Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bone loss is one of the major problems in long term spaceflight. This physiological consequence of microgravity is the rapid loss of weightbearing bone that is associated with skeletal unloading. Moreover, we have previously noted that sera deprived osteoblasts do not have a normal response to sera in microgravity. Where exercise (mechanical loading) has been shown to increase bone formation and stimulate osteoblastic function, the mechanisms underlying signal transduction of mechano-perception is yet to be fully understood. Osteoblasts have been shown to respond to mechanical stress such as fluid shear, bending, flexing and compression. The type of stress and amount of stress determine the osteoblast response Recently we have discovered that the isolated osteoblast responds to a very short pulse of g-force compression. The possible regulatory sensors include mechano-sensitive calcium channels, autrocrine responses to stress, response to FAK/integrin, alterations in the cytoskeleton as well as other known growth factor and cytokine receptors. The secondary signal may include growth factor related kinases such as ERK, p38 and JNK map kinase (MAPK) pathways. Experimental evidence suggests that normal osteoblast response to stress and sera requires normal earth gravity.
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PMID:The role of signaling pathways in osteoblast gravity perception. 1500 70

Transforming growth factor-beta1 (TGF-beta1) is a potent inducer of apoptosis in normal hepatocytes, and acquiring resistance to TGF-beta1 may be a critical step in the development of hepatocellular carcinoma (HCC). In this study, we investigated the possible involvement of c-Src in the regulation of TGF-beta1-induced apoptosis. TGF-beta1 induced transient activation of c-Src and its subsequent caspase-mediated degradation concomitant with cell death in FaO hepatoma cells, which are sensitive to TGF-beta1. In response to TGF-beta1, activated c-Src was translocated into the cytoplasmic membrane, then relocated to the nuclei of apoptotic cells during its cleavage. In TGF-beta1-induced apoptotic cells, c-Src maintained its tight association with p85 FAK fragment cleaved by caspases, possibly contributing to focal adhesion disassembly. TGF-beta1-induced apoptosis was enhanced by either inhibition of c-Src activity using PP1 or PP2, or by overexpression of dominant-negative c-Src. In contrast, overexpression of constitutively active c-Src inhibited apoptosis suppressing TGF-beta1-induced activation of p38, JNK and caspases. In many HCC cell lines resistant to TGF-beta1, enhanced c-Src activity was detected. We hypothesize that activated c-Src in HCC may contribute to resistance against the apoptotic and/ or antiproliferative properties of TGF-beta1.
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PMID:Involvement of c-Src kinase in the regulation of TGF-beta1-induced apoptosis. 1520 64

In March 2003, a novel coronavirus was isolated from patients exhibiting atypical pneumonia, and was subsequently proven to be the causative agent of the disease now referred to as SARS (severe acute respiratory syndrome). The complete genome of the SARS-CoV (SARS coronavirus) has since been sequenced. The SARS-CoV nucleocapsid (SARS-CoV N) protein shares little homology with other members of the coronavirus family. In the present paper, we show that SARS-CoV N is capable of inducing apoptosis of COS-1 monkey kidney cells in the absence of growth factors by down-regulating ERK (extracellular-signal-regulated kinase), up-regulating JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase) pathways, and affecting their downstream effectors. SARS-CoV N expression also down-regulated phospho-Akt and Bcl-2 levels, and activated caspases 3 and 7. However, apoptosis was independent of the p53 and Fas signalling pathways. Furthermore, activation of the p38 MAPK pathway was found to induce actin reorganization in cells devoid of growth factors. At the cytoskeletal level, SARS-CoV N down-regulated FAK (focal adhesion kinase) activity and also down-regulated fibronectin expression. This is the first report showing the ability of the N protein of SARS-CoV to induce apoptosis and actin reorganization in mammalian cells under stressed conditions.
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PMID:The SARS coronavirus nucleocapsid protein induces actin reorganization and apoptosis in COS-1 cells in the absence of growth factors. 1529 14

Recent studies have demonstrated that mitogen-activated protein kinases (MAPKs), including Jun N-terminus kinase (JNK), p38 and Erk, play crucial roles in cell migration. JNK, for example, regulates cell migration by phosphorylating paxillin, DCX, Jun and microtubule-associated proteins. Studies of p38 show that this MAPK modulates migration by phosphorylating MAPK-activated protein kinase 2/3 (MAPKAP 2/3), which appears to be important for directionality of migration. Erk governs cell movement by phosphorylating myosin light chain kinase (MLCK), calpain or FAK. Thus, the different kinases in the MAPK family all seem able to regulate cell migration but by distinct mechanisms.
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PMID:MAP kinases and cell migration. 1537 22

