Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human Intestine 407 cells respond to hypo-osmotic stress with a rapid stimulation of compensatory ionic conductances accompanied by a transient increase in the activity of the extracellular-signal-regulated protein kinases Erk-1 and Erk-2. In this study, we examined the upstream regulators of hypotonicity-induced Erk-1/Erk-2 activation and their possible role in cell-volume regulation. The hypotonicity-provoked Erk-1/Erk-2 activation was greatly reduced in cells pretreated with the specific mitogen-activated/Erk-activating kinase inhibitor PD098059 and was preceded by a transient stimulation of Raf-1. Pretreatment of the cells with PMA, GF109203X, wortmannin or Clostridium botulinum C3 exoenzyme did not appreciably affect the hypotonicity-provoked Erk-1/Erk-2 stimulation, suggesting the osmosensitive signalling pathway to be largely independent of protein kinase C and p21(rho). In contrast, expression of dominant negative RasN17 completely abolished the hypotonicity-induced Erk-1/Erk-2 activation. Stimulation of the swelling-induced ion efflux was independent of activation of these mitogen-activated protein kinases, as revealed by hypotonicity-provoked isotope efflux from 125I-- and 86Rb+-loaded cells after pretreatment with PD098059 and after expression of RasN17. In addition, the epidermal-growth-factor-induced potentiation of the hypotonicity-provoked anionic response did not depend on the increase in Erk-1/Erk-2 activity but, instead, was found to depend on Ca2+ influx. Taken together, these results indicate that hypotonic stress induces Erk-1/Erk-2 activation through the Ras/Raf-signalling pathway, and argue against a direct role for this pathway in cell-volume control.
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PMID:Osmotic swelling-induced activation of the extracellular-signal-regulated protein kinases Erk-1 and Erk-2 in intestine 407 cells involves the Ras/Raf-signalling pathway. 956 Mar 15

Neurofibromin, the protein encoded by the NF1 tumor-suppressor gene, negatively regulates the output of p21(ras) (Ras) proteins by accelerating the hydrolysis of active Ras-guanosine triphosphate to inactive Ras-guanosine diphosphate. Children with neurofibromatosis type 1 (NF1) are predisposed to juvenile chronic myelogenous leukemia (JCML) and other malignant myeloid disorders, and heterozygous Nf1 knockout mice spontaneously develop a myeloid disorder that resembles JCML. Both human and murine leukemias show loss of the normal allele. JCML cells and Nf1-/- hematopoietic cells isolated from fetal livers selectively form abnormally high numbers of colonies derived from granulocyte-macrophage progenitors in cultures supplemented with low concentrations of granulocyte-macrophage colony stimulating factor (GM-CSF). Taken together, these data suggest that neurofibromin is required to downregulate Ras activation in myeloid cells exposed to GM-CSF. We have investigated the growth and proliferation of purified populations of hematopoietic progenitor cells isolated from Nf1 knockout mice in response to the cytokines interleukin (IL)-3 and stem cell factor (SCF), as well as to GM-CSF. We found abnormal proliferation of both immature and lineage-restricted progenitor populations, and we observed increased synergy between SCF and either IL-3 or GM-CSF in Nf1-/- progenitors. Nf1-/- fetal livers also showed an absolute increase in the numbers of immature progenitors. We further demonstrate constitutive activation of the Ras-Raf-MAP (mitogen-activated protein) kinase signaling pathway in primary c-kit+ Nf1-/- progenitors and hyperactivation of MAP kinase after growth factor stimulation. The results of these experiments in primary hematopoietic cells implicate Nf1 as playing a central role in regulating the proliferation and survival of primitive and lineage-restricted myeloid progenitors in response to multiple cytokines by modulating Ras output.
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PMID:Nf1 regulates hematopoietic progenitor cell growth and ras signaling in response to multiple cytokines. 960 29

