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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T-cell antigen receptor (TCR) ligation of an Lck-deficient Jurkat mutant, J.CaM1, with anti-CD3 or anti-TCR beta monoclonal antibodies failed to induce tyrosine phosphorylation and activation of p42MAPK. The same stimuli activated mitogen-activated protein (MAP) kinase in J.CaM1 cells transfected with Lck, demonstrating that Lck plays a critical role in MAP kinase activation. Utilizing immunocomplex kinase assays, we demonstrated that TCR/CD3 ligation activated a MAP kinase kinase kinase (Raf-1) as well as a MAP kinase kinase (MEK-1) in Jurkat but not in J.CaM1 cells. It was possible, however, to activate Raf-1, MEK-1, and p42MAPK in J.CaM1 cells during treatment with the phorbol ester phorbol 12-myristate 13-acetate, which activates protein kinase C (PKC). This demonstrates the presence of a PKC-dependent pathway which functions independently from Lck in MAP kinase activation. Stimulation of Jurkat cells with either anti-TCR beta or anti-CD3 monoclonal antibody failed to induce substantial tyrosine phosphorylation of Shc proteins or their association with Grb2 which forms a complex with the guanine nucleotide exchange factor hSOS. However, the same stimuli induced tyrosine phosphorylation of another putative guanine nucleotide exchange factor, p95Vav, in Jurkat but not J.CaM1 cells. Moreover, Lck was reversibly co-immunoprecipitated with p95Vav, and the stoichiometry of binding increased in anti-CD3-treated Jurkat cells. Phorbol 12-myristate 13-acetate did not induce tyrosine phosphorylation of p95Vav. These data show that the TCR activates MAP kinase by way of a signaling cascade, which depends upon Lck, and may be mediated by downstream events involving PKC or p95Vav which act on Raf-1 and MEK-1.
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PMID:The T-cell antigen receptor utilizes Lck, Raf-1, and MEK-1 for activating mitogen-activated protein kinase. Evidence for the existence of a second protein kinase C-dependent pathway in an Lck-negative Jurkat cell mutant. 751 37

We report the identification of 16 of the 30 cellular proteins which are rapidly phosphorylated in tumour-necrosis-factor-(TNF)-treated or interleukin-1-(IL-1)-treated primary human fibroblasts. Phosphorylation assays of proteins found in the cytosolic extract of human fibroblasts by in vitro assays indicate that at least 12 of these proteins are likely to be substrates for mitogen-activated protein kinase(s) (MAP kinase), mitogen-activated protein-kinase-activated protein kinase 2 (MAPKAP kinase 2), a pp60c-src-like tyrosine kinase as well as for a putative dual nucleotide protein kinase (DNK) in TNF-treated or IL-1-treated cells. Comparison of the phosphorylation of cytosolic proteins in vitro by exogenously added protein kinases with that observed in cells treated with TNF or IL-1 enabled the identification of cellular substrates of TNF-activated and IL-1-activated cellular protein kinases. Comparison of protein kinase activities of cytosolic extracts derived from TNF-treated or IL-1-treated and control fibroblasts also show the activation of MAP kinase, MAPKAP kinase 2, a putative DNK and a pp60src-like tyrosine kinase 3-19 fold. The data suggest TNF or IL-1 signal transduction may involve the phosphorylation of protein phosphatase type 2A by a pp60src-like tyrosine kinase, followed by the activation of MAP kinase, MAPKAP kinase 2 and the putative DNK. However, the activation of MAP kinase and MAPKAP kinase 2 may be independent of the earlier activation of pp60src-like tyrosine kinase and the inactivation of protein phosphatase type 2A.
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PMID:Activation of protein kinases and the inactivation of protein phosphatase 2A in tumour necrosis factor and interleukin-1 signal-transduction pathways. 774 73

