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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)

Clam oocytes are arrested naturally at the G2/M border in meiosis and contain an inactive 42 kDa ERK/MAP kinase, p42MAPK. Following fertilization, p42MAPK is rapidly phosphorylated on tyrosine residues and concomitantly activated. Both tyrosine phosphorylation and activation of p42MAPK begin within 2-3 min of fertilization, peak at approximately 15 min, then rapidly decline and disappear around the end of meiosis I. Neither the tyrosine phosphorylated form of p42MAPK nor p42MAPK activity reappears during meiosis II or the succeeding mitotic cell cycles. High doses of molybdate, a potent PTPase inhibitor, block the phosphorylation of p42MAPK and entry into the cell cycle. Lower doses of molybdate delay both p42MAPK phosphorylation and the release from cell cycle arrest, but once cells have re-entered the cell cycle, they continue with near-normal timing. These results argue that the transient activation of p42MAPK at fertilization is a one-time event linked to release from cell cycle arrest. In trying to reconcile this one-time activation of p42MAPK in clam embryos with the recurring, M-phase specific activation of MBP/MAP kinases reported in other systems, we show that cdc2 kinase contributes a major portion of the MBP kinase activity in mitotic extracts. Furthermore, a small fraction of p42MAPK and other related kinases are present in p13suc1-bound material, cautioning against the use of p13suc1 beads for experiments where, in addition to cdc2, the unaccounted presence of other kinase activities could be misleading.
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PMID:Activation of p42 MAP kinase and the release of oocytes from cell cycle arrest. 132 52

The proto-oncogene c-Kit, a transmembrane receptor tyrosine kinase, is an important regulator of cell growth whose constitutively active oncogenic counterpart, v-kit, induces sarcomas in cats. Mutations in murine c-kit that reduce the receptor tyrosine kinase activity cause deficiencies in the migration and proliferation of melanoblasts, hematopoietic stem cells, and primordial germ cells. We therefore investigated whether c-Kit regulates normal human melanocyte proliferation and plays a role in melanomas. We show that normal human melanocytes respond to mast cell growth factor (MGF), the Kit-ligand that stimulates phosphorylation of tyrosyl residues in c-Kit and induces sequential phosphorylation of tyrosyl residues in several other proteins. One of the phosphorylated intermediates in the signal transduction pathway was identified as an early response kinase (mitogen-activated protein [MAP] kinase). Dephosphorylation of a prominent 180-kDa protein suggests that MGF also activates a phosphotyrosine phosphatase. In contrast, MGF did not induce proliferation, the cascade of protein phosphorylations, or MAP kinase activation in the majority of cells cultured from primary nodular and metastatic melanomas that grow independently of exogenous factors. In the five out of eight human melanoma lines expressing c-kit mRNAs, c-Kit was not constitutively activated. Therefore, although c-Kit-kinase is a potent growth regulator of normal human melanocytes, its activity is not positively associated with malignant transformation.
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PMID:c-Kit-kinase induces a cascade of protein tyrosine phosphorylation in normal human melanocytes in response to mast cell growth factor and stimulates mitogen-activated protein kinase but is down-regulated in melanomas. 137 24

Ligation of CD3/TCR on T-cells induces transient activation of lymphoid MAP-2 kinase (MAP-2K), a 43 kDa serine kinase which itself is a substrate of an unidentified tyrosine kinase (pp43). The reversibility of the MAP-2K response agrees with removal of tyrosine phosphates from pp43. Since both activity as well as tyrosine phosphorylation of MAP-2K could be prolonged by Na3VO4, a phosphotyrosine phosphatase inhibitor, we studied the effect of the common CD45 isoform, which is a member of the CD45 phosphatase family, on MAP-2K activity in vivo and in vitro. We demonstrate the ability of purified CD45 phosphatase to remove tyrosine phosphates from partially purified lymphoid MAP-2K. Utilizing the approach of heterologous receptor aggregation, we also showed that CD45 could inhibit the induction of MAP-2K activity in intact Jurkat cells during CD3 or CD3 + CD4 stimulation. We therefore suggest that this phosphatase may control the activity of lymphoid MAP-2K in vivo.
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PMID:Evidence for involvement of glycoprotein-CD45 phosphatase in reversing glycoprotein-CD3-induced microtubule-associated protein-2 kinase activity in Jurkat T-cells. 171 Aug 91

Ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), oncostatin M (OSM), and interleukin-6 (IL6) compose a family of distantly related cytokines that initiate signaling by inducing either homodimerization of the "beta" signal transducing receptor component gp130 (in the case of IL6) or heterodimerization between gp130 and the gp130-related LIFR beta (in the case of CNTF, LIF, and OSM); dimerization of beta receptor components in turn activates members of the Jak/Tyk family of receptor-associated tyrosine kinases. Here we report that CNTF, LIF, OSM, and IL6 induce most of the same protein tyrosine phosphorylations, regardless of the cell type assayed or whether they initiate signaling by inducing homo- or heterodimerization of beta components. Although several of the protein tyrosine phosphorylations induced by the CNTF/LIF/OSM/IL6 family of factors may correspond to novel tyrosine kinase targets, we have been able to demonstrate the involvement of known signaling molecules, such as phospholipase C gamma, phosphoinositol 3-kinase, phosphotyrosine phosphatase (PTP1D), pp120, SHC, GRB2, STAT91, Raf-1, and the mitogen-activated protein kinases ERK1 and ERK2, revealing substantial convergence not only between the pathways activated by this cytokine family and other cytokines, but with pathways previously known to be activated only by factors that utilize receptor tyrosine kinases. Our data suggest the beta receptor components can form complexes with some of the signaling proteins identified and may play some role in their recruitment.
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PMID:Ciliary neurotrophic factor/leukemia inhibitory factor/interleukin 6/oncostatin M family of cytokines induces tyrosine phosphorylation of a common set of proteins overlapping those induced by other cytokines and growth factors. 751 71

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

PTP1C, a protein-tyrosine-phosphatase (protein-tyrosine-phosphate phosphohydrolase, EC 3.1.3.48) containing two src homology 2 domains, is poorly active when assayed with various protein substrates in vitro. Its activity is stimulated > 1000-fold by anionic phospholipids when myelin basic protein or mitogen-activated protein kinase is used as substrate but reduced in the presence of several other substrates. Data are presented to indicate a direct interaction of the enzyme with phospholipids. Enzyme stimulation directed only toward certain specific substrates is interpreted by assuming that these compounds also bind to the phospholipid vesicles where they will be subjected to rapid enzymatic attack. A possible regulation of PTP1C by its translocation to the cell membrane is hypothesized.
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PMID:Stimulation by phospholipids of a protein-tyrosine-phosphatase containing two src homology 2 domains. 768 30

Using the human Intestine 407 cell line as a model, we investigated a possible role for tyrosine kinase(s) in regulating the ion efflux pathways induced by hyposmotic stimulation (regulatory volume decrease, RVD). Pretreatment of 125I(-)-and 86Rb(+)-loaded cells with the phosphotyrosine phosphatase inhibitor sodium orthovanadate (200 microM) potentiated isotope efflux triggered by mild hypotonicity (10-20%) but did not further increase the efflux in response to more vigorous osmotic stimulation (30% hypotonicity). The tyrosine kinase inhibitors herbimycin A and genistein largely reduced the osmoshock-induced efflux in both control and vanadate-pretreated cells, while not affecting calcium-activated 86Rb+ efflux. Potentiation of the RVD response by vanadate was confirmed by direct measurements of hypotonicity-induced changes in cell volume. Hypotonic shock alone triggered a rapid and transient increase in tyrosine phosphorylation of several proteins as well as phosphorylation of mitogen-activated protein kinase. Furthermore, the potentiating effects of vanadate on hypotonicity-induced ion efflux and mitogen-activated protein (MAP) kinase phosphorylation were mimicked by epidermal growth factor. Neither vanadate nor epidermal growth factor provoked a RVD-like ionic response under isotonic conditions. These results indicate that tyrosine phosphorylation is an essential step in the RVD response and suggest a novel role of growth factors in the cellular defense against osmotic stress.
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PMID:Protein tyrosine phosphorylation is involved in osmoregulation of ionic conductances. 769 Jul 49