Recent evidence indicates the presence of p21 Ras and of a protein with characteristics similar to mitogen-activated protein kinases (MAPKs), also known as extracellular signal-regulated kinases (ERKs), in mammalian spermatozoa, suggesting the occurrence of the Ras/ERK cascade in these cells. In the present study we investigated the subcellular localization of ERKs and their biological functions in human spermatozoa. Immunohistochemistry, immunofluorescence, confocal microscopy, and immunoelectron microscopy demonstrated localization of ERKs in the postacrosomal region of spermatozoa. After stimulation of acrosome reaction with the calcium ionophore A23187 and progesterone, ERKs were mostly localized at the level of the equatorial region, indicating redistribution of these proteins in acrosome-reacted spermatozoa. Two proteins of 42 and 44 kDa that are tyrosine phosphorylated in a time-dependent manner during in vitro capacitation were identified as p42 (ERK-2) and p44 (ERK-1) by means of specific antibodies. The increase in tyrosine phosphorylation of these proteins during capacitation was accompanied by increased kinase activity, as determined by the ability of ERK-1 and ERK-2 to phosphorylate the substrate myelin basic protein. The role of this activity in the occurrence of sperm capacitation was also investigated by using PD098059, an inhibitor of the MAPK cascade. The presence of this compound during in vitro capacitation inhibits ERK activation and significantly reduces the ability of spermatozoa to undergo the acrosome reaction in response to progesterone. Since only capacitated spermatozoa are able to respond to progesterone, these data strongly indicate that ERKs are involved in the regulation of capacitation. In summary, our data demonstrate the presence of functional ERKs in human spermatozoa and indicate that these enzymes are involved in activation of these cells during capacitation, providing new insight in clarifying the molecular mechanisms and the signal transduction pathways of this process.
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PMID:Extracellular signal-regulated kinases modulate capacitation of human spermatozoa. 962 9

Normal breast tissue as well as most breast tumors are dependent on estrogen for growth. Breast tumors often progress to a hormone-independent state which is associated with poor prognosis. It has been proposed that activation of growth factor signaling pathways in the tumor cells may free them from hormonal control. Certain growth factors can mimic estrogen responses by activating the estrogen receptor via its phosphorylation by mitogen-activated protein (MAP) kinase. In this report, however, we show that fibroblast growth factor (FGF), despite activating MAP kinase, is growth-inhibitory for estrogen-dependent MCF-7 breast cancer cells. MCF-7 cells treated with FGFs exhibit slower growth than controls in both the presence and absence of estrogen, with a concomitant increase in the number of cells in G0/G1. Expression of a constitutively activated FGF receptor in these cells further decreases their growth rate, which is no longer influenced by FGF treatment. Activation of the FGF signaling pathway also reduces the induction of an estrogen-responsive CAT reporter plasmid by estrogen, an effect which appears to be independent of serine 118 in the estrogen receptor, a MAP kinase target site. The inhibitory effects of FGF are probably mediated through the sustained induction of the cyclin kinase inhibitor p21/WAF1/CIP1, which is upregulated at the mRNA and protein level by FGF. FGF treatment also results in the phosphorylation of STAT1. This upregulation of p21 and phosphorylation of STAT1 is not detectable in T47D breast cancer cells upon which FGF has no inhibitory effect.
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PMID:FGF signaling activates STAT1 and p21 and inhibits the estrogen response and proliferation of MCF-7 cells. 963 41

Angiotensin II (Ang II) has been previously shown to stimulate the extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinase family members. Little is known regarding the upstream signaling molecules involved in Ang II-mediated JNK activation. Ang II has been shown to activate the Janus kinase/signal transducer(s) and activator(s) of transcription (JAK/STAT) pathway, suggesting similarities to cytokine signaling. In response to cytokines such as interleukin-1 and tumor necrosis factor-alpha, the p21-activated kinase (PAK) has been identified as an upstream component in JNK activation. Therefore, we hypothesized that PAK may be involved in JNK activation by Ang II in vascular smooth muscle cells (VSMCs). AlphaPAK activity was measured by myelin basic protein phosphorylation in rat aortic VSMCs. In response to Ang II, alphaPAK was rapidly stimulated within 1 minute, with a peak (5-fold increase) at 30 minutes. AlphaPAK stimulation preceded activation of JNK in VSMCs. Ang II-mediated activation of both alphaPAK and JNK was Ca2+ dependent and inhibited by downregulation of phorbol ester-sensitive protein kinase C isoforms (by pretreatment with phorbol 12,13-dibutyrate) but not by pretreatment with GF109203X. Activation of both PAK and JNK was partially inhibited by tyrosine kinase inhibitors but not by specific Src inhibitors, suggesting regulation by a tyrosine kinase other than c-Src. Finally, introduction of dominant negative PAK markedly reduced the JNK activation by Ang II in both Chinese hamster ovary and COS cells stably expressing the Ang II type 1 receptor (AT1R). Our data provide evidence for alphaPAK as an upstream mediator of JNK in Ang II signaling and extend the role of Ang II as a proinflammatory mediator for VSMCs.
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PMID:Angiotensin II stimulates p21-activated kinase in vascular smooth muscle cells: role in activation of JNK. 964 33