Activation of the hepatocyte growth factor (HGF) receptor in epithelial cells results in lamellipodia protrusion, spreading, migration, and tubule formation. We have previously reported that these morphogenic effects are dependent on MAPK activation at focal adhesions. In the present study we demonstrate that activated ERK phosphorylates paxillin on serine 83 and that mutation of this site eliminates HGF-stimulated increased association of paxillin and FAK in subconfluent cells. Failure to activate FAK at focal adhesions results in a loss of FAK-PI 3-kinase association and the marked reduction of Rac activation after HGF stimulation. Expression of paxillin mutants that disrupt ERK association or phosphorylation inhibits HGF-induced cell spreading, migration, and tubulogenesis. These data demonstrate that the paxillin-MAPK complex serves as a central regulator of HGF-stimulated FAK and Rac activation in the vicinity of focal adhesions, thus promoting the rapid focal adhesion turnover and lamellipodia extension that are required for migratory and tubulogenic responses.
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PMID:Paxillin serves as an ERK-regulated scaffold for coordinating FAK and Rac activation in epithelial morphogenesis. 1549 12

Enhanced blood pressure variability contributes to left ventricular hypertrophy and end-organ damage, even in the absence of hypertension. We hypothesized that the greater number of high-blood pressure episodes associated with enhanced blood pressure variability causes cardiac hypertrophy and dysfunction by activation of mechanosensitive and autocrine pathways. Normotensive mice were subjected to sinoaortic baroreceptor denervation (SAD) or sham surgery. Twelve weeks later, blood pressure variability was doubled in SAD compared with sham-operated mice. Blood pressure did not differ. Cardiac hypertrophy was reflected in greater heart/body weight ratios, larger myocyte cross-sectional areas, and greater left ventricular collagen deposition. Furthermore, left ventricular atrial and brain natriuretic peptide mRNA expression was greater in SAD than in sham-operated mice. SAD had higher left ventricular end-diastolic pressures and lower myocardial contractility indexes, indicating cardiac dysfunction. Cardiac protein content of phosphorylated p125 focal adhesion kinase (p125 FAK) and phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) was greater in SAD than in sham-operated mice, indicating activation of mechanosensitive pathways of cardiac hypertrophy. Furthermore, enhanced cardiac renin and transforming growth factor-beta1 (TGFbeta1) protein content indicates activation of autocrine pathways of cardiac hypertrophy. Adrenal tyrosine hydroxylase protein content and the number of renin-positive glomeruli were not different, suggesting that sympathetic activation and the systemic renin-angiotensin system did not contribute to cardiac hypertrophy. In conclusion, more frequent blood pressure rises in subjects with high blood pressure variability activate mechanosensitive and autocrine pathways leading to cardiac hypertrophy and dysfunction even in the absence of hypertension.
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PMID:Mechanisms of blood pressure variability-induced cardiac hypertrophy and dysfunction in mice with impaired baroreflex. 1556 77

The JNK interacting protein, JSAP1, has been identified as a scaffold protein for mitogen-activated protein kinase (MAPK) signaling pathways and as a linker protein for the cargo transport along the axons. To investigate the physiological function of JSAP1 in vivo, we generated mice lacking JSAP1. The JSAP1 null mutation produced various developmental deficits in the brain, including an axon guidance defect of the corpus callosum, in which phospho-FAK and phospho-JNK were distributed at reduced levels. The axon guidance defect of the corpus callosum in the jsap1-/- brain was correlated with the misplacement of glial sling cells, which reverted to their normal position after the transgenic expression of JNK interacting protein 1(JIP1). The transgenic JIP1 partially rescued the axon guidance defect of the corpus callosum and the anterior commissure of the jsap1-/- brain. The JSAP1 null mutation impaired the normal distribution of the Ca+2 regulating protein, calretinin, but not the synaptic vesicle marker, SNAP-25, along the axons of the thalamocortical tract. These results suggest that JSAP1 is required for the axon guidance of the telencephalic commissures and the distribution of cellular protein(s) along axons in vivo, and that the signaling network organized commonly by JIP1 and JSAP1 regulates the axon guidance in the developing brain.
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PMID:The axon guidance defect of the telencephalic commissures of the JSAP1-deficient brain was partially rescued by the transgenic expression of JIP1. 1557 49

