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)

Epidermal growth factor (EGF) receptor tyrosine kinase activity is down-regulated by a number of growth-modulating agents that activate protein kinase C and/or mitogen-activated protein (MAP) kinases. Although the mechanism is unclear, it has been hypothesized that phosphorylation of specific threonine residues leads to inhibition of the EGF receptor tyrosine kinase. Two sites phosphorylated on the EGF receptor in response to phorbol esters are possible mediators of this effect: threonine 654, the target of protein kinase C, and threonine 669, the target of MAP kinase and the major site of phosphorylation on the EGF receptor. In order to investigate the role of these residues in receptor regulation, we substituted glutamic acid to mimic the negative charge introduced by phosphorylation at these sites. The wild-type and mutant receptor cDNAs were then transfected into CHO cells that lack endogenous EGF receptor. The EGF binding properties of the mutant receptors were similar to those of the wild-type EGF receptors. EGF stimulated tyrosine kinase activity and DNA synthesis in cells expressing both mutant receptors, indicating that the mutant EGF receptors are biologically active. Treatment of cells with phorbol esters inhibited the high affinity EGF binding and tyrosine kinase activities of both mutant and wild-type EGF receptors. These results indicate that acidic residues at either the Thr-654 or Thr-669 site modulate but do not block EGF receptor signalling. Furthermore, this data demonstrates that the mutant EGF receptors are still a target for inhibition by phorbol esters. Thus, events other than phosphorylation of Thr-654 or Thr-669 appear to be required for receptor down-regulation by protein kinase C or MAP kinase.
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PMID:Role of threonine residues in regulation of the epidermal growth factor receptor by protein kinase C and mitogen-activated protein kinase. 839 47

The mitogen-activated protein kinases (MAP kinases) p42mapk and p44mapk are serine/threonine kinases rapidly activated in cells stimulated with various extracellular signals by dual phosphorylation of tyrosine and threonine residues. They are thought to play a pivotal role in integrating and transmitting transmembrane signals required for growth and differentiation. Here we demonstrate that activation of these ubiquitously expressed MAP kinases is essential for growth. To specifically suppress MAP kinase activation in fibroblasts, we transiently expressed either the entire p44mapk antisense RNA or p44mapk kinase-deficient mutants (T192A or Y194F). As expected, and through independent mechanisms, both approaches strongly inhibited MAP kinase activation. The antisense reduced the expression of endogenous p42mapk and p44mapk by 90%, whereas overexpression of the T192A mutant inhibited growth factor activation of both endogenous MAP kinases by up to 70%. As a consequence, we found that the antisense as well as the T192A mutant of p44mapk inhibited growth factor-stimulated gene transcription (collagenase promoter assay with chloramphenicol acetyltransferase reporter) and cell growth. These effects were proportional to the extent of MAP kinase inhibition and reversed by coexpression of the wild-type p44mapk. Therefore we conclude that growth factor activation of p42mapk and p44mapk is an absolute requirement for triggering the proliferative response.
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PMID:Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. 839 1

We have partially purified and characterized two protein kinases that were strongly activated by interleukin-1 (IL-1) or tumor necrosis factor (TNF) in MRC-5 fibroblasts. The kinases were separated by anion exchange chromatography of cytosolic fractions. They phosphorylated in vitro the small heat shock protein (hsp27) or beta-casein and were stimulated 3- and 4.5-fold, respectively, in cells that had been exposed to IL-1 or TNF for 10 min. They were distinct from the mitogen-activated protein kinases, whose activation by IL-1 or TNF has been reported recently. The hsp27 kinase phosphorylated its substrate on serine residues. Its molecular mass was estimated to be 45-kDa by gel filtration. It is probably involved in the increase in hsp27 phosphorylation seen in intact cells. The beta-casein kinase behaved as a 65-kDa protein. It phosphorylated its substrate on serine and threonine residues and had little activity on alpha-casein. The hsp27 and beta-casein kinases were not activated after stimulation of the cells with phorbol myristate acetate (PMA). In contrast, the MAP kinases were activated to a similar extent (2-3-fold) by the cytokines and by PMA. The hsp27- and beta-casein kinases probably correspond to novel enzymes whose mechanisms of activation may be independent of protein kinase C or MAP kinases.
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PMID:Interleukin 1 and tumor necrosis factor stimulate two novel protein kinases that phosphorylate the heat shock protein hsp27 and beta-casein. 844 Jul 7

