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)

T cell signaling via the CD4 surface antigen is mediated by the associated tyrosyl protein kinase p56lck. The 42-kilodalton mitogen-activated protein (MAP) kinase (p42mapk) was tyrosyl-phosphorylated and activated after treatment of the murine T lymphoma cell line 171CD4+, which expresses CD4, with antibody to CD3. Treatment of the CD4-deficient cell line 171 with the same antibody did not result in phosphorylation or activation of p42mapk. Purified p56lck both tyrosyl-phosphorylated and stimulated the seryl-threonyl phosphotransferase activity of purified p44mpk, a MAP kinase isoform from sea star oocytes. A synthetic peptide modeled after the putative regulatory phosphorylation site in murine p42mapk (Tyr185) was phosphorylated by p56lck with a similar Vmax, but a fivefold lower Michaelis constant (Km) than a peptide containing the Tyr394 autophosphorylation site from p56lck. MAP kinases may participate in protein kinase cascades that link Src family protein-tyrosyl kinases to seryl-threonyl kinases such as those encoded by rsk and raf, which are putative substrates of MAP kinases.
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PMID:Tyrosyl phosphorylation and activation of MAP kinases by p56lck. 131 Nov 28

CD30 is a transmembrane receptor of the nerve growth factor/tumor necrosis factor receptor superfamily. Its expression associated with Hodgkin's lymphoma and a subset of non-Hodgkin's lymphoma. Recently, its ligand (CD30L) has been cloned. CD30L enhances the proliferation of peripheral T cells and the Hodgkin's cell line HDLM-2 but seems to exert antiproliferative effects on large cell anaplastic lymphoma cell lines. Since tyrosine kinases are critical regulators of cell growth, we investigated whether CD30L induced changes in cellular tyrosine phosphorylation in CD30-positive lymphoma cell lines. Stimulation with CD30L or with an agonistic mAb against CD30, M44, induced a rapid, transient, and concentration-dependent tyrosine phosphorylation of a cytosolic protein of M(r) 42,000 (p42) in the Hodgkin's lymphomas cell line HDLM-2 but not in other CD30-positive lymphomas. In HDLM-2 cells, the phrobol ester phorbol 12-myristate 13-acetate also stimulated tyrosine phosphorylation of p42, and this effect was enhanced by M44. In marked contrast, agents stimulating the protein kinase A pathway, like forskolin or dibutyryl cAMP, did not affect tyrosine phosphorylation of P42. By immunoprecipitation with mAbs against mitogen-activated protein kinase (MAPK; p42ERKII), a M(r) 42,000 protein was identified which comigrated with p42 on SDS gels and which was phosphorylated on tyrosine residues in response to stimulation of CD30. Immune complex kinase assays showed that M44 mAb induced the activation of MAPK (p42ERKII) and the phosphorylation of a MAPK substrate, myelin basic protein. Taken together, the results suggest that CD30L induces the tyrosine phosphorylation and activation of the MAPK p42ERKII isoform in HDLM-2 cells. These findings may have implications for the understanding of the pathogenesis of Hodgkin's disease.
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PMID:CD30 ligand signal transduction involves activation of a tyrosine kinase and of mitogen-activated protein kinase in a Hodgkin's lymphoma cell line. 754 87

