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

---

Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The enzyme glycogen synthase kinase-3 (GSK-3) has been implicated in the control of several metabolic enzymes and transcription factors in response to extracellular signals. In the past, the enzyme has been considered to be a protein Ser/Thr kinase although it was recently reported to contain Tyr(P) (Hughes, K., Nikolakaki, E., Plyte, S. E., Totty, N. F., and Woodgett, J. R. (1993) EMBO J. 12, 803-808). A cDNA encoding rabbit skeletal muscle GSK-3 beta was cloned and expressed in Escherichia coli as an active protein kinase, with apparent M(r) 46,000, capable of phosphorylating several known GSK-3 substrates. Recombinant GSK-3 beta autophosphorylated on Ser, Thr, and Tyr residues although the enzyme already contained Tyr(P) as judged by its recognition by anti-Tyr(P) antibodies. The net result of the autophosphorylation was a 3-5-fold reduction in enzyme activity. GSK-3 alpha, purified from rabbit muscle, also underwent autophosphorylation but only on Ser and Thr residues. In this case, the autophosphorylation stabilized the enzyme activity compared with the control lacking ATP/Mg2+. Of several phosphatases tested, the lambda-phage phosphatase was the most effective in dephosphorylating at Ser and Thr residues but did not dephosphorylate at Tyr residues. The action of the lambda-phosphatase caused a reactivation of GSK-3 beta to approximately 80% of the starting activity. The protein tyrosine phosphatase PTP1B was able to dephosphorylate at Tyr residues leading to a reduction in enzyme activity. A truncated form of GSK-3 beta, apparent M(r) 40,000, had a significantly higher specific activity, was defective in autophosphorylation, and was not inactivated in the autophosphorylation reaction. We conclude that GSK-3 beta is a dual specificity protein kinase in the same sense as the mitogen-activated protein kinase/ERK family of enzymes. Phosphorylation at different residues differentially controls enzyme activity, Ser/Thr phosphorylation causing inactivation and Tyr phosphorylation resulting in increased activity.
...
PMID:Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation. 751 73

Abundant neurofibrillary tangles, neuropil threads and senile plaque neurites constitute the neurofibrillary pathology of Alzheimer's disease. They form in the nerve cells that undergo degeneration in the disease, in which their regional distribution correlates with the degree of dementia. Each lesion contains the paired helical filament (PHF) as its major fibrous component. Recent work has shown that PHFs are composed of the microtubule-associated protein tau in a hyperphosphorylated state. PHF-tau is hyperphosphorylated on six adult brain tau isoforms. As a consequence, tau is unable to bind to microtubules and is believed to self-assemble into the PHF. Current evidence suggests that protein kinases or protein phosphatases with a specificity for serine/threonine-proline residues are instrumental in the hyperphosphorylation of tau. Candidate protein kinases include mitogen-activated protein kinase, glycogen synthase kinase 3 and cyclin-dependent kinase 5, whereas the trimeric form of protein phosphatase 2A is a candidate phosphatase.
...
PMID:Molecular dissection of the neurofibrillary lesions of Alzheimer's disease. 776 34