An improved procedure has been developed for the isolation of insulin-stimulated protein kinase-1 (ISPK-1), an S6 kinase-II homologue, by which 0.5 mg highly purified enzyme can be obtained within four days. The sequences of tryptic peptides from ISPK-1 (100 residues) revealed 100% identity with the predicted protein product of rskmo-2, a cDNA clone isolated from a mouse F2 cell line library [Alcorta, D. A., Crews, C. M., Sweet, L. J., Bankston, L., Jones, S. W. and Erikson, R. L. (1989) Mol. Cell. Biol. 9, 3850-3859], demonstrating that rskmo-2 encodes an S6 kinase-II. Two isoforms of mitogen-activated protein (MAP) kinase (p42mapk and p44mapk) were the only ISPK-1-reactivating enzymes detected after Mono Q chromatography of extracts prepared from rabbit skeletal muscle or phaeochromocytoma 12 cells stimulated by nerve or epidermal growth factors. One of the residues on ISPK-1 phosphorylated by p42mapk was a threonine located nine residues N-terminal to the conserved Ala-Pro-Glu motif in the C-terminal protein kinase domain, an analogous location to phosphorylation sites essential for the activity of cAMP-dependent protein kinase, MAP kinase and p34cdc2. A further threonine located five residues N-terminal to the same Ala-Pro-Glu motif was also phosphorylated, probably via autophosphorylation catalysed by ISPK-1 itself.
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PMID:Identification of insulin-stimulated protein kinase-1 as the rabbit equivalent of rskmo-2. Identification of two threonines phosphorylated during activation by mitogen-activated protein kinase. 844 94

Ligation of the membrane immunoglobulin M receptor as well as stimulation with the protein kinase C agonist phorbol 12-myristate 13-acetate leads to a B-lymphocyte proliferation and differentiation. Both stimuli activate p42 mitogen-activated protein (MAP) kinase in human B-lymphocytes [Casillas, Hanekom, Williams, Katz and Nel (1991) J. Biol. Chem. 266, 19088-19094]. MAP kinase activation is dependent on tyrosine as well as threonine phosphorylation of the kinase and its activity is inhibited by tyrosine as well as threonine/serine phosphatases. Okadaic acid, a specific inhibitor of type 1 and 2A serine/threonine phosphatases, induced MAP kinase activity in a potent and dose-dependent fashion, but failed to induce [3H]thymidine incorporation into normal human tonsil B-cells. Moreover, in combination with membrane immunoglobulin M ligation, okadaic acid decreased rather than increased [3H]thymidine incorporation. The kinetics of MAP kinase activation by okadaic acid differed from phorbol 12-myristate 13-acetate and anti-membrane immunoglobulin M stimulation. Okadaic acid induced tyrosine phosphorylation of 42 kDa and 44 kDa proteins which co-electrophoresed and co-chromatographed with ERK-2 and ERK-1 respectively. Ramos cells also contained a constitutively active 46 kDa MAP kinase which appeared as a separate peak in chromatography and could be immunoprecipitated by an antiserum against a rat ERK-1 fusion protein.
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PMID:Okadaic acid activates p42 mitogen-activated protein kinase (MAP kinase; ERK-2) in B-lymphocytes but inhibits rather than augments cellular proliferation: contrast with phorbol 12-myristate 13-acetate. 845 45