An emerging subclass of protein-tyrosine phosphatases (PTPases) exhibits sequence identity to the vaccinia H-1 (VH-1) gene product. These VH-1-like PTPases possess the canonical HCXAGXXR(S/T) sequence common to all PTPases, but unlike other PTPases they exhibit dual catalytic activity toward phosphotyrosine and nearby phosphothreonine residues in substrate proteins. We have isolated a novel VH-1-like PTPase, hVH-3, from the human placenta and compared various aspects of its expression with previously isolated members of this subfamily. The mammalian members of this subfamily including hVH-3 commonly localize to the nucleus and exhibit catalytic activity toward phosphorylated extracellular signal-regulated kinase. However, while the expression of some VH-1-like PTPases is extremely transient and independent of protein synthesis, hVH-3 expression is sustained over 3 h after being cell stimulated. Tissue-specific expression of hVH-3 is also distinct from other VH-1-like PTPases. Although VH-1-like PTPases have overlapping substrate specificity, there are differences in their mRNA regulation, response to extracellular stimuli, and tissue-specific expression, suggesting they serve specific roles in cellular function.
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PMID:Multiple dual specificity protein tyrosine phosphatases are expressed and regulated differentially in liver cell lines. 783 74

We have cloned a developmentally regulated mitogen-activated protein kinase (extracellular signal-regulated kinase) from Dictyostelium discoideum designated ERK1. Using anti-pTyr antibodies, we show that ERK1 is phosphorylated on tyrosine in vivo and that it will phosphorylate myelin basic protein. The gene expresses two transcripts, one that is preferentially expressed during vegetative growth and early development and one that is induced during the multicellular stages. Developmental Western blots (immunoblots) using anti-ERK1 antibodies indicate that ERK1 is present throughout development. ERK1/lacZ reporter constructs suggest that, in the multicellular stages, the gene is preferentially expressed in a subpopulation of cells scattered throughout the organism, similar to the pattern seen with anterior-like cell markers. Antisense mutagenesis from a derepressible promoter indicates that ERK1 is essential for vegetative growth. Overexpression of ERK1 from either the Actin 15 promoter or the ERK1 promoter results in abnormal morphogenesis starting at the slug stage. Overexpression of ERK1 in null mutants of the phosphotyrosine phosphatase PTP2 results in the production of large aggregation streams and subsequent abnormal morphogenesis that indicate a genetic interaction between ERK1 and PTP2. These cells produce very large aggregation streams that break up into very small mounds that undergo abnormal morphogenesis. The genetic interaction between ERK1 and PTP2 appears to be specific since overexpression of ERK1 in a ptp1- null mutant does not produce the same phenotype. Our results indicate that ERK1 plays an essential role during the growth and differentiation of D. discoideum.
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PMID:Identification and functional analysis of a developmentally regulated extracellular signal-regulated kinase gene in Dictyostelium discoideum. 793 16

We have isolated from KB cells stimulated with interleukin-1 (IL-1) a protein kinase that phosphorylates a peptide (T669) based on the sequence around T669 of the epidermal growth factor (EGF) receptor. The enzyme, which had an apparent molecular mass of 45 kDa on gel-filtration chromatography, was purified 170,000-fold from cytosolic extracts by sequential chromatography on Mono Q, Mono S, phenyl-Sepharose, Superose 12, ATP-Sepharose and Mono Q. The enzyme activity co-chromatographed at the last step with a 45 kDa protein band that stained for phosphotyrosine. This peak fraction also contained some actin and a 60 kDa protein that stained weakly for phosphotyrosine. The T669 peptide is a substrate for mitogen-activated protein (MAP) kinase. Amounts of IL-1-induced T669 kinase and activated recombinant p42 MAP kinase having equal activity on T669 peptide were compared on commonly used MAP kinase substrates. T669 kinase was two or three orders of magnitude less active on myelin basic protein or microtubule-associated protein-2 than was MAP kinase. The IL-1-induced T669 kinase did not react with antiserum to p42/p44 MAP kinase. It was inactivated by treatment with protein phosphatase 2A or protein phosphotyrosine phosphatase 1B, so it may be regulated by dual phosphorylation in similar fashion to MAP kinase. The dephosphorylated enzyme was not re-activated by MAP kinase kinase. This novel enzyme could lie on a kinase cascade induced by IL-1. It may be responsible for phosphorylating T669 of the EGF receptor.
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PMID:Interleukin-1 activates a novel protein kinase that phosphorylates the epidermal-growth-factor receptor peptide T669. 794 18


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