Pyramidal neurons in affected regions of Alzheimer's disease (AD) brain contain neurofibrillary tangles (NFT), aggregates of paired helical filaments (PHF) composed mainly of phosphorylated microtubule-associated protein tau. To explore the role of tau phosphorylation in the aggregation of tau into PHF, we constructed mammalian cell culture systems producing high levels of intracellular phosphorylated tau. COS-1 fibroblast-like cells were transiently transfected to simultaneously express tau, MAP kinase (MAPK), and MAP kinase kinase (MAPKK), or alternatively to express tau and glycogen synthase kinase 3 (GSK3). B103 neuron-like cells (which contain MAPK but little tau or GSK3) were stably transfected to express tau or tau and GSK3. In both systems, GSK3-transfected cells contained tau AT8/M (defined by AT8 staining and tau PHF-like mobility), but MAPK-transfected cells required phosphatase inhibitors, such as okadaic acid (OKA) or calyculin (CAL), to produce tau AT8/M. In vitro, the same concentrations of CAL and OKA inhibit phosphatases 1 and 2A (PP1 and PP2A), except that 100-1000 times as much OKA is needed to inhibit PP1. Inducing tau phosphorylation at the AT8 site in MAPK-transfected cells required 2-10 times more OKA than CAL, suggesting both PP1 and PP2A helped block the phosphorylation. Though levels of tau AT8/M reached 2-8% of total cellular proteins in COS-1 cells, the ratio of particulate to supernatant tau levels did not increase, and no tangles were observed; perhaps post-translational modifications or co-aggregating proteins are needed to induce PHF.
...
PMID:Overexpressed tau protein in cultured cells is phosphorylated without formation of PHF: implication of phosphoprotein phosphatase involvement. 875 Aug 56

Using immunohistochemistry, we examined the localization of four types of proline-directed kinases in the brains of control rats and in the brains of non-demented aged human subjects, subjects with Alzheimer's disease and those with Down's syndrome. The four kinases were: cyclin-dependent kinase (cdk) 5, a component of tau protein kinase (TPK) II; TPK I/glycogen synthase kinase (GSK)-3 beta; GSK-3 alpha; and mitogen-activated protein kinase (MAPK/ERK2). Each of these kinases has been reported to promote the hyperphosphorylation of tau protein in vitro. The kinases were located essentially in neurons, although the intensity and distribution of labeling varied. Antiserum for cdk5 showed the most preferential and consistent labeling of intraneuronal neurofibrillary tangles (NFT). Antiserum for TPK I/GSK-3 beta also labeled intraneuronal NFT. Double immunolabeling for TPK I/GSK-3 beta and tau 1 showed that TPK I/GSK-3 beta was closely associated with NFT. Antiserum for GSK-3 alpha labeled neurons weakly, and the intensity of labeling did not differ between neurons with and without NFT. Antiserum for MAPK labeled neurons in superficial cortical layers, but NFT appeared in both superficial and deep cortical layers. These findings suggest that cdk5 and TPK I/GSK-3 beta are the critically important kinases for the generation in vivo of hyperphosphorylated tau, the main component of the paired helical filaments in NFT.
...
PMID:Preferential labeling of Alzheimer neurofibrillary tangles with antisera for tau protein kinase (TPK) I/glycogen synthase kinase-3 beta and cyclin-dependent kinase 5, a component of TPK II. 887 Aug 24

Mammalian heat shock genes are regulated at the transcriptional level by heat shock factor-1 (HSF-1), a sequence-specific transcription factor. We have examined the role of serine phosphorylation of HSF-1 in the regulation of heat shock gene transcription. Our experiments show that mitogen-activated protein kinases (MAPKs) of the ERK-1 family phosphorylate HSF-1 on serine residues and repress the transcriptional activation of the heat shock protein 70B (HSP70B) promoter by HSF-1 in vivo. These effects of MAPK are transmitted through a specific serine residue (Ser-303) located in a proline-rich sequence within the transcriptional regulatory domain of human HSF-1. However, despite the importance of Ser-303 in transmitting the signal from the MAPK cascade to HSP70 transcription, there was no evidence that Ser-303 could be phosphorylated by MAPK in vitro, although an adjacent residue (Ser-307) was avidly phosphorylated by MAPK. Further studies revealed that Ser-303 is phosphorylated by glycogen synthase kinase 3 (GSK3) through a mechanism dependent on primary phosphorylation of Ser-307 by MAPK. Secondary phosphorylation of Ser-303 by GSK3 may thus repress the activity of HSF-1, and its requirement for priming by MAPK phosphorylation of Ser-307 provides a potential link between the MAPK cascade and HSF-1. Our experiments thus indicate that MAPK is a potent inhibitor of HSF-1 function and may be involved in repressing the heat shock response during normal growth and development and deactivating the heat shock response during recovery from stress.
...
PMID:Sequential phosphorylation by mitogen-activated protein kinase and glycogen synthase kinase 3 represses transcriptional activation by heat shock factor-1. 894 68