Hepatocyte growth factor (HGF) is a potent mitogen for a variety of cell types, but it is also known as an antimitogenic factor for several types of tumor cell lines. The biological processes by which HGF inhibits tumor cell growth remain poorly understood. Here we report a comparative study of HGF-mediated signal transduction events between two opposite responding types of human hepatoblastoma cell lines, HuH6 and HepG2. Following serum starvation, both cell lines were cultured in hepatocyte growth medium (HGM), a chemically defined medium, in the presence or absence of HGF. Under these culture conditions, cell growth in HuH6 was promoted by HGF, while it was inhibited in HepG2. Phosphorylation of p42/mitogen-activated protein (MAP) kinase was observed within 10 min after HGF stimulation in both cell lines. The level of phosphorylated MAP kinase in HuH6 declined to basal levels after 2 hr. However, in HepG2 the phosphorylated form was detectable at 6 hr. p21/waf1 was induced in both cell lines where levels peaked 4-6 hr after HGF stimulation. In HuH6, a marked decrease of p21/waf1 was observed at 8-12 hr, while a high level of p21/waf1 was sustained for at least 24 hr in HepG2. HGF treatment depressed cdk2 activity in a time-dependent manner in HepG2 while the activity increased in HuH6. When serum-starved HepG2 was growth stimulated with serum in the presence or absence of HGF, the cells treated with HGF underwent growth inhibition correlating with a sustained induction of p21/waf1 and a decrease of cdk2 activity. Immunoprecipitation analysis revealed accumulation of cdk2-associated p21/waf1 in the HGF-treated HepG2. Together, the results suggest that sustained induction of p21/waf1 mediates growth inhibition in HepG2 in the presence of HGF.
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PMID:Possible involvement of p21/waf1 in the growth inhibition of HepG2 cells induced by hepatocyte growth factor. 973 53

Cdc42, Rac1 and other Rho-type GTPases regulate gene expression, cell proliferation and cytoskeletal architecture [1,2]. A challenge is to identify the effectors of Cdc42 and Rac1 that mediate these biological responses. Protein kinases of the p21-activated kinase (PAK) family bind activated Rac1 and Cdc42, and switch on mitogen-activated protein (MAP) kinase pathways; however, their roles in regulating actin cytoskeleton organization have not been clearly established [3-5]. Here, we show that mutants of the budding yeast Saccharomyces cerevisiae lacking the PAK homologs Ste20 and Cla4 exhibit actin cytoskeletal defects, in vivo and in vitro, that resemble those of cdc42-1 mutants. Moreover, STE20 overexpression suppresses cdc42-1 growth defects and cytoskeletal defects in vivo, and Ste20 kinase corrects the actin-assembly defects of permeabilized cdc42-1 cells in vitro. Thus, PAKs are effectors of Cdc42 in pathways that regulate the organization of the cortical actin cytoskeleton.
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PMID:Actin cytoskeleton organization regulated by the PAK family of protein kinases. 974 99