The aim of this study was to explore the role of protein kinase C (PKC) in the activation of mitogen-activated protein kinases (MAPK) in T lymphocytes. The MAPK extracellular signal-regulated kinase-2 (ERK2) is activated in response to phorbol esters which stimulate PKC, by transient expression of a constitutively active ras mutant by cell activation via the G protein-coupled type 1 muscarinic acetylcholine receptor (HM1R) or in response to triggering of the T cell antigen receptor (TCR). The relative contribution of PKC to TCR and HM1R regulation of ERK2 was explored by examining the effects of a PKC inhibitor (Ro 31-8425) on ERK2 activation. The data demonstrate that phorbol ester and HM1R regulation of ERK2 was prevented by the PKC inhibitor, but that the inhibitor had no effect on ERK2 activation induced by expression of a constitutively active ras mutant p21v-Ha-ras. Furthermore, the TCR stimulates both PKC and p21ras but TCR regulation of ERK2 was only weakly suppressed by the PKC inhibitor. These data indicate that PKC has a potential but not a predominant role in TCR regulation of ERK2.
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PMID:The role of protein kinase C in the regulation of extracellular signal-regulated kinase by the T cell antigen receptor. 792 76

Vav and Dbl are members of a novel class of oncogene proteins that share significant sequence identity in a approximately 250-amino-acid domain, designated the Dbl homology domain. Although Dbl functions as a guanine nucleotide exchange factor (GEF) and activator of Rho family proteins, recent evidence has demonstrated that Vav functions as a GEF for Ras proteins. Thus, transformation by Vav and Dbl may be a consequence of constitutive activation of Ras and Rho proteins, respectively. To address this possibility, we have compared the transforming activities of Vav and Dbl with that of the Ras GEF, GRF/CDC25. As expected, GRF-transformed cells exhibited the same reduction in actin stress fibers and focal adhesions as Ras-transformed cells. In contrast, Vav- and Dbl-transformed cells showed the same well-developed stress fibers and focal adhesions observed in normal or RhoA(63L)-transformed NIH 3T3 cells. Furthermore, neither Vav- or Dbl-transformed cells exhibited the elevated levels of Ras-GTP (60%) observed with GRF-transformed cells. Finally, GRF, but not Vav or Dbl, induced transcriptional activation from Ras-responsive DNA elements (ets/AP-1, fos promoter, and kappa B). However, like Ras- and GRF-transformed cells, both Vav- and Dbl-transformed cells exhibited constitutively activated mitogen-activated protein kinases (MAPKs) (primarily p42MAPK/ERK2). Since kinase-deficient forms of p42MAPK/ERK2 and p44MAPK/ERK1 inhibited Dbl transformation, MAPK activation may be an important component of its transforming activity. Taken together, our observations indicate that Vav and Dbl transformation is not a consequence of Ras activation and instead may involve the constitutive activation of MAPKs.
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PMID:Dbl and Vav mediate transformation via mitogen-activated protein kinase pathways that are distinct from those activated by oncogenic Ras. 793 2

Arginine vasopressin (AVP) has been shown to stimulate tyrosine phosphorylation and activation of p42 mitogen-activated protein (MAP) kinase (p42MAPK) in vascular smooth muscle cells (VSMC). In VSMC, AVP increases free intracellular Ca2+ concentration ([Ca2+]i) and activates protein kinase C (PKC) through activation of phospholipase C. The contribution of PKC and [Ca2+]i in p42MAPK regulation was therefore determined. Activation of PKC by phorbol 12-myristate 13-acetate (PMA) stimulated tyrosine phosphorylation and activation of p42MAPK to the same extent as AVP. Inhibition of PKC by staurosporine or downregulation of PKC by PMA pretreatment abolished AVP-induced stimulation of p42MAPK. When [Ca2+]i was elevated to the same level as with AVP, using either ionomycin (0.1 microM) or thapsigargin (0.1 microM), MAP kinase was only partially activated. Elevation of [Ca2+]i to supraphysiological levels by 1 microM ionomycin stimulated MAP kinase activity to the same extent as AVP. This effect was blocked by downregulation of PKC. The intracellular Ca2+ chelator BAPTA [1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid] blocked AVP-induced [Ca2+]i increase but did not affect AVP stimulation of p42MAPK. Thus AVP-induced activation of p42MAPK requires only the activation of PKC but not an increase in [Ca2+]i.
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PMID:AVP-induced activation of MAP kinase in vascular smooth muscle cells is mediated through protein kinase C. 823 19

