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

Activation and control of the yeast HOG (High Osmolarity Glycerol) MAP kinase cascade is accomplished, in part, by a two-component sensory-response circuit comprised of the osmosensing histidine protein kinase Sln1p, the phospho-relay protein Ypd1p, and the response regulator protein Ssk1p. We found that deletion of SLN1 and/or YPD1 reduces reporter gene transcription driven by a second two-component response regulator -- Skn7p. The effect of sln1delta and ypd1delta mutations upon Skn7p activity is dependent on a functional two-component phosphorylation site (D427) in Skn7p, suggesting that Sln1p and Ypd1p may act as phosphodonors for Skn7p. We also observed that loss of PTC1 (a protein serine/threonine phosphatase implicated in negative control of the HOG pathway) in a skn7delta background results in severely retarded growth and in morphological defects. Deletion of either PBS2 or HOG1 alleviates the slow growth phenotype of ptc1delta skn7delta cells, suggesting that Skn7p may participate, in concert with known regulatory components, in modulating HOG pathway activity. The contribution of Skn7p to HOG pathway regulation appears to be modulated by the receiver domain, since non-phosphorylatable Skn7pD427N is unable to fully restore growth to ptc1/skn7 cells.
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PMID:Yeast Skn7p activity is modulated by the Sln1p-Ypd1p osmosensor and contributes to regulation of the HOG pathway. 979 May 91

The yeast alpha-1,3-mannosyltransferase (Mnn1p) is localized to the Golgi by independent transmembrane and lumenal domain signals. The lumenal domain is localized to the Golgi complex when expressed as a soluble form (Mnn1-s) by exchange of its transmembrane domain for a cleavable signal sequence (Graham, T. R., and V. A. Krasnov. 1995. Mol. Biol. Cell. 6:809-824). Mutants that failed to retain the lumenal domain in the Golgi complex, called lumenal domain retention (ldr) mutants, were isolated by screening mutagenized yeast colonies for those that secreted Mnn1-s. Two genes were identified by this screen, HOG1, a gene encoding a mitogen-activated protein kinase (MAPK) that functions in the high osmolarity glycerol (HOG) pathway, and LDR1. We have found that basal signaling through the HOG pathway is required to localize Mnn1-s to the Golgi in standard osmotic conditions. Mutations in HOG1 and LDR1 also perturb localization of intact Mnn1p, resulting in its loss from early Golgi compartments and a concomitant increase of Mnn1p in later Golgi compartments.
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PMID:The high osmolarity glycerol response (HOG) MAP kinase pathway controls localization of a yeast golgi glycosyltransferase. 981 52

The HOG mitogen-activated protein kinase pathway mediates the osmotic stress response in Saccharomyces cerevisiae, activating genes like GPD1 (glycerol phosphate dehydrogenase), required for survival under hyperosmotic conditions. Activity of this pathway is regulated by Sln1p, a homolog of the "two-component" histidine kinase family of signal transduction molecules prominent in bacteria. Sln1p also regulates the activity of a Hog1p-independent pathway whose transcriptional output can be monitored using an Mcm1p-dependent lacZ reporter gene. The relationship between the two Sln1p branches is unclear, however, the requirement for unphosphorylated pathway intermediates in Hog1p pathway activation and for phosphorylated intermediates in the activation of the Mcm1p reporter suggests that the two Sln1p branches are reciprocally regulated. To further investigate the signals and molecules involved in modulating Sln1p activity, we have screened for new mutations that elevate the activity of the Mcm1p-dependent lacZ reporter gene. We find that loss of function mutations in FPS1, a gene encoding the major glycerol transporter in yeast activates the reporter in a SLN1-dependent fashion. We propose that elevated intracellular glycerol levels in the fps1 mutant shift Sln1p to the phosphorylated state and trigger the Sln1-dependent activity of the Mcm1 reporter. These observations are consistent with a model in which Sln1p autophosphorylation is triggered by a hypo-osmotic stimulus and indicate that the Sln1p osmosensor is tied generally to osmotic balance, and may not specifically sense an external osmolyte.
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PMID:Intracellular glycerol levels modulate the activity of Sln1p, a Saccharomyces cerevisiae two-component regulator. 986 51

Osmoregulation in Saccharomyces cerevisiae involves a multistep phosphorelay system requiring three proteins, SLN1, YPD1, and SSK1, that are related to bacterial two-component signaling proteins, in particular, those involved in regulating sporulation in Bacillus subtilis and anaerobic respiration in Escherichia coli. The SLN1-YPD1-SSK1 phosphorelay regulates a downstream mitogen-activated protein kinase cascade which ultimately controls the concentration of glycerol within the cell under hyperosmotic stress conditions. The C-terminal response regulator domains of SLN1 and SSK1 and full-length YPD1 have been overexpressed and purified from E. coli. A heterologous system consisting of acetyl phosphate, the bacterial chemotaxis response regulator CheY, and YPD1 has been developed as an efficient means of phosphorylating SLN1 and SSK1 in vitro. The homologous regulatory domains of SLN1 and SSK1 exhibit remarkably different phosphorylated half-lives, a finding that provides insight into the distinct roles that these phosphorylation-dependent regulatory domains play in the yeast osmosensory signal transduction pathway.
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PMID:Differential stabilities of phosphorylated response regulator domains reflect functional roles of the yeast osmoregulatory SLN1 and SSK1 proteins. 988 53