While cross-linking of the membrane IgM (mIgM) molecules expressed on WEHI 231 lymphoma cells induces these cells to undergo apoptosis, we have previously observed that ligation of the mIgD expressed on IgD-transfected WEHI 231 (W delta) cells is not associated with induction of cell death. Thus mIgM+IgD+ W delta cells provide a valuable reagent for delineating the molecular events which modulate the physiologic outcome of B cell antigen receptor (BCR) engagement. In view of recent data implicating the cytosolic phosphotyrosine phosphatase PTP1C in the regulation of BCR signaling capacity, we used W delta cells to investigate the potential role for PTP1C in modulating the cell response to BCR activation. The results of this analysis revealed PTP1C to undergo rapid tyrosine phosphorylation following mIgM or mIgD cross-linking and to associate with a number of other phosphoproteins in stimulated W delta cells. Among these latter phosphoproteins, one prominent species of about 44 kDa (pp44) which co-precipitated with PTP1C in mIgM-ligated cells was not detected in PTP1C immunoprecipitates from mIgD-ligated cells. The association of PTP1C with this 44-kDa phosphoprotein following mIgM cross-linking was also observed in two additional B cell lines representing an immature state of differentiation, but was not detected after BCR engagement in two representative mature B cell lines or in splenic B cells. Initial data concerning the identity of pp44 indicate that this molecule does not represent the Shc, MAPK or Ig-beta proteins and may, therefore, constitute a previously unidentified signaling effector. While the structural and biochemical properties of pp44 require further definition, the findings suggest that BCR-triggered interactions of PTP1C with pp44 occur only in the context of an immature state of cellular differentiation and the induction of apoptosis. These data therefore suggest that PTP1C interactions with pp44 may be relevant to the transduction of BCR signals which evoke cell death.
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PMID:Antigen receptor-triggered apoptosis in immature B cell lines is associated with the binding of a 44-kDa phosphoprotein to the PTP1C tyrosine phosphatase. 766 92

The B cell antigen receptor is a complex containing the antigen-binding immunoglobulin molecules and the Ig-alpha/Ig-beta heterodimer which presumably connects the B cell antigen receptor to intracellular signaling components. To analyze the functional properties of the cytoplasmic parts of the B cell antigen receptor, we used the K46 B lymphoma line (IgG2a, kappa) to express chimeric molecules composed of the extracellular and transmembrane part of the CD8 alpha molecule and the cytoplasmic sequence of either the Ig-alpha (CD8 alpha/Ig-alpha), the Ig-beta (CD8 alpha/Ig-beta) protein or the membrane-bound gamma 2a heavy chain (CD8 alpha/gamma 2a). From these three types of chimeric molecules only (CD8 alpha/Ig-alpha and CD8 alpha/Ig-beta, but not CD8 alpha/gamma 2a, could transduce signals, thus providing the first evidence that the cytoplasmic tail of Ig-alpha and Ig-beta have a signaling capacity. After cross-linking with anti-CD8 alpha antibodies, both molecules induced a similar increase in intracellular free calcium ion and in MAP kinase phosphorylation. Protein tyrosine kinases, however, were strongly activated via the CD8 alpha/Ig-alpha and only marginally via the CD8 alpha/Ig-beta molecule. This suggests that the Ig-alpha and Ig-beta proteins have distinct roles during signal transduction through the B cell antigen receptor.
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PMID:Differential signaling through the Ig-alpha and Ig-beta components of the B cell antigen receptor. 768 2

The coupling of prolactin (PRL) receptor ligation to activation of mitogen-activated protein (MAP) kinase was sought in rat Nb2 lymphoma cells, a pre-T lymphocyte line dependent upon lactogens for proliferation. Addition of PRL (20 ng/ml) to Nb2 cells, growth arrested in the early G1 phase of cell cycle, stimulated rapid tyrosyl phosphorylation of MAP kinase (min). Phosphorylated MAP kinase subsequently translocated to the nucleus, with kinetics essentially identical to those demonstrated for nuclear accumulation of PRL. The rapidity of MAP kinase activation suggests an intermediary role for this enzyme in PRL receptor signalling. Moreover, nuclear translocation of MAP kinase provides an interactive mechanism by which PRL, together with its nuclear receptor, may regulate transcription requisite for mitogenesis.
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PMID:Prolactin-induced phosphorylation and nuclear translocation of MAP kinase in Nb2 lymphoma cells. 798 May 91