Apical ectoplasmic specialization (ES) is a unique testis-specific cell-cell actin-based adherens junction type restricted to the Sertoli-round/elongating/elongate spermatid interface in the seminiferous epithelium. An endogenous testosterone (T) suppression model was used to study the regulation of apical ES dynamics in the testis. By providing sustained releases of T and estradiol using subdermal implants in rats, this treatment reduced endogenous testicular T level. This in turn led to sloughing of spermatids (step 8 and beyond) from the seminiferous epithelium, which can be reversed by removing the implants, or replacing them with a higher dose of T implants. This model thus allows us to study the restructuring events at the apical ES. It was shown that apical ES restructuring involved proteins that were usually restricted to the cell-matrix focal adhesion site in other epithelia. For instance, the protein levels of beta1-integrin, Tyr-phosphorylated focal adhesion kinase (p-FAK), and c-Src were induced during the T suppression-induced germ cell loss and recovery, implicating that these proteins are putative regulators of ES dynamics. Indeed, the formation of p-FAK/c-Src protein complex, but not their association with beta1-integrin, was stimulated during T suppression-induced germ cell loss. ERK, a MAPK known to regulate focal adhesion turnover, was also activated during the androgen suppression-induced spermatid loss and the early phase of the recovery when germ cells began to repopulate the epithelium. Collectively, these data suggest that the apical ES is a cell-cell adherens junction type with the characteristics of cell-matrix focal contacts. In addition to its role in conferring cell adhesion formation, the p-FAK/c-Src protein complex apparently also regulates apical ES disruption via the ERK signaling pathway.
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PMID:Regulation of ectoplasmic specialization dynamics in the seminiferous epithelium by focal adhesion-associated proteins in testosterone-suppressed rat testes. 1559 Nov 41

Hyperglycemia increases expression of platelet-derived growth factor (PDGF)-beta receptor and potentiates chemotaxis to PDGF-BB in human aortic vascular smooth muscle cells (VSMCs) via PI3K and ERK/MAPK signaling pathways. The purpose of this study was to determine whether increased activation of protein kinase C (PKC) isoforms had a modulatory effect on the PI3K and ERK/MAPK pathways, control of cell adhesiveness, and movement. All known PKC isoforms were assessed but only PKCalpha and PKCbetaII levels were increased in 25 mmol/L glucose. However, only PKCbetaII inhibition affected (decreased) PI3K pathway and MAPK pathway activities and inhibited PDGF-beta receptor upregulation in raised glucose, and specific MAPK inhibition was required to completely block the effect of glucose. In raised glucose conditions, activity of the ERK/MAPK pathway, PI3K pathway, and PKCbetaII were all sensitive to aldose reductase inhibition. Chemotaxis to PDGF-BB (360 pmol/L), absent in 5 mmol/L glucose, was present in raised glucose and could be blocked by PKCbetaII inhibition. Formation of lamellipodia was dependent on PI3K activation and filopodia on MAPK activation; both lamellipodia and filopodia were eliminated when PKCbetaII was inhibited. FAK phosphorylation and cell adhesion were reduced by PI3K inhibition, and although MAPK inhibition prevented chemotaxis, it did not affect FAK phosphorylation or cell adhesiveness. In conclusion, chemotaxis to PDGF-BB in 25 mmol/L glucose is PKCbetaII-dependent and requires activation of both the PI3K and MAPK pathways. Changes in cell adhesion and migration speed are mediated mainly through the PI3K pathway.
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PMID:Modification of PI3K- and MAPK-dependent chemotaxis in aortic vascular smooth muscle cells by protein kinase CbetaII. 1559 Dec 31

The effects of oxidative stress on collagen and DNA biosynthesis, beta-galactosidase and prolidase activities, and the expression of prolidase, beta1-integrin receptor, FAK, IGF-IR and MAP-kinases (ERK1, ERK2) were evaluated in human dermal fibroblasts. Subconfluent cells were subjected to repetitive stresses with 30 microM t-BHP for 1 hour per day over the course of 5 days. It was found that oxidative stress induced the inhibition of collagen biosynthesis in these cells in a time-dependent manner. Exposure of the cells to 5 stresses contributed to a decrease in collagen and DNA biosynthesis to about 30% and 50% of the control values, respectively. Prolidase activity and expression were only suppressed in fibroblasts subjected to 1 and 3 stresses. In these cells prolidase activity was decreased by about 20%. As a result of 5 stresses, no further inhibition of prolidase activity occurred; however, expression of the enzyme was slightly increased, as demonstrated by Western blot analysis. It was found that these phenomena were neither related to the expression of beta1-integrin receptor nor to that of FAK. However, the exposure of the cells to 3 and 5 stresses contributed to a distinct decrease in IGF-IR and MAP-kinases (ERK1, ERK2) expression, which is probably responsible for the collagen biosynthesis inhibition.
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PMID:Oxidative stress induces IGF-I receptor signaling disturbances in cultured human dermal fibroblasts. A possible mechanism for collagen biosynthesis inhibition. 1564 87


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