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 small G protein RhoA is a convergence point for multiple signals that regulate smooth muscle cell functions. NO plays a major role in the structure and function of the normal adult vessel wall, mainly through modulation of gene transcription. This study was thus performed to analyze in vitro and in vivo the effect of NO signaling on RhoA expression in arterial smooth muscle cells. In rat or human artery smooth muscle cells, sodium nitroprusside or 8-(2-chlorophenylthio)-cGMP induced a rise in RhoA mRNA and protein expression, which was inhibited by the cGMP-dependent protein kinase (PKG) inhibitor (R(p))-8-bromo-beta-phenyl-1,N(2)-ethenoguanosine 3':5'-phosphorothioate. The NO/PKG stimulation of RhoA expression involved both an increase in RhoA protein stability and stimulation of rhoA gene transcription. Cloning and functional analysis of the human rhoA promoter revealed that the effect of NO/PKG involved phosphorylation of ATF-1 and subsequent binding to the cAMP-response element. Chronic inhibition of NO synthesis in N(omega)-nitro-l-arginine-treated rats induced a strong decrease in RhoA mRNA and protein expression in aorta and pulmonary artery associated with inhibition of RhoA-mediated Ca(2+) sensitization. These effects were prevented by oral administration of the cGMP phosphodiesterase inhibitor sildenafil. These results show that NO/PKG signaling positively controls RhoA expression and suggest that the basal release of NO is necessary to maintain RhoA expression and RhoA-dependent functions in vascular smooth muscle cells.
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PMID:RhoA expression is controlled by nitric oxide through cGMP-dependent protein kinase activation. 1252 25

Signaling via the p42/p44 mitogen activated protein kinase (MAPK) pathway has been implicated as an intermediate event coupling light to entrainment of the mammalian circadian clock located in the suprachiasmatic nucleus (SCN). To examine how photic input dynamically regulates the activation state of the MAPK pathway, we monitored extracellular signal-regulated kinase (ERK) activation using different light stimulus paradigms. Compared with control animals not exposed to light, a 15 min light exposure during the early night triggered a marked increase in ERK activation and the translocation of ERK from the cytosol to the nucleus. ERK activation peaked 15 min after light onset, then returned to near basal levels within approximately 45 min. The MAPK pathway could be reactivated multiple times by light pulses spaced 45 min apart, indicating that the MAPK cascade rapidly resets and resolves individual light pulses into discrete signaling events. Under conditions of constant light (120 min), the time course for ERK activation, nuclear translocation, and inactivation was similar to the time course observed after a 15-min light treatment. The parallels between the ERK inactivation profiles elicited by a 15 and a 120 min light exposure suggest that SCN cells contain a MAPK pathway signal-termination mechanism that limits the duration of pathway activation. This concept was supported by the observation that the small G protein Ras, a regulator of the MAPK pathway, remained in the active, GTP-bound, state under conditions of constant light (120-min duration), indicating that photic information was relayed to the SCN and that SCN cells maintained their responsiveness for the duration of the light treatment. The SCN expressed both nuclear MAPK phosphatases (MKP-1 and MKP-2) and the cytosolic MAPK phosphatase Mkp-3, thus providing mechanisms by which light-induced ERK activation is terminated. Collectively, these observations provide important new information regarding the regulation of the MAPK cascade, a signaling intermediate that couples light to resetting of the SCN clock.
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PMID:Temporal regulation of light-induced extracellular signal-regulated kinase activation in the suprachiasmatic nucleus. 1293 Aug 17

