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

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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)

EGF is involved in the regulation of cell proliferation in normal as well as in neoplastic tissues. The A431 cells that over-express EGFR, display in vitro ambivalent growth properties in response to EGF, since stimulation induced by low concentrations (10(-12) M-10(-10) M) is reversed with increasing concentrations (10(-9) M-10(-8) M). To assess differential mechanisms of signal transduction that determine growth stimulatory and inhibitory activity, we have studied the MAP kinase activation induced by mitotic and antimitotic concentrations of EGF. We demonstrate that the presence of a growth stimulatory concentration of EGF (10(-12) M) leads to a moderate but persistent activation of p42 MAP kinase during all the time of the EGF treatment. Conversely, an early peak of kinase activation that rapidly falls down below the basal level, is observed when a growth inhibitory concentration of EGF (10(-8) M) is used. Moreover, the addition of Na-orthovanadate in 10(-8) M EGF-treated cells leads to the rescue of the MAP kinase activity, suggesting that the loss of kinase activity induced by growth inhibitory EGF concentrations involves the dephosphorylation of the MAP kinase. In conclusion, our data demonstrate that the dual effect (stimulator/inhibitor) of EGF on the proliferation of A431 cells is associated to differential mechanisms of p42 MAP kinase regulation.
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PMID:Relationship between the MAP kinase activity and the dual effect of EGF on A431 cell proliferation. 809 84

We have studied in cultured rat astroglial cells MAP kinases, known for their role in intracellular signal transduction. The MAP kinase activity was stimulated by growth factors (FGFb, FGFa, EGF, PDGF, and IGF1), by a phorbol ester (TPA) activating-protein kinase C (PKC), by a neuropeptide (endothelin-1), and by a neuromediator (carbachol). Astrocytes pretreated for 18 h with TPA were still stimulated by growth factors and endothelin, suggesting that down-regulated isoforms of PKC are not involved in MAP kinase activation. In contrast, the small effect of carbachol was suppressed by TPA pretreatment. Astrocytes contained two proteins (p41 and p44) recognized by MAP kinase antibody. These proteins were phosphorylated on tyrosine residues in the cytosols of stimulated astrocytes. The kinetics of MAP kinase activation by FGFb and IGF1 were very different. FGFb promoted a rapid activation of MAP kinase (about 10 min) plus a prolonged phase that lasted at least 12 h. IGF1 produced only a rapid transient peak of activation at about 20 min. Hence, extracellular signals might generate different effects in astrocytes by differentially modulating the MAP kinase cascade. On a Mono Q column the growth factor-stimulated MAP kinase activity was separated into two peaks containing p41 and p44. Stimulation of astrocytes altered the elution pattern of p44 as a result of its phosphorylation. An ATP-dependent MAP kinase activator (MW = 40-45 kDa) was found in fractions of FGFb-stimulated cells which were not retained on Mono Q column, indicating the existence of a MAP kinase kinase (MEK) in astrocytes. C-Raf, identified in other cells as a MAP kinase kinase kinase, was also present in astrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:MAP kinase cascade in astrocytes. 816 69

Mitogen activated protein kinases (MAP) or extracellular signal regulated protein kinases (ERK) are a family of protein serine/threonine kinases that are activated very rapidly in response to many extracellular stimuli. elk-1, an ets related gene codes for two transcriptional factors elk-1, which regulates c-fos transcription and delta elk-1, both of which are substrates for MAP kinases. A part of the C-terminal transcriptional activation domain (ETA-2) which is common to both the proteins was previously shown to function as an activator of MAP kinases. In this report, in an attempt to investigate the mechanism of activation of MAP kinases, purified preparations of recombinant elk-1 and P44mpk/ERK-1/ERK-2 proteins were used to show the association of elk-1 proteins with MAP kinases. The specific interactions of elk-1 proteins with MAP kinases were confirmed by co-immunoprecipitation studies. Thus elk-1 proteins appear to regulate the activity of MAP kinases by interacting with them ensuring a conformational change and stimulating their autophosphorylation and activation property. The activation was dependent on the presence of ATP and Mg2+. In vitro phosphorylation of elk-1 protein was not regulatory for autonomous DNA binding activity of elk-1 protein. Cells which were exposed to EGF showed a rapid stimulation of an elk-1 specific kinase activity, probably MAP kinase which phosphorylated MBP and was found to be associated with immobilized GST-elk-1. Furthermore, dephosphorylation studies indicate that elk-1 proteins can activate only tyrosine phosphorylated MAP kinase. These results demonstrate the presence of an alternative pathway/mechanism (other than MAP kinase kinase, MAPKK/Mek) for the activation of MAP kinases with tyrosine phosphorylation occurring before serine/threonine autophosphorylation and activation by elk-1 proteins.
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PMID:elk-1 proteins interact with MAP kinases. 820 31