The exact mechanism of the spatial organization of the insulin signaling pathway leading to nuclear events remains unknown. Here, we investigated the involvement of the actin cytoskeleton in propagation of insulin signaling events leading to DNA synthesis and expression of the immediate early genes c-fos and c-jun in L6 muscle cells. Insulin reorganized the cellular actin network and increased the rate of DNA synthesis and the levels of c-fos mRNA, but not those of c-jun mRNA, in undifferentiated L6 myoblasts. Similarly, insulin markedly elevated the levels of c-fos mRNA but not of c-jun mRNA in differentiated L6 myotubes. Disassembly of the actin filaments by cytochalasin D, latrunculin B, or botulinum C2 toxin significantly inhibited insulin-mediated DNA synthesis in myoblasts and abolished stimulation of c-fos expression by the hormone in myoblasts and myotubes. Actin disassembly abolished insulin-induced phosphorylation and activation of extracellulor signal-regulated kinases, activation of a 65-kda member of the p21-activated kinases, and phosphorylation of p38 mitogen-activated protein kinases but did not prevent activation of phosphatidylinositol 3-kinase and p70(S6k). Under these conditions, insulin-induced Ras activation was also abolished, and Grb2 association with the Src and collogen homologous (Shc) molecule was inhibited without inhibition of the tyrosine phosphorylation of Shc. We conclude that the actin filament network plays an essential role in insulin regulation of Shc-dependent signaling events governing gene expression by facilitating the interaction of Shc with Grb2.
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PMID:Actin filaments facilitate insulin activation of the src and collagen homologous/mitogen-activated protein kinase pathway leading to DNA synthesis and c-fos expression. 977 56

During the last 10 years, multiple signal transduction pathways within cells have been discovered. These pathways have been linked to the regulation of many diverse cellular events such as proliferation, senescence, differentiation and apoptosis. This review will focus upon the many roles of signaling by the p42/p44 mitogen-activated protein (MAP) kinase pathway. Recent evidence suggests that signaling by the MAP kinase pathway can both enhance proliferation by increased expression of molecules such as cyclin D1, but also cause growth arrest by increased expression of molecules such as the cyclin kinase inhibitor protein p21(Cip-1/MDA6/WAF1). These differential effects on growth have been correlated to the amplitude and duration of the MAP kinase activity signal. Furthermore several laboratories are reporting data suggesting that inhibition of the MAP kinase pathway, as well as a family of upstream MAP kinase activators, the protein kinase C family, represent an important route to both radio- and chemo-sensitization of tumor cells. Herein, we describe the historical discovery and characterization of the MAP kinase pathway. In addition we describe potential mechanisms by which inhibition of protein kinase C, the MAP kinase pathway, and potentially of p21(Cip-1/MDA6/WAF1) expression, may alter the sensitivities of leukemic and carcinoma cells to cytotoxic insults, leading to increased apoptosis and loss of clonogenicity.
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PMID:The roles of signaling by the p42/p44 mitogen-activated protein (MAP) kinase pathway; a potential route to radio- and chemo-sensitization of tumor cells resulting in the induction of apoptosis and loss of clonogenicity. 984 14

Hormones and growth factors regulate cell growth via the mitogen-activated protein (MAP) kinase cascade. Here we examine the actions of the hormone somatostatin on the MAP kinase cascade through one of its two major receptor subtypes, the somatostatin receptor 1 (SSTR1) stably expressed in CHO-K1 cells. Somatostatin antagonizes the proliferative effects of fibroblast growth factor in CHO-SSTR1 cells via the SSTR1 receptor. However, in these cells, somatostatin robustly activates MAP kinase (also called extracellular signal regulated kinase; ERK) and augments fibroblast growth factor-stimulated ERK activity. We show that the activation of ERK via SSTR1 is pertussis toxin sensitive and requires the small G protein Ras, phosphatidylinositol 3-kinase, the serine/threonine kinase Raf-1, and the protein tyrosine phosphatase SHP-2. The activation of ERK by SSTR1 increased the expression of the cyclin-dependent protein kinase inhibitor p21(cip1/WAF1). Previous studies have suggested that somatostatin-stimulated protein tyrosine phosphatase activity mediates the growth effects of somatostatin. Our data suggest that SHP-2 stimulation by SSTR1 may mediate some of these effects through the activation of the MAP kinase cascade and the expression of p21(cip1/WAF1).
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PMID:Somatostatin activation of mitogen-activated protein kinase via somatostatin receptor 1 (SSTR1). 989 10


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