In vitro data support that extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), members of mitogen-activated protein (MAP) kinases, mediate the signal transduction pathways responsible for the cell proliferation. However, in vivo role of these MAP kinases is poorly understood. Intramuscular injection of 50% glycerol solution induces acute renal failure in rats. This injury is known as a model of rhabdomyolysis in human. To investigate the molecular mechanism of the signaling pathway in this injury, we examined the role of ERK and JNK. After the glycerol injection JNK was rapidly and transiently activated at about 4 h, while the activation of ERK was gradually increased and the levels were sustained at least to 24 h. Next, we examined the expression of cell-cycle related proteins after the glycerol injection using Western blot analysis. The levels of proliferating cell nuclear antigen (PCNA) protein as a marker for cell proliferation were induced at 2 h and significantly increased to 24 h after the injection. In addition, cyclins D1, D2, and D3 as markers for G1 phase also increased with similar time courses. To examine whether activation of ERK and/or JNK are involved in the renal regeneration after the glycerol injection, we examined the effect of genistein, which is an inhibitor of tyrosine kinase, on the activation of ERK and JNK. Administration of genistein to rats with this injury decreased the activation of ERK, but not JNK. The induction of PCNA and cyclin D1 was also prevented by this treatment. In this condition, renal function was further worsened as compared to control rats. These results provide the first evidence that ERK may be involved in the repair process of renal tubules damaged by this injury.
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PMID:Extracellular signal-regulated kinase mediates renal regeneration in rats with myoglobinuric acute renal injury. 992 Jul 37

In Schizosaccharomyces pombe, recent studies have uncovered a set of putative transcription factors of the basic leucine zipper (bZIP) type (e.g., Atf1, Pcr1, Pap1), which function downstream of the Sty1 mitogen-activated protein kinase (MAPK) cascade which is involved in stress-activated signal transduction. Accordingly, a delta atf1 mutant is known to exhibit osmosensitivity for growth, since one of the targets of Atf1 is the gpd1+ gene, which is responsible for the osmoadaptive glycerol production mediated by the Sty1 MAPK cascade. During the course of our studies on the osmotic response in S. pombe, we found that growth of a delta atf1 mutant is highly sensitive to the level of Ca2+ ions in the medium (but less sensitive to Mg2+ and Na+ ions). This phenotype seemed to be relevant to the osmosensitivity, because an delta gpd1 mutant showed a similar phenotype. An attempt was therefore made to isolate multicopy suppressors of the calcium sensitivity exhibited by the delta atf1 cells. Among such suppressors were several bZIP factors, including two known proteins (Atf21 and Pcr1), and two new ones (named Atf31 and Zip1). These factors were characterized further, in comparison to Atf1, with special reference to the Sty1 MAPK signaling pathway.
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PMID:Isolation of multicopy suppressors of the calcium sensitivity of a mutant lacking the bZIP transcription factor Atf1 in fission yeast. 1010 65

The function of the extracellular domain (ECD) of Sln1p, a plasma membrane two-transmembrane domain (TMD) sensor of the high-osmolarity glycerol (HOG) response pathway, has been studied in the yeast Saccharomyces cerevisiae. Truncations of SLN1 that retain an intact kinase domain are capable of complementing the lethality of an sln1Delta strain. By observing levels of Hog1p phosphorylation as well as the phosphorylation state of Sln1p, the kinase activities of various SLN1 constructions were determined. In derivatives that do not contain the first TMD, Sln1p activity was no longer dependent on medium osmolarity but appeared to be constitutively active even under conditions of high osmolarity. Removal of the first TMD (DeltaTMD1 construct) gave a protein that was strongly phosphorylated whereas Hog1p was largely dephosphorylated, as expected if the active form of Sln1p is phosphorylated. When both TMDs as well as the ECD were deleted, so that the kinase domain is cytosolic, Sln1p was not phosphorylated whereas Hog1p became constitutively hyperphosphorylated. Surprisingly, this hyperactivity of the HOG mitogen-activated protein kinase signaling pathway was not sufficient to result in cell lethality. When the ECD of the DeltaTMD1 construct was replaced with a leucine zipper motif, Sln1p was hyperactive, so that Hog1p became mostly unphosphorylated. In contrast, when the Sln1p/leucine zipper construct was crippled by a mutation of one of the internal leucines, the Sln1 kinase was inactive. These experiments are consistent with the hypothesis that the ECD of Sln1p functions as a dimerization and activation domain but that osmotic regulation of activity requires the presence of the first TMD.
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PMID:The extracellular domain of the Saccharomyces cerevisiae Sln1p membrane osmolarity sensor is necessary for kinase activity. 1019 19