In examining the protein kinase components of mitogen-activated protein (MAP) kinase (MAPK) cascades that regulate the c-Jun N-terminal kinase (JNK) in Drosophila S2 cells, we previously found that distinct upstream kinases were involved in responses to sorbitol and lipopolysaccharide. Here we have extended that analysis to the possible MAPK kinase kinase kinases (MAP4Ks) in the JNK pathway. Fray, a putative Drosophila MAP4K, provided a major contribution to JNK activation by sorbitol. To explore the possible link to JNK in mammalian cells, we isolated and characterized OSR1 (oxidative stress-responsive 1), one of two human Fray homologs. OSR1 is a 58-kDa protein of 527 amino acids that is widely expressed in mammalian tissues and cell lines. Of potential regulators surveyed, endogenous OSR1 is activated only by osmotic stresses, notably sorbitol and to a lesser extent NaCl. However, OSR1 did not increase the activity of coexpressed JNK, nor did it activate three other MAPKs, p38, ERK2, and ERK5. A two-hybrid screen implicated another Ste20p family member, the p21-activated protein kinase PAK1, as an OSR1 target. OSR1 phosphorylated threonine 84 in the N-terminal regulatory domain of PAK1. Replacement of threonine 84 with glutamate reduced the activation of PAK1 by an active form of the small G protein Cdc42, suggesting that phosphorylation by OSR1 modulates the G protein sensitivity of PAK isoforms.
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PMID:Characterization of OSR1, a member of the mammalian Ste20p/germinal center kinase subfamily. 1470 32

Recent studies suggest that the tyrosine kinase Src plays an important role in the hormonal regulation of extracellular signal-regulated kinases (ERKs) via cyclic AMP (cAMP). Src has also been proposed to mediate signals downstream of nerve growth factor (NGF). Here, we report that the cAMP-dependent protein kinase A (PKA) induced the phosphorylation of Src at residue serine17 (S17) in multiple cell types including PC12, Hek293, AtT-20 and CHO cells. In PC12 cells, Src phosphorylation on S17 participates in the activation of the small G protein Rap1 by both cAMP and NGF. In these cells, Rap1 is required for cAMP/PKA signaling to ERKs and also for the sustained activation of ERKs by NGF. The activation of Rap1 by both cAMP and NGF was blocked by PP2, an inhibitor of Src family kinases, and by a Src mutant incapable of being phosphorylated by PKA (SrcS17A), consistent with the requirement of PKA phosphorylation of Src at S17 in these actions. PP2 and SrcS17A also inhibited the Rap1-dependent activation of ERKs by both agents. These results strongly indicate that PKA phosphorylation of Src at S17 is essential for cAMP and NGF signaling in PC12 cells and identify PKA as an important downstream target of NGF. PKA phosphorylation of Src may therefore be required for Rap1 activation in PC12 cells.
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PMID:PKA phosphorylation of Src mediates Rap1 activation in NGF and cAMP signaling in PC12 cells. 1554 18

In Drosophila embryos, the Torso receptor tyrosine kinase (RTK) activates the small G protein Ras (D-Ras1) and the protein kinase Raf (D-Raf) to activate ERK to direct differentiation of terminal structures . However, genetic studies have demonstrated that Torso, and by extension other RTKs, can activate Raf and ERK independently of Ras . In mammalian cells, the small G protein Rap1 has been proposed to couple RTKs to ERKs. However, the ability of Rap1 to activate ERKs remains controversial, in part because direct genetic evidence supporting this hypothesis is lacking. Here, we present biochemical and genetic evidence that D-Rap1, the Drosophila homolog of Rap1, can activate D-Raf and ERK. We show that D-Rap1 binds D-Raf and activates ERKs in a GTP- and D-Raf-dependent manner. Targeted disruption of D-Rap1 expression decreased both Torso-dependent ERK activation and the ERK-dependent expression of the zygotic genes tailless and huckebein to levels similar to those achieved in D-Ras1 null embryos. Furthermore, combined deficiencies of D-Ras1 and D-Rap1 completely abolished expression of these genes, mimicking the phenotype observed in embryos lacking D-Raf. These studies provide the first direct genetic evidence of Rap1-mediated activation of the MAP kinase cascade in eukaryotic organisms.
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PMID:Ras-independent activation of ERK signaling via the torso receptor tyrosine kinase is mediated by Rap1. 1572 99