Recent findings have suggested that certain ligand-dependent responses to EGF may be propagated in a manner that is not dependent on the intrinsic tyrosine kinase activity of the epidermal growth factor receptor (EGF-R, Campos-Gonzalez, R., and Glenney, J. R., Jr. (1992) J. Biol. Chem. 267, 14535-14538) or, alternatively, that these responses may occur through the interaction of the human tyrosine kinase-deficient EGF-R with an as yet unidentified kinase (Selva, E., Raden, D. L., and Davis, R. J. (1993) J. Biol. Chem. 268, 2250-2254). These conclusions represent a significant departure from our current understanding of signal transduction by receptor tyrosine kinases. Therefore we examined the effect of expression of tyrosine kinase-negative human EGF receptor in murine NIH-3T3-2.2 cells on the EGF-dependent phosphorylation of mitogen-activated protein (MAP-2) kinase. In parental cells (NIH-3T3-2.2) that express low levels of endogenous murine EGF-R, there was no demonstrable EGF-dependent coupling to MAP-2 kinase. In NIH-3T3-2.2 cells transfected with tyrosine kinase-negative human EGF-R, there was unexpected EGF-dependent phosphorylation of MAP-2 kinase. Analysis of the tyrosine kinase-negative human EGF-R in these cells revealed significant tyrosine phosphorylation of the EGF-R. A low level of endogenous murine EGF-R present in these cells were also phosphorylated on tyrosine residues and displayed autokinase activity. Similar results were obtained using an unrelated cell line (B82L cells), in which EGF-dependent phosphorylation of MAP-2 kinase was previously attributed to signal propagation through a tyrosine kinase-negative human EGF-R (Campos-Gonzalez, R., and Glenney, J. R., Jr. (1992) J. Biol. Chem. 267, 14535-14538). Taken together, these results suggest that the tyrosine kinase-negative human EGF-R are able to amplify the response to activation of low levels of endogenous murine EGF-R, thus leading to EGF-dependent phosphorylation of MAP-2 kinase in cells expressing tyrosine kinase-negative human EGF-R.
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PMID:Expression of human tyrosine kinase-negative epidermal growth factor receptor amplifies signaling through endogenous murine epidermal growth factor receptor. 825 71

Treatment of NIH-3T3 cells expressing human TrkA with nerve growth factor (NGF) resulted in a rapid cessation of growth. Cells stopped dividing within 24 h of NGF treatment and failed to divide as long as NGF was present, accumulating in the G1 stage of the cell cycle. NGF caused a prolonged activation of mitogen-activated protein kinase relative to EGF. NGF treatment of cells greatly increased levels of the p21Cip1/WAF1 protein, an inhibitor of cyclin-dependent kinases, without affecting levels of p27KIP1 or p16INK4. Levels of p21Cip1/WAF1 remained elevated for at least 48 h following NGF addition. EGF had little effect on p21Cip1/WAF1 expression in the same parental cells expressing the human EGF receptor. NGF treatment of cells completely inhibited the activity of the cyclin-dependent protein kinases CDK2 and CDK4. Inhibition correlated with a 10-20-fold increase in the amount of p21Cip1/WAF1 complexed with CDK2 and CDK4. Levels of CDK2 and CDK4 were decreased following NGF treatment of cells; however, levels of cyclin E and cyclin D were increased. These data indicate that NGF can induce cell cycle arrest of NIH-3T3, perhaps through modulation of p21Cip1/WAF1 levels. The data also show that distinct signals are generated by TrkA versus the EGF receptor in NIH-3T3 cells.
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PMID:Nerve growth factor-induced growth arrest and induction of p21Cip1/WAF1 in NIH-3T3 cells expressing TrkA. 853 34