Budding yeast adjusts to increases in external osmolarity via a specific mitogen-activated protein kinase signal pathway, the high-osmolarity glycerol response (HOG) pathway. Studies with a functional Hog1-green fluorescent protein (GFP) fusion reveal that even under nonstress conditions the mitogen-activated protein kinase Hog1 cycles between cytoplasmic and nuclear compartments. The basal distribution of the protein seems independent of its activator, Pbs2, and independent of its phosphorylation status. Upon osmotic challenge, the Hog1-GFP fusion becomes rapidly concentrated in the nucleus from which it is reexported after return to an iso-osmotic environment or after adaptation to high osmolarity. The preconditions and kinetics of increased nuclear localization correlate with those found for the dual phosphorylation of Hog1-GFP. The duration of Hog1 nuclear residence is modulated by the presence of the general stress activators Msn2 and Msn4. Reexport of Hog1 to the cytoplasm does not require de novo protein synthesis but depends on Hog1 kinase activity. Thus, at least three different mechanisms contribute to the intracellular distribution pattern of Hog1: phosphorylation-dependent nuclear accumulation, retention by nuclear targets, and a kinase-induced export.
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PMID:Kinase activity-dependent nuclear export opposes stress-induced nuclear accumulation and retention of Hog1 mitogen-activated protein kinase in the budding yeast Saccharomyces cerevisiae. 1019 63

The salt-tolerant yeast Zygosaccharomyces rouxii can adjust its osmotic balance when responding to osmotic shock by accumulating glycerol as the compatible osmolyte. However, the mechanism of glycerol production in Z. rouxii cells and its genetic regulation remain to be elucidated. Two putative mitogen-activated protein (MAP) kinase genes, ZrHOG1 and ZrHOG2, were cloned from Z. rouxii by their homology with HOG1 from Saccharomyces cerevisiae. The deduced amino acid sequences of ZrHog1p and ZrHog2p indicated close homology to that of Hog1p and contained a TGY motif for phosphorylation by MAP kinase kinase. When ZrHOG1 or ZrHOG2 was expressed in an S. cerevisiae hog1delta null mutant, the salt tolerance and osmotic tolerance characteristics of wild-type S. cerevisiae were restored. In addition, the aberrant cell morphology and low glycerol content of the hog1delta null mutant were corrected, indicating that ZrHog1p and ZrHog2p have functions similar to Hog1p. While the transcription of the glycerol-3-phosphate dehydrogenase gene (GPD1) of the ZrHOG1-harbouring S. cerevisiae mutant was similar to that of wild-type S. cerevisiae, the ZrHOG2-harbouring strain showed prolonged GPD1 transcription. Both Zrhog1delta and Zrhog2delta Z. rouxii null mutants showed a decrease in salt tolerance compared to the wild-type strain. The present study suggested the presence of a high-osmolarity glycerol response (HOG) pathway in Z. rouxii similar to that elucidated in S. cerevisiae. Two putative MAP kinase genes in Z. rouxii appeared to be significant in either osmotic regulation or ion homeostasis.
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PMID:Two putative MAP kinase genes, ZrHOG1 and ZrHOG2, cloned from the salt-tolerant yeast Zygosaccharomyces rouxii are functionally homologous to the Saccharomyces cerevisiae HOG1 gene. 1020 4

The Saccharomyces cerevisiae Ste11p protein kinase is a homologue of mammalian MAPK/extracellular signal-regulated protein kinase kinase kinases (MAPKKKs or MEKKs) as well as the Schizosaccharomyces pombe Byr2p kinase. Ste11p functions in several signaling pathways, including those for mating pheromone response and osmotic stress response. The Ste11p kinase has an N-terminal domain that interacts with other signaling molecules to regulate Ste11p function and direct its activity in these pathways. One of the Ste11p regulators is Ste50p, and Ste11p and Ste50p associate through their respective N-terminal domains. This interaction relieves a negative activity of the Ste11p N terminus, and removal of this negative function is required for Ste11p function in the high-osmolarity glycerol (HOG) pathway. The Ste50p/Ste11p interaction is also important (but not essential) for Ste11p function in the mating pathway; in this pathway binding of the Ste11p N terminus with both Ste50p and Ste5p is required, with the Ste5p association playing the major role in Ste11p function. In vitro, Ste50p disrupts an association between the catalytic C terminus and the regulatory N terminus of Ste11p. In addition, Ste50p appears to modulate Ste11p autophosphorylation and is itself a substrate of the Ste11p kinase. Therefore, both in vivo and in vitro data support a role for Ste50p in the regulation of Ste11p activity.
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PMID:Functional characterization of the interaction of Ste50p with Ste11p MAPKKK in Saccharomyces cerevisiae. 1039 74


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