dorsal horn. The i.t. administration of ERK5 antisense oligodeoxynucleotide reversed heat hyperalgesia, but not mechanical allodynia, produced by capsaicin injection. Taken together, these findings suggest that the in vivo activation of the ERK5 signaling pathway in sensory neurons by noxious stimulation may be, at least in part, correlated with functional activity and, further, involved in the development of pain hypersensitivity.
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PMID:Intensity-dependent activation of extracellular signal-regulated protein kinase 5 in sensory neurons contributes to pain hypersensitivity. 1723 56

Aberrant patterns of pre-mRNA processing are typical of human malignancies, yet the mechanisms responsible for these changes remain undefined. We have recently shown overexpression of a core splice regulatory protein, serine-arginine protein kinase 1 (SRPK1), in dysplastic and neoplastic pancreatic ductular cells. In the present study, we have established that SRPK1 levels are similarly up-regulated in breast and colonic tumors where its expression increases coordinately with tumor grade. Targeting SRPK1 for inhibition using small interfering RNA in breast and colonic tumor cell lines in vitro resulted in both increased apoptotic potential and enhanced cell killing after treatment with gemcitabine and cisplatin. Recent reports have described multifaceted interactions between the mitogen-activated protein kinase (MAPK) and AKT signaling networks and the splice regulatory machinery. Consequently, we have shown that targeted inhibition of SRPK1 in tumor cells results in reduced phosphorylation of MAPK3, MAPK1, and AKT. Alterations in the splice pattern and resulting expression of MAPK kinase are implicated in mediating the antitumoral effects resulting from SRPK1 down-regulation. The up-regulation of SRPK1 in multiple cancers and its ability to regulate multiple relevant signaling pathways provide support for developing agents to inhibit this kinase for possible broad application to treat epithelial cancers.
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PMID:Serine-arginine protein kinase 1 overexpression is associated with tumorigenic imbalance in mitogen-activated protein kinase pathways in breast, colonic, and pancreatic carcinomas. 1733 36

HIV-associated nephropathy (HIVAN) is the leading cause of end-stage renal failure in HIV-1 seropositive patients. The pathologic findings include collapsing focal segmental glomerulosclerosis with proliferation of epithelial cells in Bowman's space. Anatomically, these cells correspond to podocytes and exhibit a unique phenotype with loss of many differentiation markers including synaptopodin and dysregulation of the cell cycle markers consistent with proliferation. Podocyte dysfunction appears to be a direct result of HIV-1 protein expression, specifically Nef and Vpr as well as specific host factors that have yet to be elucidated. The mechanism by which Nef induces podocyte proliferation and dedifferentiation has been traced to its ability to activate several signaling pathways including Src-Stat3 and ras-raf-MAPK1, 2. Activation of the cAMP/PKA pathway with all-trans-retinoic acid appears to modulate these changes and returns podocytes to a differentiated, nonproliferating phenotype.
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PMID:Podocytes in HIV-associated nephropathy. 1757 Sep 32

The role of cell size and shape in controlling local intracellular signaling reactions, and how this spatial information originates and is propagated, is not well understood. We have used partial differential equations to model the flow of spatial information from the beta-adrenergic receptor to MAPK1,2 through the cAMP/PKA/B-Raf/MAPK1,2 network in neurons using real geometries. The numerical simulations indicated that cell shape controls the dynamics of local biochemical activity of signal-modulated negative regulators, such as phosphodiesterases and protein phosphatases within regulatory loops to determine the size of microdomains of activated signaling components. The model prediction that negative regulators control the flow of spatial information to downstream components was verified experimentally in rat hippocampal slices. These results suggest a mechanism by which cellular geometry, the presence of regulatory loops with negative regulators, and key reaction rates all together control spatial information transfer and microdomain characteristics within cells.
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PMID:Cell shape and negative links in regulatory motifs together control spatial information flow in signaling networks. 1855 61

Nef-induced podocyte proliferation and dedifferentiation via mitogen-activated protein kinase 1,2 (MAPK1,2) activation plays a role in human immunodeficiency virus (HIV) nephropathy pathogenesis. All-trans retinoic acid (atRA) reverses the HIV-induced podocyte phenotype by activating cyclic AMP (cAMP)/protein kinase A (PKA) and inhibiting MAPK1,2. Here we show that atRA, through cAMP and PKA, triggers a feed-forward loop involving CREB and USF1 to induce biphasic stimulation of MKP1. atRA stimulated CREB and USF1 binding to the MKP1 gene promoter, as shown by gel shifting and chromatin immunoprecipitation assays. CREB directly mediated the early phase of atRA-induced MKP1 stimulation; whereas the later phase was mediated by CREB indirectly through induction of USF1. These findings were confirmed by a reporter gene assay using the MKP1 promoter with mutation of CRE or Ebox binding sites. Consistent with these findings, the biological effects of atRA on podocytes were inhibited by silencing either MKP1, CREB, or USF1 with small interfering RNA. atRA also induced CREB phosphorylation and MKP1 expression and reduced MAPK1,2 phosphorylation in kidneys of HIV type 1-infected transgenic mice. We conclude that atRA induces sustained activation of MKP1 to suppress Nef-induced activation of the Src-MAPK1,2 pathway, thus returning the podocyte to a more differentiated state. The mechanism involves a feed-forward loop where activation of one transcription factor (TF) (CREB) leads to induction of a second TF (USF1).
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PMID:Retinoic acid utilizes CREB and USF1 in a transcriptional feed-forward loop in order to stimulate MKP1 expression in human immunodeficiency virus-infected podocytes. 1862 21

The mobilization of free fatty acids (FFA) from adipose tissue to the bloodstream primarily depends on triacylglycerol lipolysis in adipocytes. Catecholamines are major hormones that govern lipolysis through elevating cellular cAMP production and activating protein kinase, cAMP dependent, catalytic, alpha (PKA) and mitogen-activated protein kinase 1/2 (MAPK1/3). Obesity and type 2 diabetes are associated with elevated levels of systemic FFA, which restricts glucose utilization and induces insulin resistance. The biguanide metformin exerts its antihyperglycemic effect by enhancing insulin sensitivity, which is associated with decreased levels of circulating FFA. In this study, we examined the characteristics and basis of the inhibitory effect of metformin on adrenergic-stimulated lipolysis in primary rat adipocytes. We measured the release of FFA and glycerol as an index of lipolysis and examined the major signalings of the lipolytic cascade in primary rat adipocytes. Metformin at 250-500 microM efficiently attenuated FFA and glycerol release from the adipocytes stimulated with 1 microM isoproterenol. To elucidate the basis for this antilipolytic action, we showed that metformin decreased cellular cAMP production, reduced the activities of PKA and MAPK1/3, and attenuated the phosphorylation of perilipin during isoproterenol-stimulated lipolysis. Further, metformin suppressed isoproterenol-promoted lipase activity but did not affect the translocation of lipase, hormone-sensitive from the cytosol to lipid droplets in adipocytes. This study provides evidence that metformin acts on adipocytes to suppress the lipolysis response to catecholamine. This antilipolytic effect could be a cellular basis for metformin decreasing plasma FFA levels and improving insulin sensitivity.
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PMID:Mechanisms of metformin inhibiting lipolytic response to isoproterenol in primary rat adipocytes. 1895 35


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