The recent discovery of the vaccinia virus protein phosphatase VH1, and its mammalian counterparts has highlighted a novel subfamily of protein tyrosine phosphatases that exhibit dual specificity toward phosphotyrosine- and phosphoserine/threonine-residues. We have identified further members of this subfamily. The characterisation of one clone in particular, which we have named threonine-tyrosine phosphatase 1 (TYP 1), encodes a protein homologous to CL100, but differs dramatically in its regulation. TYP 1 is not expressed in human fibroblasts unlike other CL100-like genes. Furthermore, northern analysis has demonstrated that following mitogenic stimulation of squamous cells, induction of TYP 1 mRNA reaches its maximal levels after four hours, in contrast to the immediate early CL100-like genes. Both TYP 1 and CL100 mRNAs are induced upon TGF-beta treatment of squamous cell lines sensitive to the growth factors antiproliferative effects. When TYP 1 is transfected into COS-1 cells, the gene product inhibits both ERK2 and p54 MAP kinase subfamilies. In addition, we show that purified TYP 1 protein efficiently inactivates recombinant ERK2 in vitro by the concomitant dephosphorylation of both its phosphothreonine and -tyrosine residues. TYP 1 encodes a nuclear protein, which when expressed in COS cells is stabilised by EGF treatment.
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PMID:Isolation and characterisation of a uniquely regulated threonine, tyrosine phosphatase (TYP 1) which inactivates ERK2 and p54jnk. 854 12

Treatment of rat 3Y1 fibroblasts with vasopressin (AVP) results in a transient activation of MAP kinase as potent as with EGF and serum. An antagonist of vasopressin receptor V1, but not an antagonist of V2, inhibited the AVP-induced activation of MAP kinases, indicating that AVP activates MAP kinases through V1 receptor. Prolonged TPA treatment of cells resulted in partial MAP kinase activation, indicating the presence of PKC-independent pathway. The pathway was inhibited by wortmannin, an inhibitor of PI3-kinase. The results suggest that wortmannin-sensitive molecules such as PI3-kinase, are involved in the V1 receptor-mediated activation of the MAP kinase pathway independent of TPA-sensitive PKC.
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PMID:Wortmannin inhibits the activation of MAP kinase following vasopressin V1 receptor stimulation. 854 62

The effects of EGF, TPA, UV radiation, okadaic acid and anisomycin on ERK and JNK/SAPK MAP kinase cascades have been compared with their ability to elicit histone H3/HMG-14 phosphorylation and induce c-fos and c-jun in C3H 10T1/2 cells. EGF and UV radiation activate both ERKs and JNK/SAPKs but to markedly different extents; EGF activates ERKs more strongly than JNK/SAPKs, whereas UV radiation activates JNK/SAPKs much more strongly than ERKs. Anisomycin and okadaic acid activate JNK/SAPKs but not ERKs, and conversely, TPA activates ERKs but not JNK/SAPKs. Nevertheless, all these agents elicit phosphorylation of ribosomal and pre-ribosomal S6, histone H3 and HMG-14, and the induction of c-fos and c-jun, showing that neither cascade is absolutely essential for these responses. We then analysed the relationship between ERKs, JNK/SAPKs and the transcription factors Elk-1 and c-Jun, implicated in controlling c-fos and c-jun, respectively. JNK/SAPKs bind to GST-cJun1-79, and ERKs, particularly ERK-2, to GST-Elk1(307-428); there is no cross-specificity of binding. Further, GST-Elk1(307-428) binds preferentially to active rather than inactive ERK-2. In vitro, JNK/SAPKs phosphorylate both GST-cJun1-79 and GST-Elk1(307-428), whereas ERKs phosphorylate GST-Elk1(307-428) but not GST-cJun1-79. Thus, neither ERKs nor JNK/SAPKs are absolutely essential for nuclear signalling and c-fos and c-jun induction. The data suggest either that activation of a single MAP kinase subtype is sufficient to elicit a complete nuclear response, or that other uncharacterised routes exist.
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PMID:Neither ERK nor JNK/SAPK MAP kinase subtypes are essential for histone H3/HMG-14 phosphorylation or c-fos and c-jun induction. 858 71