Several peptides derived from microtubule-associated tau protein, have been tested as substrates for glycogen synthase kinase 3 (GSK 3). In the absence of cofactors, GSK 3 can modify serines or threonines followed by prolines. In other cases, a phosphorylation in position +4 is required for the phosphorylation of threonine/serine residues. A third type of substrate can be modified by GSK 3 in the presence of heparin. The comparison of GSK 3 with other kinases suggests some similar features of this kinase with proline-directed protein kinases, such as cdc-2 or mitogen-activated protein kinase (MAP Kinases,) and also with casein kinase 2 (CK 2). Thus, all these kinases are specifically inhibited by 5,6-Dichloro-1-(beta-D-ribofuranosyl)-benzimidazole (DRB). However, heparin is an inhibitor of CK 2 whereas it activates the modification of certain substrates by GSK 3. A possible explanation for the obtained results is that the consensus sequence for GSK 3 phosphorylation is a serine/threonine adjacent to a proline or other beta-turn former residue and that such recognition could be favoured by the presence of adjacent negative charges or the addition of polyanions.
...
PMID:Glycogen synthase kinase 3 phosphorylation of different residues in the presence of different factors: analysis on tau protein. 897 80

Various biological responses stimulated by insulin have been thought to be regulated by phosphatidylinositol 3-kinase, including glucose transport, glycogen synthesis, and protein synthesis. However, the molecular link between phosphatidylinositol 3-kinase and these biological responses has been poorly understood. Recently, it has been shown that protein kinase B (PKB/c-Akt/Rac) lies immediately downstream from phosphatidylinositol 3-kinase. Here, we show that expression of a constitutively active form of PKB induced glucose uptake, glycogen synthesis, and protein synthesis in L6 myotubes downstream of phosphatidylinositol 3-kinase and independent of Ras and mitogen-activated protein kinase activation. Introduction of constitutively active PKB induced glucose uptake and protein synthesis but not glycogen synthesis in 3T3L-1 adipocytes, which lack expression of glycogen synthase kinase 3 different from L6 myotubes. Furthermore, we show that deactivation of glycogen synthase kinase 3 and activation of rapamycin-sensitive serine/threonine kinase by PKB in L6 myotubes might be involved in the enhancement of glycogen synthesis and protein synthesis, respectively. These results suggest that PKB acts as a key enzyme linking phosphatidylinositol 3-kinase activation to multiple biological functions of insulin through regulation of downstream kinases in skeletal muscle, a major target tissue of insulin.
...
PMID:Potential role of protein kinase B in insulin-induced glucose transport, glycogen synthesis, and protein synthesis. 947 90