cAMP and cyclic GMP-dependent kinases (PKA and PKG) phosphorylate the small G protein RhoA on Ser188. We have previously demonstrated that phosphorylation of Ser188 inhibits RhoA-dependent functions and positively regulates RhoA expression, and that the nitric oxide (NO)/cGMP-dependent protein kinase pathway plays an essential role, both in vitro and in vivo, in the regulation of RhoA protein expression and functions in vascular smooth muscle cells. Here we analyze the consequences of Ser188 phosphorylation on RhoA protein degradation. By expressing Ser188 phosphomimetic wild-type (WT-RhoA-S188E) and active RhoA proteins (Q63L-RhoA-S188E), we show that phosphorylation of Ser188 of RhoA protects RhoA, particularly its active form, from ubiquitin-mediated proteasomal degradation. Coimmunoprecipitation experiments indicate that the resistance of the phosphorylated active form of RhoA to proteasome-mediated degradation is because of its cytoplasmic sequestration through enhanced RhoGDI interaction. In rat aortic smooth muscle cells, stimulation of PKG and inhibition of proteasome by lactacystin, induce nonadditive increases in RhoA protein expression. In addition, stimulation of PKG leads to the accumulation of GTP-bound RhoA in the cytoplasm. In vivo stimulation of the NO/PKG signaling by treating rats with sildenafil increased RhoA level and RhoA phosphorylation, and enhanced its association to RhoGDI in the pulmonary artery, whereas opposite effects are induced by chronic inhibition of NO synthesis in N-omega-nitro-L-arginine-treated rats. Our results thus suggest that Ser188 phosphorylation-mediated protection against degradation is a physiological process regulating the level of endogenous RhoA and define a novel function for RhoGDI, as an inhibitor of Rho protein degradation.
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PMID:Phosphorylation of serine 188 protects RhoA from ubiquitin/proteasome-mediated degradation in vascular smooth muscle cells. 1589 Sep 75

Small G proteins serve as critical control points in signal transduction, integrating a wide range of stimuli to dictate discrete cellular outcomes. The outcomes of small G-protein signaling can both potentiate and antagonize one another. Studies in hematopoietic cells have uncovered multiple functions for the small G protein, Rap1 (Ras-proximate-1). Because Rap1 can regulate cell proliferation, differentiation, and adhesion through distinct mechanisms, it serves as a paradigm for the need for tight cellular control of small G-protein function. Rap1 has received recent attention for its role in enhancing integrin-dependent signals. This action of Rap1 augments a variety of processes that characterize hematopoietic-cell function, including aggregation, migration, extravasation, and homing to target tissues. Rap1 may also regulate cellular differentiation and proliferation via pathways that are distinct from those mediating adhesion, and involve regulation of the mitogen-activated protein (MAP) kinase or ERK (extracellular signal-regulated kinase) cascade. These actions of Rap1 occur in selected cell types to enhance or diminish ERK signaling, depending on the expression pattern of the MAP kinase kinase kinases of the Raf family: Raf-1 and B-Raf. This review will examine the functions of Rap1 in hematopoietic cells, and focus on 3 cellular scenarios where the multiple actions of Rap1 function have been proposed. Recent studies implicating Rap1 in the maturation of megakaryocytes, the pathogenesis of chronic myelogenous leukemia (CML), and activation of peripheral T cells will receive particular attention.
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PMID:Multiple roles of Rap1 in hematopoietic cells: complementary versus antagonistic functions. 1607 73