A systematic analysis reveals that out of 20 protein kinases examined, specific for either Ser/Thr or Tyr, the majority are extremely sensitive to staurosporine, with IC50 values in the low nanomolar range. A few of them however, notably protein kinases CK1 and CK2, mitogen-activated protein (MAP) kinase and protein-tyrosine kinase CSK, are relatively refractory to staurosporine inhibition, exhibiting IC50 values in the micromolar range. With all protein kinases tested, namely PKA, CK1, CK2, MAP kinase (ERK-1), c-Fgr, Lyn, CSK and TPK-IIB/p38Syk, staurosporine inhibition was competitive with respect to ATP, regardless of its inhibitory power. In contrast, either uncompetitive or noncompetitive kinetics of inhibition with respect to the phosphoacceptor substrate were exhibited by Ser/Thr and Tyr-specific protein kinases, respectively, consistent with a different mechanism of catalysis by these two sub-families of kinases. Computer modeling based on PKA crystal structure in conjunction with sequence analysis suggest that the low sensitivity to staurosporine of CK2 may be accounted for by the bulky nature of three residues, Val66, Phe113 and Ile174 which are homologous to PKA Ala70, Met120 and Thr183, respectively. In contrast these PKA residues are either conserved or replaced by smaller ones in protein kinases highly sensitive to staurosporine inhibition. On the other hand, His160 which is homologous to PKA Glu170, appears to be responsible for the unique behaviour of CK2 with respect to a staurosporine derivative (CGP44171A) bearing a negatively charged benzoyl substituent: while CGP44171A is 10- 100-fold less effective than staurosporine against PKA and most of the other protein kinases tested, it is actually more effective than staurosporine for CK2 inhibition, but it looses part of its efficacy if it is tested on a CK2 mutant (H160D) in which His160 has been replaced by Asp. It can be concluded from these data that the catalytic sites of protein kinases are divergent enough as to allow a competitive inhibitor like staurosporine to be fairly selective, a feature that can be enhanced by suitable modifications designed based on the structure of the catalytic site of the kinase.
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PMID:Different susceptibility of protein kinases to staurosporine inhibition. Kinetic studies and molecular bases for the resistance of protein kinase CK2. 852 58

The expression of mitogen-activated protein kinases (MAPKs) and MAPK kinases (MEKs) in rat islets of Langerhans and the involvement of MAPKs in regulated insulin secretion were examined. Two major isoforms of both MEK (45 and 46 kDa) and MAPK (42 and 44 kDa) were detected in rat islets and shown to be localized to insulin-secreting beta cells by detection of their expression in the beta cell line MIN6. The tyrosine phosphatase inhibitor sodium pervanadate, and, to a lesser extent, the serine/threonine phosphatase inhibitor okadaic acid, stimulated MAPK phosphorylation, as assessed by a shift in its electrophoretic mobility and by increased phosphotyrosine immunoreactivity of immunoprecipitated MAPK. The increase in MAPK phosphorylation stimulated by sodium pervanadate was not coupled to an increase in MAPK activity, but okadaic acid, either alone or in the presence of sodium pervanadate, caused an increase in myelin basic protein phosphorylation by MAPK. Neither okadaic acid nor sodium pervanadate, either individually or combined, stimulated insulin secretion. 4 beta-phorbol myristate acetate stimulated an increase in phosphorylation of the 42 kDa isoform of MAPK (erk2) in human umbilical vein endothelial cells, but neither it nor glucose affected either the phosphorylation state of islet erk2 or the activities of immunoprecipitated islet MAPKs. These results provide evidence for the presence of a regulated MAPK pathway in adult rat islets, but our data suggest that MAPK activation alone is not a sufficient stimulus for insulin secretion.
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PMID:The mitogen-activated protein kinase pathway in rat islets of Langerhans: studies on the regulation of insulin secretion. 854 72

