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:3.4.11.18 (MAP)
7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

For characterization of a high molecular-weight protein group prevailing in the tumor nuclear matrix, monoclonal antibodies to MAP-like protein p260 and to fibronectin were used. Immunoperoxidase reaction in Western blots of nuclear matrix electrophoregrams revealed protein p260 both in normal liver and hepatomas 27 and 22a while fibronectin was found in hepatomas, but absent in the normal liver. Immunoelectron microscopy with gold-conjugated antibodies showed p260 to be uniformly spread in the nuclei while fibronectin was localized mostly at the periphery of the tumour nuclei.
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PMID:[The immunochemical demonstration of high-molecular proteins in the nuclear matrix of tumor cells]. 811 72

The MAP kinase pathway is a major regulator of both normal and oncogenic growth. We report that activation of the MAP kinase ERK2 by serum or purified growth factors is strongly dependent on cell adhesion to extracellular matrix proteins. This effect is specific to soluble growth factors, since suspended cells still activate ERK2 in response to plating on fibronectin, and is reversible. Analysis of endogenous Ras and Raf show that these proteins are still activated by serum in suspended cells, whereas MEK activity is inhibited. Conversely, activation of ERK2 by activated mutants of Ras and Raf is still adhesion-dependent but activation by MEK is not. Consistent with these results, activated MEK enhances growth of ras-transformed cells in suspension but not when adherent. These results identify a novel synergism between cell adhesion- and growth factor-regulated pathways, and explain how oncogenic activation of MAP kinases induces both serum- and anchorage-independent growth.
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PMID:Growth factor activation of MAP kinase requires cell adhesion. 931 18

The lymphocyte integrin alpha 4 beta 7 is a cell surface adhesion receptor involved in initiating lymphocyte homing to gut-associated/mucosal lymphoid tissues by binding the mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Other known ligands are vascular cell adhesion molecule-1, fibronectin, and the alpha 4 integrin chain itself. Here, we demonstrate that stimulation of the alpha 4 beta 7 integrin through its alpha 4 subunit (mAb R1-2), beta 7 subunit (mAb M293), or the combinatory epitope (mAb DATK32) enhances tyrosine phosphorylation of several cellular proteins in the murine TK1 lymphoma cell line. The two src-kinases p56lck and p59fyn were identified as possible mediators and substrates of the detected tyrosine phosphorylation. Furthermore, we observed activation of the MAP-kinases ERK1/2.
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PMID:Stimulation of TK1 lymphoma cells via alpha 4 beta 7 integrin results in activation of src-tyrosine- and MAP-kinases. 934 71

Recently we showed that human epidermal keratinocytes express the extracellular matrix protein tenascin-C (TN-C) during wound healing, but not in normal adult skin. To gain further insight into the regulation of epidermal TN-C expression, we tested the effect of various stimuli on TN-C expression by cultured keratinocytes. Our results indicate that IL-4 is a very strong inducer of TN-C protein and mRNA expression in normal keratinocytes. Furthermore, TNFalpha and IFNgamma moderately increased TN-C expression. No other cytokines and growth factors that we tested, including various factors that stimulate TN-C expression in mesenchymal cells, significantly affected TN-C secretion by cultured keratinocytes. The regulation of TN-C expression in keratinocytes is distinct from that of fibronectin, since IL-4 and IFNgamma did not affect fibronectin expression in our experiments, and TNFalpha only slightly increased fibronectin levels. To investigate the role of cellular stress response pathways that can be activated by TNFalpha in the regulation of TN-C expression, we tested the effect of different inhibitors and an activator of these intracellular signalling cascades. The results show that the p38 MAP-kinase pathway is not involved in TNFalpha-induced TN-C expression in cultured keratinocytes. Activation of the JNK/SAPK-1 pathway by the addition of sphingomyelinase resulted in a dose-dependent increase of TN-C expression. TN-C expression by squamous carcinoma cell lines was differentially affected by the cytokines that stimulated TN-C expression in normal keratinocytes: TNFalpha again increased TN-C secretion, but IL-4 and IFNgamma had little effect. We conclude that there are distinct regulation mechanisms for TN-C expression in normal keratinocytes, tumor-derived keratinocytes and mesenchymal cells. The observation that TN-C is abundant in inflamed skin is a strong indication that inflammatory cytokines such as IL-4, TNFalpha and IFNgamma could also be involved in the regulation of epidermal TN-C expression in vivo.
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PMID:Tenascin-C expression in human epidermal keratinocytes is regulated by inflammatory cytokines and a stress response pathway. 974 46

