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 demonstrate here that growth hormone (GH) stimulates the activation of RhoA and its substrate Rho kinase (ROCK) in NIH-3T3 cells. GH-stimulated formation of GTP-bound RhoA requires JAK2-dependent dissociation of RhoA from its negative regulator p190 RhoGAP. Inactivation of RhoA does not affect GH-stimulated JAK2 tyrosine phosphorylation nor p44/42 MAPK activity. However, RhoA and ROCK activities are required for GH-stimulated, Stat5-mediated transcription. RhoA-dependent enhancement of GH-stimulated, Stat5-mediated transcription is due to repression of histone deacetylase 6 activity recruited by transcription cofactor p300 that negatively regulates GH-stimulated, Stat5-mediated transcription. We also demonstrate that RhoA is the pivot for cAMP-dependent protein kinase inhibition of GH-stimulated, Stat5-mediated transcription as a consequence of cAMP-dependent protein kinase inactivation of RhoA through serine residue 188 of RhoA. We have therefore provided a novel mechanism by which a Ras-like small GTPase, RhoA, can regulate Stat5-mediated transcription.
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PMID:RhoA/ROCK activation by growth hormone abrogates p300/histone deacetylase 6 repression of Stat5-mediated transcription. 1510 57

The Ras-like guanine-nucleotide-binding protein Rap1 controls integrin alpha(IIb)beta3 activity and platelet aggregation. Recently, we have found that Rap1 activation can be blocked by the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) signaling pathway by type 1 cGMP-dependent protein kinase (cGKI). In search of possible targets of NO/cGMP/cGKI, we studied the expression of Rap1-specific GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) in platelets. We could detect mRNAs for a new protein most closely related to Rap1GAP and for postsynaptic density-95 discs-large and zona occludens protein 1 (PDZ)-GEF1 and CalDAG-GEFs I and III. Using 5'-rapid amplification of cDNA ends (RACE), we isolated the complete cDNA of the new GAP encoding a 715-amino acid protein, which we have termed Rap1GAP2. Rap1GAP2 is expressed in at least 3 splice variants, 2 of which are detectable in platelets. Endogenous Rap1GAP2 protein partially colocalizes with Rap1 in human platelets. In transfected cells, we show that Rap1GAP2 exhibits strong GTPase-stimulating activity toward Rap1. Rap1GAP2 is highly phosphorylated, and we have identified cGKI as a Rap1GAP2 kinase. cGKI phosphorylates Rap1GAP2 exclusively on serine 7, a residue present only in the platelet splice variants of Rap1GAP2. Phosphorylation of Rap1GAP2 by cGKI might mediate inhibitory effects of NO/cGMP on Rap1. Rap1GAP2 is the first GTPase-activating protein of Rap1 found in platelets and is likely to have an important regulatory role in platelet aggregation.
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PMID:Rap1GAP2 is a new GTPase-activating protein of Rap1 expressed in human platelets. 1563 3

cAMP is a second messenger controlling various cellular processes through cAMP-dependent protein kinase (cAPK, PKA) and cyclic nucleotide-gated ion channels. Recently, the PKA-independent-cAMP-mediated signaling pathway by means of exchange protein directly activated by cAMP (Epac) has been demonstrated. Epac is a guanine nucleotide-exchange factor (GEF) for Rap, a Ras-like small GTPase. To investigate this new target for cAMP in development, we have isolated Xepac, the Xenopus laevis homologue of Epac by cDNA library screening. Xepac (Xepac1) encodes 890 amino acids, which have 57% identity with human Epac1 and 59% with that of rat Epac1 in amino acids. Whole-mount in situ hybridization and reverse transcriptase-polymerase chain reaction analysis show that XEpac is expressed both maternally and zygotically and is restricted within the developing hatching gland. Intriguingly, overexpression of XEpac induces the anterior markers XAG-1 and XOtx2 and can convert ectoderm into cement- and hatching gland-expressing cells. These results suggest that XEpac contains anterior positional information.
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PMID:XEpac, a guanine nucleotide-exchange factor for Rap GTPase, is a novel hatching gland specific marker during the Xenopus embryogenesis. 1575 76