A number of studies have demonstrated that the proliferative capacity of cells declines with aging. In particular, epidermal growth factor (EGF)-stimulated DNA synthesis is reduced in hepatocytes from aged rats relative to young rats. Growth factor stimulation activates a genetic program in large part regulated by a family of mitogen-activated protein kinases (MAPK) that phosphorylate and thereby activate transcription factors involved in controlling the expression of proliferation-associated genes. In the present study, we compared the activation of the extracellular signal-regulated kinase 2 (ERK2) and c-Jun N-terminal kinase 1 (JNK1) MAPK in EGF-stimulated hepatocytes derived from young (6-month) and aged (24-month) rats. JNK activity was not appreciably altered by EGF treatment of cells from either age group. In contrast, ERK2 was highly activated by EGF treatment, but the magnitude of activation was significantly lower in hepatocytes of aged animals compared to those of young animals (7-fold versus 20-fold, respectively). The reduced ERK2 activity in response to EGF was associated with decreased c-fos and c-jun mRNA expression and lower levels of AP-1 transcription factor DNA binding activity in the aged hepatocytes. Finally, the basal expression of MAPK phosphatase 1, a MAPK-regulated gene involved in regulating MAPK activity, was higher in aged hepatocytes. Taken together, these findings suggest that an alteration in the balance between MAP kinase-phosphatase activities could contribute to the age-related decline in proliferative capacity.
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PMID:Age-related decline in mitogen-activated protein kinase activity in epidermal growth factor-stimulated rat hepatocytes. 863 68

The potential mechanisms of angiotensin II (ANG II)-induced mitogenesis were studied in a Chinese hamster ovary fibroblast cell line overexpressing the rat vascular type 1a ANG II receptor (CHO-AT1a). ANG II had potent mitogenic effects in these CHO-AT1a cells, leading to a sustained increase in cell number as well as a dose-dependent increase in DNA synthesis. ANG II treatment also induced a biphasic elevation of mitogen-activated protein (MAP) kinase activity of both p42MAPK and p44MAPK with a rapid early peak at 5 min (2- to 6-fold) followed by a second sustained increase that reached a peak at 3 h (1.5- to 3-fold). We have previously shown that the 12-lipoxygenase (12-LO) pathway of arachidonate metabolism plays a key role in ANG II-induced growth of vascular smooth muscle and adrenal cells. In the present study, ANG II (10(-7) M) increased the formation of the 12-LO product, 12-hydroxyeicosatetraenoic acid (12-HETE). ANG II-induced DNA synthesis was inhibited by a specific LO inhibitor, cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (CDC, 10 microM). In contrast, a cyclooxygenase blocker of arachidonate metabolism such as ibuprofen had no effect on ANG II-induced DNA synthesis. ANG II-induced DNA synthesis was also partially (32%) blocked by pertussis toxin (PTX). CDC and PTX also selectively blocked only the late (3 h) peak of ANG II-induced MAP kinase activity, suggesting that the late sustained peak of MAP kinase activity may be linked to the mitogenic effect of ANG II. Direct addition of 12-HETE (10(-7) M) led to a sustained increase in cell number similar to the effect of ANG II. 12-HETE also caused an increase in MAP kinase activity, and 12-HETE effects were blocked by PTX. These results suggest that ANG II-induced mitogenic response is associated with sustained MAP kinase activation and that LO activation may play a key role in this process.
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PMID:Mechanisms of ANG II-induced mitogenic responses: role of 12-lipoxygenase and biphasic MAP kinase. 889 27

Green tea polyphenols, major constituents of green tea, are potent chemopreventive agents in a number of experimental models of cancer in animals. The mechanisms of cancer protection by these agents are not clear, but may involve modulation of the enzyme systems responsible for the detoxification of chemical carcinogens. The present studies show that a green tea polyphenol extract (GTP) induces chloramphenicol acetyltransferase (CAT) activity in human heptoma HepG2 cells transfected with a plasmid construct which contains an antioxidant-responsive element (ARE) and a minimal glutathione S-transferase Ya promoter linked to the CAT reporter gene. This indicates that GTP stimulates the transcription of Phase II detoxifying enzymes through the ARE. To explore the upstream signaling pathways leading to gene expression, we studied the involvement of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase 2 (ERK2) and c-Jun N-terminal kinase 1 (JNK1). Potent activation of ERK2 was seen following treatment of HepG2 cells with different concentrations of GTP. Similar to ERK2, JNK1 was also strongly activated by treatment with GTP, although to a lesser extent and in a different dose-dependent fashion. Kinetic studies revealed that GTP activation of JNK1 was delayed and sustained, whereas ERK2 activation was rapid and transient. Furthermore, GTP treatment also increased mRNA levels of the immediate-early genes c-jun and c-fos, as determined by reverse transcriptase-coupled polymerase chain reaction. Taken together, these studies provide insights into the action of GTP and suggest that the stimulation MAPKs may be the potential signaling pathways utilized by GTP to activate ARE-dependent genes.
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PMID:Activation of mitogen-activated protein kinases by green tea polyphenols: potential signaling pathways in the regulation of antioxidant-responsive element-mediated phase II enzyme gene expression. 905 42