The ability of signaling via the JNK (c-Jun NH2-terminal kinase)/stress-activated protein kinase cascade to stimulate or inhibit DNA synthesis in primary cultures of adult rat hepatocytes was examined. Treatment of hepatocytes with media containing hyperosmotic glucose (75 mM final), tumor necrosis factor alpha (TNFalpha, 1 ng/ml final), and hepatocyte growth factor (HGF, 1 ng/ml final) caused activation of JNK1. Glucose, TNFalpha, or HGF treatments increased phosphorylation of c-Jun at serine 63 in the transactivation domain and stimulated hepatocyte DNA synthesis. Infection of hepatocytes with poly-L-lysine-coated adenoviruses coupled to constructs to express either dominant negatives Ras N17, Rac1 (N17), Cdc42 (N17), SEK1-, or JNK1- blunted the abilities of glucose, TNFalpha, or HGF to increase JNK1 activity, to increase phosphorylation of c-Jun at serine 63, and to stimulate DNA synthesis. Furthermore, infection of hepatocytes by a recombinant adenovirus expressing a dominant-negative c-Jun mutant (TAM67) also blunted the abilities of glucose, TNFalpha, and HGF to stimulate DNA synthesis. These data demonstrate that multiple agonists stimulate DNA synthesis in primary cultures of hepatocytes via a Ras/Rac1/Cdc42/SEK/JNK/c-Jun pathway. Glucose and HGF treatments reduced glycogen synthase kinase 3 (GSK3) activity and increased c-Jun DNA binding. Co-infection of hepatocytes with recombinant adenoviruses to express dominant- negative forms of PI3 kinase (p110alpha/p110gamma) increased basal GSK3 activity, blocked the abilities of glucose and HGF treatments to inhibit GSK3 activity, and reduced basal c-Jun DNA binding. However, expression of dominant-negative PI3 kinase (p110alpha/p110gamma) neither significantly blunted the abilities of glucose and HGF treatments to increase c-Jun DNA binding, nor inhibited the ability of these agonists to stimulate DNA synthesis. These data suggest that signaling by the JNK/stress-activated protein kinase cascade, rather than by the PI3 kinase cascade, plays the pivotal role in the ability of agonists to stimulate DNA synthesis in primary cultures of rat hepatocytes.
...
PMID:The Ras/Rac1/Cdc42/SEK/JNK/c-Jun cascade is a key pathway by which agonists stimulate DNA synthesis in primary cultures of rat hepatocytes. 948 26

Oncoprotein 18 or stathmin was isolated from bovine brain, characterized and novel features of its function as a microtubule depolymerizing factor were tested. The effect of phosphorylation of stathmin on its function as a microtubule depolymerizing factor has been tested in vitro. Five different protein kinases, protein kinase A, MAP kinase, cdc2 kinase, glycogen synthase kinase 3 and casein kinase 2, were used to modify stathmin, since it is known that these kinases could phosphorylate several residues that are modified in vivo and could have important roles in stathmin function. The residues phosphorylated in vitro by the different protein kinases were identified and in some cases they correspond to those modified in vivo. Recombinant unphosphorylated stathmin and native stathmin, which was previously dephosphorylated with alkaline phosphatase, showed similar microtubule depolymerizing activity. This activity is higher than that of stathmin phosphorylated by protein kinase A, MAP kinase or cdc 2 kinase, whereas phosphorylation of the protein with casein kinase 2 or glycogen synthase kinase 3 resulted in a slight increase of the depolymerizing activity.
...
PMID:Phosphorylation of stathmin modulates its function as a microtubule depolymerizing factor. 965 97

Heat shock factor 1 (HSF1) is the key transcriptional regulator of the heat shock genes that protect cells from environmental stress. However, because heat shock gene expression is deleterious to growth and development, we have examined mechanisms for HSF1 repression at growth temperatures, focusing on the role of phosphorylation. Mitogen-activated protein kinases (MAPKs) of the ERK family phosphorylate HSF1 and represses transcriptional function. The mechanism of repression involves initial phosphorylation by MAP kinase on serine 307, which primes HSF1 for secondary phosphorylation by glycogen synthase kinase 3 on a key residue in repression (serine 303). In vivo expression of glycogen synthase kinase 3 alpha or beta thus represses HSF1 through phosphorylation of serine 303. HSF1 is also phosphorylated by MAPK in vitro on a second residue (serine 363) adjacent to activation domain 1, and this residue is additionally phosphorylated by protein kinase C. In vivo, HSF1 is repressed through phosphorylation of this residue by protein kinase Calpha or -zeta but not MAPK. Regulation at 37 degrees C, therefore, involves the action of three protein kinase cascades that repress HSF1 through phosphorylation of serine residues 303, 307, and 363 and may promote growth by suppressing the heat shock response.
...
PMID:Transcriptional activity of heat shock factor 1 at 37 degrees C is repressed through phosphorylation on two distinct serine residues by glycogen synthase kinase 3 and protein kinases Calpha and Czeta. 966 Aug 38


1 2 3 4 5 6 7 8 9 10 Next >>

---