Endothelin A (ET(A)) transmembrane receptors predominate in rat cardiac myocytes. These are G protein-coupled receptors whose actions are mediated by the G(q) heterotrimeric G proteins. Through these, ET-1 binding to ET(A)-receptors stimulates the hydrolysis of membrane phosphatidylinositol 4,5-bisphosphate to diacylglycerol and inositol 1,4,5-trisphosphate. Diacylglycerol remains in the membrane whereas inositol 1,4,5-trisphosphate is soluble (though its importance in the cardiac myocyte is still debated). Isoforms of the phospholipid-dependent protein kinase, protein kinase C (PKC), are intracellular receptors for diacylglycerol. Cytoplasmic nPKCdelta and nPKCepsilon detect increases in membrane diacylglycerols and translocate to the membrane. This brings about PKC activation, though modifications additional to binding to phospholipids and diacylglycerol are involved. The next event (probably associated with PKC activation) is the activation of the membrane-bound small G protein Ras by exchange of GTP for GDP. Ras.GTP loading translocates Raf family mitogen-activated protein kinase (MAPK) kinase kinases to the membrane, initiates the activation of Raf, and thus activates the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade. Over longer times, two analogous protein kinase cascades, the c-Jun N-terminal kinase and p38-mitogen-activated protein kinase cascades, become activated. As the signals originating from the ET(A) receptor are transmitted through these protein kinase pathways, other signalling molecules become phosphorylated, thus changing their biological activities. For example, ET-1 increases the expression of the c-jun transcription factor gene, and increases abundance and phosphorylation of c-Jun protein. These changes in c-Jun expression and phosphorylation are likely to be important in the regulation of gene transcription.
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PMID:Endothelin signalling in the cardiac myocyte and its pathophysiological relevance. 1624 77

Beta1Pix (PAK-interacting exchange factor) is a recently identified guanine nucleotide exchange factor (GEF) for the Rho family small G protein Cdc42/Rac. On stimulation with extracellular signals, GEFs induce the exchange of guanosine diphosphate to guanosine triphosphate, resulting in the activation of the small guanosine 5C-triphosphatases. This activation enables the signal to propagate to downstream effectors. Herein, we show that G(salpha) stimulation by cholera toxin increased Cdc42 activation by endothelin-1 (ET-1), whereas pertussis toxin had no effect. H-89, a protein kinase A (PKA) inhibitor, strongly inhibited Cdc42 activation by ET-1. Moreover, the overexpression of beta1Pix enhanced ET-1-induced Cdc42 activation. The essential role of beta1Pix in ET-1-induced Cdc42 activation was evidenced by the blocking of Cdc42 activation in cells expressing beta1Pix mutant lacking the ability to bind PAK (beta1Pix SH3m[W43K]) or mutant lacking GEF activity (beta1PixdeltaDH). The overexpression of mutant lacking the pleckstrin homology domain beta1PixdeltaPH, which is unable to bind phospholipids, had no effect on Cdc42 activation. These results demonstrate that beta1Pix, along with PKA, plays a crucial role in the regulation of Cdc42 activation by ET-1.
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PMID:Endothelin 1 stimulates beta1Pix-dependent activation of Cdc42 through the G(salpha) pathway. 1674 Sep 95

Cyclic adenosine 3',5'-monophosphate (cAMP) signaling regulates the expression of fertilizing ability in mammalian spermatozoa. Many articles indicate that this signaling is mediated mainly via protein kinase A. Recently, a guanine nucleotide exchange factor for small G protein Rap1 (an exchange protein directly activated by cAMP: Epac) was discovered as a new mediator of cAMP signaling in somatic cells. The aim of this study was to reveal the existence of cAMP-Epac signaling in mouse spermatozoa. Northern blot analysis and in situ hybridization suggested that Epac1 and Epac2 mRNAs were transcribed in the seminiferous epithelia of the testis. This shows that expression of Epac mRNAs is present in mouse testicular germ cells. Indirect immunofluorescence with specific polyclonal antibodies suggested possible co-localization of Epac1 and Rap1 proteins in the heads of epididymal spermatozoa. Moreover, treatment of epididymal spermatozoa with an Epac-specific cAMP analog, 8-pMeOPT-2'-O-Me-cAMP, induced activation of Rap1, as revealed with a commercial kit for pull-down assay. These results indicate the existence of cAMP-Epac signaling in the heads of mouse epididymal spermatozoa.
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PMID:Evidence for existence of cAMP-Epac signaling in the heads of mouse epididymal spermatozoa. 1707 80


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