Mn(2+) treatment has been shown to promote neurite outgrowth in rat pheochromocytoma (PC12) cells in a time- and dose-dependent manner. This process is mediated through the interactions of extracellular matrix (ECM) proteins and integrin receptors. Studies were performed to determine whether the phosphorylation of the MAP kinases, ERK1 and 2, is required for Mn(2+)-induced neurite outgrowth. A time- and dose-dependent increase in phosphorylation of both ERK1 and 2 was observed upon treatment of PC12 cells with Mn(2+). Phosphorylation of the ERKs occurred as early as 2 hr after initiating treatment, with a maximum increase occurring at approximately 24 hr. Inhibition of MEK with the specific inhibitor, PD98059, blocked the phosphorylation of ERK1 and 2 and increased Mn(2+) toxicity. When cells were grown in serum-free defined medium, Mn(2+)-induced phosphorylation of ERK1 and ERK2 occurred in cells grown on surfaces treated with growth serum or fibronectin but not on surfaces treated with poly-L-lysine. In addition, the pentapeptide GRGDS, which blocks RGD-mediated interactions, inhibited Mn(2+)-induced phosphorylation of ERK1 and 2. The Mn(2+)-induced increase in phosphorylated ERK1 and 2 was not seen in a PC12 cell line that does not respond to Mn(2+). These data support the hypothesis that integrin-mediated activation of the MAPK signal transduction pathway leading to the activation of ERK1 and 2 is required for Mn(2+)-induced PC12 differentiation and neurite outgrowth.
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PMID:Activation of ERK1 and ERK2 is required for manganese-induced neurite outgrowth in rat pheochromocytoma (PC12) cells. 1046 56

Several modifications of the alpha5beta1 integrin, which alter its intracellular and extracellular interaction with fibronectin and other proteins, have been reported. However, the significance of the lateral mobility of integrin molecules in the plasma membrane, as a regulator of their distribution and function, is poorly understood. We examined this problem by increasing the cholesterol content of plasma membranes, and consequently modifying the fluidity of membrane phospholipids, in rat fibroblasts. Under these conditions, the clustering of alpha5beta1 integrin molecules in focal adhesions, their adhesion to the cell-binding domain of fibronectin, and their association with the cytoskeletal protein talin were significantly enhanced as compared to control cells. However, the activation of MAP-kinase pathways by the association of fibronectin with alpha5beta1 integrin, and its association with integrin-linked kinase (ilk), were suppressed. The treated cells also showed distinct changes in shape, and their actin stress fiber network was more dense and thick as compared to control cells. The changes in fluidity of phospholipids occurred differentially and fluidity of phosphatidyl-ethanolamine increased, while that of phosphatidyl-choline was reduced. Our results suggest that proteins in focal adhesions could be partitioned in specific lipid domains, which regulate specific aspects of alpha5beta1 integrin functions.
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PMID:Modulation of alpha5beta1 integrin functions by the phospholipid and cholesterol contents of cell membranes. 1077 9

The molecular processes that maintain the stem cell pool are largely unknown. Using polymerase chain reaction-driven subtraction, we examined genes that are differentially expressed by early hematopoietic progenitors. We expected that identifying genes that are uniquely expressed by the earliest precursors would provide insight into the mechanism(s) through which stem cell number is maintained and differentiation is regulated. Using CD34(+)CD38(-) cells as starting material, we identified four mRNAs, expressed by these cells, that are either absent or present in reduced amounts in more mature CD34(+)CD38(+) cells. One of these cDNAs (C40) encodes a known member of the subfamily of protein phosphatases (CL100) that exhibits dual substrate specificity for phosphotyrosine- and phosphoserine/threonine-containing substrates and specifically inactivates MAP kinases. This phosphatase has been shown to play a role in regulating the differentiation of several cell types. The second cDNA (C23) is identical to LR11 (gp250), a member of the low-density lipoprotein receptor family. LR11 is unusual in that, in addition to 11 ligand-binding repeats, it contains a series of fibronectin type III repeats near its carboxyl terminal end that are similar to those found in cytokine receptors. It is highly expressed in developing brain, but hematopoietic expression has not been reported. The 178-bp fragment that we originally cloned is part of a 4,145-bp 3' untranslated region (UTR) that had not been previously sequenced and is among the largest human 3' UTRs ever reported. The other isolates (C21 and C12) do not correspond to known protein sequences. They are homologous to EST sequences from a fetal brain library. C21 encodes a previously unknown gene that is a member of the WD-40 family. An open reading frame encoding a 515 amino acid protein has been identified. Four mRNAs, differentially expressed by CD34(+)CD38(-) human bone marrow cells, have been identified. Although this population is highly enriched for early hematopoietic progenitors, none of these genes encodes a message whose expression is limited to the hematopoietic system. They all are expressed in a variety of tissues, suggesting that they are involved in processes that are fundamental to the development of many cell types. All of these cDNAs possess atypically long 3' UTRs, and one of them is among the longest ever described. Their differential expression by immature hematopoietic cells, in contrast to more mature cells, suggest that long 3' UTRs may be characteristic of genes that play a regulatory role during development.
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PMID:Identification of four human cDNAs that are differentially expressed by early hematopoietic progenitors. 1106 77