Interleukin-1beta (IL-1beta) significantly influences renal cellular function through the induction of several gene products. The molecular mechanisms involved in gene regulation by IL-1beta are poorly understood; however, the appearance of novel tyrosine phosphoproteins in IL-1beta-treated cells suggests that IL-1beta may function through tyrosine phosphoprotein intermediates. The mitogen-activated protein (MAP) kinases are tyrosine phosphoproteins that could potentially mediate the effects of IL-1beta. Protein tyrosine phosphorylation following IL-1beta treatment may be dependent on redox changes since the IL-1beta receptor is not a protein-tyrosine kinase and oxidation has been shown to induce tyrosine phosphorylation. In this report we demonstrate that conditioning human glomerular mesangial cells with IL-1beta results in the tyrosine phosphorylation and activation of two members of the MAP kinase family, extracellular signal-regulated protein kinase 2 (ERK2) and p54 Jun-NH2-terminal kinase (JNK). This effect of IL-1beta is abrogated by pretreating cells with the antioxidants N-acetyl-L-cysteine or dithiothreitol. Furthermore, the effects of IL-1beta on ERK and JNK activation are reproduced by treating mesangial cells with membrane-permeable oxidants. IL-1beta and oxidants also cause phosphorylation and activation of the upstream ERK regulatory element MAP kinase kinase. Interestingly, IL-1beta, but not exogenous oxidants, causes phosphorylation of the upstream JNK activator, JNK kinase. These data indicate that IL-1beta activates ERK2 through an oxidation-dependent pathway. Exogenous oxidants and IL-1beta activate JNK through different upstream mechanisms; however, antioxidant inhibition of JNK activation indicates that endogenous oxidants may play a role in IL-1beta-induced JNK activation. Thus IL-1beta may affect mesangial cell function by activating MAP kinases, which can then regulate gene transcription. Furthermore, reactive oxygen species released during inflammatory glomerular injury may also affect mesangial function through a MAP kinase signal.
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PMID:Interleukin-1beta induction of mitogen-activated protein kinases in human mesangial cells. Role of oxidation. 909 44

We demonstrate herein the ability of transforming growth factor-beta-2 (TGFbeta2) to potently activate extracellular signal-regulated kinase 2 (ERK2) in the highly TGFbeta-sensitive breast cancer cell (BCC) line Hs578T. The ERK2 isoform was activated by 3-fold within 5 min of TGFbeta2 addition to Hs578T cells. However, TGFbeta2 only slightly activated ERK2 (1.5-fold) in the partially TGFbeta-responsive BCC line MDA-MB-23 1. The magnitude of the difference in activation of ERK2 by TGFbeta2 in the two cell lines paralleled the difference in the IC50 values for TGFbeta inhibition of DNA synthesis; the IC50 value in the MDA-MB-231 cells was 32-fold greater than that in the Hs578T cells. Further, our data demonstrate that TGFbeta2 activated the stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) type of mitogen-activated protein kinases (MAPKs); maximal induction levels were 2.5-fold above basal values and were attained at 30 min after TGFbeta2 treatment. Transient co-transfection of a luciferase reporter construct (3TP-Lux) containing three AP-1 sites and the plasminogen activator inhibitor-1 (PAI-1) promoter, in conjunction with a construct that directs expression of a dominant-negative mutant ERK2 (TAYF) protein, did not block the ability of TGFbeta to induce AP-1 or PAI-1 activity. In contrast, TAYF ERK2 was able to block EGF and insulin-induced 3TP-Lux-reporter activity. These results indicate that in these BCCs, the activation of ERK2 by TGFbeta is more tightly linked to the ability of TGFbeta to inhibit DNA synthesis than to the ability to stimulate promoter regions important for TGFbeta production and control of the extracellular matrix. In addition, this is the first demonstration that TGFbeta can activate the SAPK/JNK type of MAPK in TGFbeta-sensitive human BCCs.
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PMID:TGFbeta regulation of mitogen-activated protein kinases in human breast cancer cells. 923 30


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