Thrombopoietin (Tpo) is a cytokine regulating megakaryocyte maturation and platelet formation. We studied Tpo-induced signal transduction, and found that Tpo induces phosphorylation of adapter molecules. Shc and Vav, and of serine/threonine kinases Raf-1 and mitogen-activated protein (MAP) kinases. Further, Tpo induced activation of Ras, MAP kinase kinase, MAP kinase and Pim-1. Taken together with other observations, we concluded that Tpo induces the activation of at least two distinct signaling pathways, a specific Tyk2-JAK2/STAT1-STAT3-STAT5 signaling cascade and a common Shc/Vav/Ras/Raf-1/MAP kinase kinase/MAP kinase signaling cascade.
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PMID:Thrombopoietin induces activation of at least two distinct signaling pathways. 854 84

Persistent stimulation of specific protein kinase pathways has been proposed as a key feature of receptor tyrosine kinases and intracellular oncoproteins that signal neuronal differentiation of rat pheochromocytoma (PC12) cells. Among the protein serine/threonine kinases identified to date, the p42/44 mitogen-activated protein (MAP) kinases have been highlighted for their potential role in signalling PC12 cell differentiation. We report here that retrovirus-mediated expression of GTPase-deficient, constitutively active forms of the heterotrimeric Gq family members, G alpha qQ209L and G alpha 16Q212L, in PC12 cells induces neuronal differentiation as indicated by neurite outgrowth and the increased expression of voltage-dependent sodium channels. Differentiation was not observed after cellular expression of GTPase-deficient forms of alpha i2 or alpha 0, indicating selectivity for the Gq family of G proteins. As predicted, overexpression of alpha qQ209L and alpha 16Q212L constitutively elevated basal phospholipase C activity approximately 10-fold in PC12 cells. Significantly, little or no p42/44 MAP kinase activity was detected in PC12 cells differentiated with alpha 16Q212L or alpha qQ209L, although these proteins were strongly activated following expression of constitutively active cRaf-1. Rather, a persistent threefold activation of the cJun NH2-terminal kinases (JNKs) was observed in PC12 cells expressing alpha qQ209L and alpha 16Q212L. This level of JNK activation was similar to that achieved with nerve growth factor, a strong inducer of PC12 cell differentiation. Supportive of a role for JNK activation in PC12 cell differentiation, retrovirus-mediated overexpression of cJun, a JNK target, in PC12 cells induced neurite outgrowth. The results define a p42/44 MAP kinase-independent mechanism for differentiation of PC12 cells and suggest that persistent activation of the JNK members of the proline-directed protein kinase family by GTPase-deficient G alpha q and G alpha 16 subunits is sufficient to induce differentiation of PC12 cells.
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PMID:GTPase-deficient G alpha 16 and G alpha q induce PC12 cell differentiation and persistent activation of cJun NH2-terminal kinases. 855 93

Regulation of the activity of the extracellular signal regulated kinase (ERK) mitogen-activated protein kinases was examined in Rat-1 HIR, a fibroblast cell line overexpressing the human insulin receptor. Insulin or phorbol ester induced partial activations of ERKs, while a combination of insulin and phorbol ester resulted in a synergistic activation. Preincubation with phorbol ester increased the subsequent response to insulin. Phorbol ester did not enhance tyrosine phosphorylation of the insulin receptor. Insulin did not enhance activation of phospholipase D in response to phorbol ester. Lysophosphatidic acid also acted synergistically with insulin to induce ERK activation. Lysophosphatidic acid alone had little effect on ERK, and did not activate phospholipase D. The combination of phorbol ester and insulin maintained tyrosine phosphorylation of focal adhesion kinase, while insulin alone decreased its tyrosine phosphorylation. Phorbol ester induced phosphorylation of She on serine/threonine, while insulin induced tyrosine phosphorylation of She and She-Grb2 binding. These results suggest that full activation of ERKs in fibroblasts can require the cooperation of at least two signaling pathways, one of which may result from a protein kinase C-dependent phosphorylation of effectors regulating ERK activation. In this manner, phorbol esters may enhance mitogenic signals initiated by growth factor receptors.
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PMID:Synergistic effects of insulin and phorbol ester on mitogen-activated protein kinase in Rat-1 HIR cells. 857 69


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