Overexpression of the erbB-2 gene contributes to aggressive behavior of various human adenocarcinomas, including breast cancer, through an unknown molecular mechanism. The erbB-2-encoded protein is a member of the ErbB family of growth factor receptors, but no direct ligand of ErbB-2 has been reported. We show that in various cells ErbB-2 can form heterodimers with both EGF receptor (ErbB-1) and NDF receptors (ErbB-3 and ErbB-4), suggesting that it may affect the action of heterologous ligands without the involvement of a direct ErbB-2 ligand. This possibility was addressed in breast cancer cells through either overexpression of ErbB-2 or by blocking its delivery to the cell surface by means of an endoplasmic reticulum-trapped antibody. We report that ErbB-2 overexpression enhanced binding affinities to both EGF and NDF, through deceleration of ligand dissociation rates. Likewise, removal of ErbB-2 from the cell surface almost completely abolished ligand binding by accelerating dissociation of both growth factors. The kinetic effects resulted in enhancement and prolongation of the stimulation of two major cytoplasmic signaling pathways, namely: MAP kinase (ERK) and c-Jun kinase (SAPK), by either ligand. Our results imply that ErbB-2 is a pan-ErbB subunit of the high affinity heterodimeric receptors for NDF and EGF. Therefore, the oncogenic action of ErbB-2 in human cancers may be due to its ability to potentiate in trans growth factor signaling.
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PMID:ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. 861 1

We recently showed that EGF and anisomycin activate two kinases, p45 and p55, whose distinguishing feature is that their detection in in-gel kinase assays is enhanced by copolymerised poly-Glu/Tyr or poly-Glu/Phe (Cano E, Hazzalin CA and Mahadevan LC, Mol. Cell. Biol., 20:117-121). Their activation characteristics and sizes are strikingly similar to those of JNK/SAPKs, which are also strongly activated by anisomycin. However, we show here that p45 and p55 are not JNK/SAPKs but murine forms of MAPKAP kinase-2 because: (i) Detection of immunoprecipitated JNK/SAPKs is completely dependent on the presence of c-Jun as substrate in the in-gel kinase assays, whereas detection of p45 and p55 is not. (ii) Detection of p45 and p55 activity is enhanced by the presence of poly-Glu/Tyr or poly-Glu/Phe, whereas JNK/SAPKs are not detectable under these conditions. (iii) Although the sizes of the murine JNK/SAPKs and MAPKAP K-2 are similar, human JNK/SAPKs migrate at 45 and 55 kDa whereas human MAPKAP K-2 migrates at 50 kDa; the poly-Glu/Tyr-enhanced activity in human cells migrates at 50 KDa. (iv) Purified rabbit muscle MAPKAP K-2 is detectable as two bands of activity on in-gel kinase assays and their detection is enhanced by poly-Glu/Tyr. (v) Finally, the anisomycin-activated poly-Glu/Tyr-enhanced p45 and p55 kinases can be immunoprecipitated from murine cells using an anti-MAPKAP K-2 antibody. Thus, EGF- and anisomycin-activated p45 and p55 are not JNK/SAPKs but MAPKAP K-2, implying that both these agents activate the p38/RK MAP kinase cascade.
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PMID:Identification of anisomycin-activated kinases p45 and p55 in murine cells as MAPKAP kinase-2. 863 2


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