B chronic lymphocytic leukemia (B-CLL) and hairy cell leukemia (HCL) cells are refractory to many of the signals which activate normal B cells but are stimulated to proliferate by tumor necrosis factor (TNF). Cell signalling by TNF is mediated in part by the induction of the transcription factor families AP-1 and NF-kappa B. In some cellular contexts, these factors play a role in regulating cell cycle transit. AP-1 binds DNA as dimers of jun and fos family proteins and is regulated by a cascade of protein kinases which eventually activate a mitogen-activated protein kinase (MAP kinase) and also by protein kinase C. Three pathways have been implicated in the activation of NF-kappa B by extracellular ligands. 1, the activation of protein kinase C by diacylglycerol generated by ligand-mediated activation of phosphatidylcholine hydrolysis, 2, stimulation of specific protein kinases by ceramide generated following activation of a sphingomyelinase by diacylglycerol and 3, a novel pathway involving ligand-induced generation of free radical species. In B-CLL and HCL cells, the generation of nuclear-localized c-jun and c-fos proteins (components of AP-1) in response to TNF or PMA appears to be blocked. Whereas PMA failed to induce NF-kappa B in these cells, this factor was readily induced by TNF. TNF induction of NF-kappa B was abolished by antioxidants, suggesting involvement of the free radical pathway. The data discussed here suggest defects in coupling of some protein kinase C-dependent pathways in B-CLL and HCL cells and that TNF is able to bypass these blocks by the activation of NF-kappa B via a free radical-dependent pathway which is independent of protein kinase C.(ABSTRACT TRUNCATED AT 250 WORDS)
Leuk Lymphoma 1995 Jun
PMID:Defects in signal transduction pathways in chronic B lymphocytic leukemia cells. 858 Aug 20

We describe the involvement of endotoxin tolerance in the refractoriness of its anti-metastatic effect against murine syngeneic tumors. Three i.v. administrations of LPS at intervals of 4 days after tumor inoculation inhibited liver metastasis of L5178Y-ML25 cells, whereas 3 consecutive i.v. administrations of LPS showed only a slight suppressive effect. Multiple i.v. administrations of LPS, synthetic lipid A, its synthetic derivative DT-5461, Staphylococcus aureus (S. aureus) BioParticles or Staphylococcal enterotoxin B (SEB) on days 1, 5 and 9 after tumor inoculation inhibited liver metastasis of T-lymphoma cells in normal mice. The anti-metastatic effects of LPS, synthetic lipid A or DT-5461 but not S. aureus BioParticles or SEB were diminished in mice injected with LPS at daily intervals for 7 days before tumor inoculation. Mice receiving 3 consecutive i.v. administrations of LPS at daily intervals exhibited suppression of LPS-induced production of endogenous tumor necrosis factor-alpha (TNF-alpha), tumoricidal activity of macrophages, and natural-killer (NK) activity of splenocytes when compared with those of normal mice. Macrophages from mice receiving consecutive daily i.v. administrations of LPS for 3 days showed reduction of LPS-induced tyrosine phosphorylation of several intracellular proteins, including p42(mapk) /ERK2 when compared with that of the cells obtained from normal mice. These data suggest that the LPS-induced anergic state of monocytes/macrophages plays a crucial role in endotoxin tolerance with respect to the metastasis of T lymphoma in the liver.
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PMID:Tolerance to the anti-metastatic effect of lipopolysaccharide against liver metastasis in mice. 860 74

Ligation of the B cell Ag receptor (BCR) activates a protein-tyrosine kinase (PTK) and CD45 protein-tyrosine phosphatase (PTPase)-dependent signaling cascade that results in the activation of Ras. This pathway of Ras activation can operate independently of protein kinase C (PKC) activity. Activation of Ras may lead to two distinct Ras-dependent pathways involving either a Raf1/MEK/MAPK module or a MEKK/SEK/SAPK module; however, it is unclear as to how Ras controls the independent activation of either of these pathways. We have used genistein and phenylarsine oxide (PAO) as inhibitors of PTK and PTPase, respectively, to investigate whether they regulate the BCR- and Ca2+/PKC-dependent activation of the Ras/Raf1/MEK/MAPK module. Assays of phosphotransferase activities conducted with Ag (TNP6-OVA)-specific 7.9 murine B lymphoma cells demonstrated that BCR-mediated stimulation of the Raf1/MEK/MAPK module is controlled by PTK and PTPase activities. An elevation in [Ca2+]i was required to optimally activate Raf1 and MEK through the BCR. However, when signaling through the BCR was bypassed by direct stimulation of the Raf1/MEK/MAPK module via a rise in [Ca2+]i and phorbol ester-induced PKC activation, the phosphotransferase activities of Raf1, MEK and MAPK were still regulated in a PTK-dependent manner that was also partially sensitive to the PTPase inhibitor PAO. Thus, at least two alternate routes, i.e. a BCR/PTK/Ras-dependent route and another PKC/Ca(2+)-dependent route, may converge at the level of Raf1 for activation of the Raf1/MEK/MAPK module in B cells.
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PMID:Regulation of BCR- and PKC/Ca(2+)-mediated activation of the Raf1/MEK/MAPK pathway by protein-tyrosine kinase and -tyrosine phosphatase activities. 864 50