Stromal cell-derived factor-1alpha (SDF-1alpha) is a potent chemoattractant for hematopoietic progenitor cells (HPC), suggesting that it could play an important role during their migration within or to the bone marrow (BM). The integrin VLA-4 mediates HPC adhesion to BM stroma by interacting with CS-1/fibronectin and VCAM-1. It is required during hematopoiesis and homing of HPC to the BM. As HPC migration in response to SDF-1alpha might require dynamic regulation of integrin function, we investigated if SDF-1alpha could modulate VLA-4 function on BM CD34(hi) cells.CD34(hi) BM cells and hematopoietic cell lines were tested for the effect of SDF-1alpha on VLA-4-dependent adhesion to CS-1/fibronectin and VCAM-1, as well as to BM stroma. CD34(hi) BM cells that adhered to VLA-4 ligands after SDF-1alpha treatment were characterized in colony-forming and long-term culture-initiating cell (LTC-IC) assays.SDF-1alpha rapidly (1 minute) and transiently upregulated the adhesion of CD34(hi) BM cells and hematopoietic cell lines to both CS-1/fibronectin and VCAM-1, and to BM stromal cells. The upregulation of VLA-4-dependent cell adhesion by SDF-1alpha targeted primitive LTC-IC as well as committed CD34(hi) cells. SDF-1alpha-triggered enhancement in VLA-4 function was inhibited by pertussis toxin (PTx) and cytochalasin D, indicating the involvement of G(i) protein downstream signaling and an intact cytoskeleton. Instead, activation of p44/42 MAP kinases by SDF-1alpha did not functionally correlate with enhancement of VLA-4-dependent cell adhesion. Modulation of VLA-4-mediated CD34(hi) BM cell adhesion by SDF-1alpha could play a key role in their migration within and to the BM and therefore influence their proliferation and differentiation.
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PMID:Chemokine stromal cell-derived factor-1alpha modulates VLA-4 integrin-dependent adhesion to fibronectin and VCAM-1 on bone marrow hematopoietic progenitor cells. 1127 63

The p53 tumor suppressor is activated in response to various stresses driving the cells into growth arrest or apoptosis. We have addressed the question of how disintegration of microtubule system induces activation of p53. Depolymerization of microtubules by colcemid in rat and human quiescent fibroblasts resulted in accumulation of transcriptionally active p53 that caused cell-cycle arrest at the G1/S boundary. The p53 activation correlated with prominent activation of Erk1/2 MAP kinases that resulted from colcemid-stimulated development of focal adhesions. Inhibition of focal contacts development by plating of cells onto poly-L-lysine abrogated both Erk1/2 and p53 activations in colcemid-treated cells, while plating of cells onto fibronectin caused transient up-regulation of p53 even in the absence of colcemid. Pre-treatment of cells with the specific MEK1 inhibitor PD098059 also attenuated colcemid-induced p53 activation and G1 cell cycle arrest. Cell types which either failed to develop focal adhesions in response to colcemid treatment (human MCF-7 epithelial cells), or lacked colcemid-induced sustained Erk activation (primary mouse embryo fibroblasts and 12(1) cells) showed virtually no p53 up-regulation in response to disruption of microtubules during G0/G1. Our results indicate that p53 activation is not triggered by disintegration of microtubule system by itself, but rather originates from some of the consequences of such disintegration, in particular, from the development of focal adhesions leading to activation of Erk signaling pathway.
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PMID:p53 activation in response to microtubule disruption is mediated by integrin-Erk signaling. 1131 25

Myocardium consists of diverse cell types suggesting a role for cell-cell interaction in maintaining the structural and functional integrity of the heart. Cardiac fibroblasts are the source of extracellular matrix, growth factors and cytokines in the heart and their interactions with cardiac myocytes are recognized. Their effects on biological responses of endothelial cells, however, are vastly unexplored. Proliferation of endothelial cells is an essential stage of angiogenesis and contributes to development of coronary collaterals. This study was designed to evaluate the effect of soluble factors produced by cardiac fibroblasts on endothelial cell proliferation. Human cardiac fibroblast-conditioned medium (CF-CM) caused a significant increase (47%, P < 0.0001) in DNA synthesis in human umbilical vein endothelial cells (HUVEC), as determined by [(3)H]thymidine incorporation. This effect was dependent on de novo protein synthesis and activation of MAP kinases. Consistently, CF-CM induced the expression and activation of ERK2 in HUVEC. The CF-CM from which heparin-binding proteins were removed, had a significantly enhanced stimulatory effect on DNA synthesis in HUVEC compared to that of 'whole CF-CM'. Western analysis showed the presence of VEGF, bFGF, PDGF, TGF-beta(1), fibronectin and thrombospondin-1 in whole CF-CM. The individual immunodepletion of each factor from whole CF-CM showed that all were necessary for full activity of CF-CM. CF-CM caused a significant reversal of hypoxia-induced inhibition of DNA synthesis and enhanced expression of survival-associated protein, Bcl(2), in HUVEC. Together, these data show that cardiac fibroblasts release inhibitory and stimulatory factors, the net effect of which is an enhancement of DNA synthesis in endothelial cells. These results point to the role that cardiac fibroblasts may play in angiogenesis in the heart.
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PMID:Release of pro- and anti-angiogenic factors by human cardiac fibroblasts: effects on DNA synthesis and protection under hypoxia in human endothelial cells. 1133 98


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