The kinase non-catalytic c-lobe domain (KIND) evolved from the catalytic protein kinase fold into a potential protein interaction module for signalling proteins. Spir family actin organizers and the non-receptor phosphatase type 13 (PTP type 13) encode a KIND domain in the very N-terminal parts of the proteins. Here we report the characterization and cloning of a third member of the KIND protein family, which we have named very-KIND (VKIND) because of its two KIND domains. Like the other members of the protein family, VKIND has a KIND domain at the N-terminus. A second KIND domain is located in the central part of the protein. The C-terminal half encodes a guanine nucleotide exchange factor motif for Ras-like GTPases (RasGEF) and a RasGEF N-terminal module (RasGEFN). There is only one VKIND gene in the mammalian genomes and up to now we have found the gene only in vertebrates. During mouse embryogenesis the VKIND gene was specifically expressed in the developing nervous system. In adult mice Northern hybridizations revealed high expression only in brain. Low expression could be detected in ovary. In situ hybridizations showed a specific expression of VKIND in neuronal cells of the granular and Purkinje cell layers of the cerebellum.
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PMID:Very-KIND is a novel nervous system specific guanine nucleotide exchange factor for Ras GTPases. 1609 29

Leucine-rich repeat kinase 2 (LRRK2), a product of a causative gene for the autosomal-dominant form of familial Parkinson's disease (PARK8), harbors a Ras-like small GTP binding protein-like (ROC) domain besides the kinase domain, although the relationship between these two functional domains remains elusive. Here we show by thin-layer chromatographic analysis that LRRK2 stably binds GTP but lacks a GTPase activity in HEK293 and Neuro-2a cells. A ROC domain mutation that converts LRRK2 to a guanine nucleotide-free form (T1348N) abolishes the kinase activity of LRRK2 as well as its phosphate incorporation upon metabolic labeling. The phosphorylation of LRRK2 was inhibited by potential inhibitors for cyclic AMP-dependent protein kinase. These data suggest that binding of GTP to the ROC domain regulates the kinase activity of LRRK2 as well as its phosphorylation by other kinase(s).
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PMID:GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease. 1726 Sep 67

Cyclic AMP (cAMP)-dependent processes are pivotal during the early stages of adipocyte differentiation. We show that exchange protein directly activated by cAMP (Epac), which functions as a guanine nucleotide exchange factor for the Ras-like GTPases Rap1 and Rap2, was required for cAMP-dependent stimulation of adipocyte differentiation. Epac, working via Rap, acted synergistically with cAMP-dependent protein kinase (protein kinase A [PKA]) to promote adipogenesis. The major role of PKA was to down-regulate Rho and Rho-kinase activity, rather than to enhance CREB phosphorylation. Suppression of Rho-kinase impaired proadipogenic insulin/insulin-like growth factor 1 signaling, which was restored by activation of Epac. This interplay between PKA and Epac-mediated processes not only provides novel insight into the initiation and tuning of adipocyte differentiation, but also demonstrates a new mechanism of cAMP signaling whereby cAMP uses both PKA and Epac to achieve an appropriate cellular response.
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PMID:Cyclic AMP (cAMP)-mediated stimulation of adipocyte differentiation requires the synergistic action of Epac- and cAMP-dependent protein kinase-dependent processes. 1839 Oct 18