Several serine/threonine and tyrosine kinase signal transduction pathways have been recently linked to prolactin (PRL) action in lymphoid cells. Utilizing the lactogen-dependent, rat pre-T lymphoma cell line, Nb2-11, and the autonomous subline, Nb2-SFJCD1, studies were conducted to determine whether PRL- or interleukin-2 (IL-2)-stimulated Nb2 cell proliferation is coupled to the activation of p21ras and mitogen-activated protein (MAP) kinase. Stimulation of Nb2-11 cells, growth-arrested in the early G1 phase of the cell cycle, with PRL or IL-2 rapidly (5-10 min) provoked GTP binding to Ras, enhanced tyrosyl phosphorylation of MAP kinase, significantly increased its enzymatic activity, and caused its nuclear translocation. The phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), which directly activates protein kinase C, similarly activated Ras and MAP kinase but failed to cause its nuclear translocation. Tyrosine kinase antagonism with genistein inhibited PRL-stimulated Ras and MAP kinase activation. In other experiments, Ras and MAP kinase were each found to be constitutively active in the Nb2-SFJCD1 line. The addition of PRL to these cultures enhanced the activity of these signaling proteins. Finally, the effects of PRL, IL-2, TPA, and phosphatase inhibition on Nb2-11 cell population density and [3H]thymidine uptake were compared. The addition of PRL, IL-2, and TPA significantly stimulated[3H] thymidine incorporation, while only the polypeptide growth factors augmented cell density. Phosphatase inhibition had no effect on either parameter. These results indicate that Nb2 cell proliferation is associated with the early activation of Ras and MAP kinase. Moreover, tyrosyl phosphorylation upstream of Ras activation appears to be required for its subsequent stimulation of mediators, which activate MAP kinase. Protein kinase C activation may be coupled to MAP kinase activation but is not sufficient for Nb2 cell proliferation.
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PMID:Rapid activation of mitogen-activated protein kinase and p21ras by prolactin and interleukin 2 in rat Nb2 node lymphoma cells. 884

B cell antigen receptor (BCR)-induced apoptosis in the WEHI-231 B lymphoma cell line can be prevented by engaging CD40. We have used this cell line to investigate the role of mitogen-activated protein (MAP) kinases in integrating BCR and CD40 signaling. Each of the three types of MAP kinases, the extracellular signal-regulated kinases (ERKs), the c-Jun N-terminal kinases (JNKs), and p38, phosphorylates a distinct set of transcription factors. Thus, activating different combinations of MAP kinases could lead to distinct biological responses. We found that BCR engagement in WEHI-231 cells caused a 15- to 20-fold activation of ERK2 and a 2- to 3-fold stimulation of ERK1. CD40 did not activate either of these kinases, nor did it affect BCR-induced ERK activation. In contrast, CD40 engagement caused a 50- to 70-fold increase in JNK activity. BCR cross-linking caused a modest (4- to 8-fold) increase in JNK activity by itself and also potentiated CD40-induced JNK activation. Finally, CD40 caused strong activation of the p38 kinase as well as MAPKAP kinase-2, a downstream target of p38. BCR engagement caused only weak activation of the p38 pathway. In summary, the BCR strongly activates ERK2 and weakly activates ERK1, JNK, and p38, while CD40 markedly stimulates the JNK and p38 kinases. Thus, activation of only ERK2 correlates with apoptosis in WEHI-231 cells, whereas full activation of all three MAP kinase pathways correlates with cell survival. The role of MAP kinases in regulating these responses remains to be tested.
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PMID:Differential activation of the ERK, JNK, and p38 mitogen-activated protein kinases by CD40 and the B cell antigen receptor. 887 35


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