The Ras-like GTPases, RalA and RalB, are key components of the oncogenic Ras signaling network. Recent evidence suggests that RalA and RalB collaborate to support tumorigenic transformation through distinct cell regulatory events. While RalA is apparently required to bypass normal restraints on cell proliferation, RalB is required to bypass normal restraints on cell survival. A direct Ral effector protein, Sec5, is a subunit of the exocyst complex, and is required to mediate RalB-dependent survival signals in transformed cells. Further analysis identified TBK1, a key mediator of the host defense response to viral challenge, as a novel Sec5 interacting protein essential for the capacity of RalB and Sec5 to deflect cell death in transformed cells. RalB activation promotes a direct interaction between Sec5 and TBK1 that results in TBK1 kinase activation via an unknown mechanism. Accordingly, both RalB and Sec5 are required for initiating host defense pathway activation upon virus infection. These observations revealed a novel relationship between molecular components of cell-autonomous innate immune signaling pathways and oncogenic transformation, and identified TBK1 as a potential target for therapeutic intervention in cancer. Here we describe details of methods, including protein complex analysis, protein kinase assays, host defense-response pathway activation, and cell transformation analysis, that can be used to investigate the contribution of the RalB-Sec5-TBK1 signaling cascade to both innate immune signaling and cell transformation.
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PMID:Characterization of RalB-Sec5-TBK1 function in human oncogenesis. 1841 58

cAMP is known to participate in the regulation of apoptosis in leukocytes. Depending on the cell type, pro- and antiapoptotic effects of cAMP have been described. Thus far, most of the cAMP-dependent effects have been attributed to the activation of PKA. However, Epac proteins (direct cAMP targets and guanine nucleotide exchange factors for Ras-like GTPases) have been shown recently to contribute to cAMP-dependent regulation of apoptosis. Therefore, we investigated the effects of the selective Epac activators 8-pCPT and Sp on apoptosis in human leukocytic cells (U937, HL-60, primary human mononuclear cells). We report here that Epac activation inhibits leukocyte apoptosis significantly.
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PMID:Epac inhibits apoptosis of human leukocytes. 1956 76

Exchange proteins directly activated by cyclic AMP (Epac) were discovered 10 years ago as new sensors for the second messenger cyclic AMP (cAMP). Epac family, including Epac1 and Epac2, are guanine nucleotide exchange factors for the Ras-like small GTPases Rap1 and Rap2 and function independently of protein kinase A. Given the importance of cAMP in the cardiovascular system, numerous molecular and cellular studies using specific Epac agonists have analyzed the role and the regulation of Epac proteins in cardiovascular physiology and pathophysiology. The specific functions of Epac proteins may depend upon their microcellular environments as well as their expression and localization. This review discusses recent data showing the involvement of Epac in vascular cell migration, endothelial permeability, and inflammation through specific signaling pathways. In addition, we present evidence that Epac regulates the activity of various cellular compartments of the cardiac myocyte and influences calcium handling and excitation-contraction coupling. The potential role of Epac in cardiovascular disorders such as cardiac hypertrophy and remodeling is also discussed.
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PMID:Role of the cAMP-binding protein Epac in cardiovascular physiology and pathophysiology. 1985 95

Chronic degenerative inflammatory diseases, such as chronic obstructive pulmonary disease and Alzheimer's dementia, afflict millions of people around the world, causing death and debilitation. Despite the global impact of these diseases, there have been few innovative breakthroughs into their cause, treatment or cure. As with many debilitating disorders, chronic degenerative inflammatory diseases may be associated with defective or dysfunctional responses to second messengers, such as cyclic adenosinemonophosphate (cAMP). The identification of the cAMP-activated guanine nucleotide exchange factors for Ras-like GTPases, Epac1 (also known as cAMP-GEF-I) and Epac2 (also known as cAMP-GEF-II), profoundly altered the prevailing assumptions concerning cAMP signalling, which until then had been solely associated with protein kinase A (PKA). Studies of the molecular mechanisms of Epac-related signalling have demonstrated that these novel cAMP sensors regulate many physiological processes either alone and/or in concert with PKA. These include calcium handling, cardiac and smooth muscle contraction, learning and memory, cell proliferation and differentiation, apoptosis, and inflammation. The diverse signalling properties of cAMP might be explained by spatio-temporal compartmentalization, as well as A-kinase anchoring proteins, which seem to coordinate Epac signalling networks. Future research should focus on the Epac-regulated dynamics of cAMP, and, hopefully, the development of compounds that specifically interfere with the Epac signalling system in order to determine the precise significance of Epac proteins in chronic degenerative inflammatory disorders.
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PMID:The role of Epac proteins, novel cAMP mediators, in the regulation of immune, lung and neuronal function. 1991 28


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