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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the Ras-MAPK signal transduction pathway is necessary for biological responses both to growth factors and ECM. Here, we provide evidence that phosphorylation of S298 of MAPK kinase 1 (MEK1) by p21-activated kinase (PAK) is a site of convergence for integrin and growth factor signaling. We find that adhesion to fibronectin induces PAK1-dependent phosphorylation of MEK1 on S298 and that this phosphorylation is necessary for efficient activation of MEK1 and subsequent MAPK activation. The rapid and efficient activation of MEK and phosphorylation on S298 induced by cell adhesion to fibronectin is influenced by FAK and Src signaling and is paralleled by localization of phospho-S298 MEK1 and phospho-MAPK staining in peripheral membrane-proximal adhesion structures. We propose that FAK/Src-dependent, PAK1-mediated phosphorylation of MEK1 on S298 is central to the organization and localization of active Raf-MEK1-MAPK signaling complexes, and that formation of such complexes contributes to the adhesion dependence of growth factor signaling to MAPK.
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PMID:PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation. 1287 77

Keloid fibroproliferation appears to be influenced by epithelial-mesenchymal interactions between keloid keratinocytes (KKs) and keloid fibroblasts (KFs). Keloid and normal fibroblasts exhibit accelerated proliferation and collagen I and III production in co-culture with KKs compared with single cell culture or co-culture with normal keratinocytes. ERK and phosphatidylinositol 3-kinase (PI3K) pathway activation has been observed in excessively proliferating KFs in co-culture with KKs. We hypothesized that ERK and PI3K pathways might be involved in collagen and extracellular matrix production in KFs. To test our hypothesis, four samples of KFs were co-cultured in defined serum-free medium with KKs for 2-5 days. KF cell lysate was subjected to Western blot analysis. Compared with KF single cell culture, phospho-ERK1/2 and downstream phospho-Elk-1 showed up-regulation in the co-culture groups, as did phospho-PI3K and phospho-Akt-1, indicating ERK and PI3K pathway activation. Western blotting of the conditioned medium demonstrated increased collagen I-III, laminin beta2, and fibronectin levels. Addition of the MEK1/2-specific inhibitor U0126 or the PI3K-specific inhibitor LY294002 (but not p38 kinase and JNK inhibitors) completely nullified collagen I-III production and significantly decreased laminin beta2 and fibronectin secretion. In the presence of the MEK1/2 or PI3K inhibitor, fibronectin demonstrated changes in molecular mass reflected by faster in-gel migration. These data strongly suggest that synchronous activation of both the ERK and PI3K pathways is essential for collagen I-III and laminin beta2 production. These pathways additionally appear to affect the side chain attachments of fibronectin. Modulation of these pathways may suggest a direction for keloid therapy.
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PMID:Synchronous activation of ERK and phosphatidylinositol 3-kinase pathways is required for collagen and extracellular matrix production in keloids. 1290 81

Characterization of intracellular signaling pathways should lead to a better understanding of ovarian epithelial carcinogenesis and provide an opportunity to interfere with signal transduction targets involved in ovarian tumor cell growth, survival, and progression. Challenges toward such an effort are significant because many of these signals are part of cascades within an intricate and likely redundant intracellular signaling network (Fig.1). For instance, a given signal may activate a dual intracellular pathway (ie, MEK1-MAPK and PI3K/Akt required for fibronectin-dependent activation of matrix metalloproteinase 9). A single pathway also may transduce more than one biologic or oncogenic signal (ie, PI3K signaling in epithelial and endothelial cell growth and sprouting of neovessels). Despite these challenges, evidence for therapeutic targeting of signal transduction pathways is accumulating in human cancer. For instance, the EGF-specific tyrosine kinase inhibitor ZD 1839 (Iressa) may have a beneficial therapeutic effect on ovarian epithelial cancer. Therapy of this cancer may include inhibitors of PI kinase (quercetin), ezrin and PIP kinase (genistein). The G protein-coupled family of receptors, including LPA, also is an attractive target to drugs, although their frequent pleiotropic functions may be at times toxic and lack specificity. Because of the lack of notable toxicity, PI3K/Akt pathway inhibitors such as FTIs are a promising targeted therapy of ovarian epithelial cancer. Increasing insight into the oncogenic pathways involved in ovarian epithelial cancer also is helping clinicians to understand better the phenomenon of chemoresistance in this malignancy. Oncogenic activation of gamma-synuclein promotes cell survival and provides resistance to paclitaxel, but such a resistance is partially overcome by an MEK inhibitor that suppresses ERK activity. Ovarian epithelial cancer is a complex group of neoplasms with an overall poor prognosis. Comprehension of this cancer pathobiology suffers because of an incomplete understanding of precursor lesions and the absence of an orthotopic animal model until very recently. It can be predicted with confidence, however, that the discovery of potent inhibitors of signal transduction and the development of discovery tools, such as proteomics and metabolomics, may change the way by which clinicians may now address basic biomedical questions in this insidious and lethal disease.
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PMID:Oncogenic pathways implicated in ovarian epithelial cancer. 1295 83

Recently we demonstrated that lipopolysaccharide (LPS) promotes activation of the Ras/ERK cascade in medfly hemocytes and that phagocytosis of Escherichia coli by insect hemocytes is mediated by an integrin-dependent process via the activation of FAK/Src complex (J Biol Chem 273 (1998) 14813; FEBS Letters 496 (2001) 55). In the current study we wanted to further elucidate the effects of LPS on medfly hemocytes, in order to better understand the regulation of the evolutionary conserved signaling mechanisms between insects and mammals. We initially observed that different stimuli, including LPS, E. coli, RGD, fibronectin and heat shock activate hemocyte ERK. The response of hemocytes to these stimuli denoted that hemocyte ERK is evidently stimulated by at least an LPS receptor and via an integrin-mediated process. The medfly hemocytes respond to LPS by changing their morphology, inducing the activation of several signaling pathways, including Ras/MEK/ERK, PI-3K/ERK and Rho pathways and contributing to LPS uptake. Experiments based on inhibitors of specific signaling pathways, such as manumycin A, toxin A, U0126, PD98059 and wortmannin revealed that Ras, MEK and PI-3K are involved in the activation of ERK. Whether PI-3K is an intermediate of Ras/MEK/ERK pathway or activates ERK via other signaling pathway it remains to be elucidated. ERK is not activated via Rho pathway, denoting that Rho may not be an upstream effector molecule of ERK pathway. Regarding the role(s) that these kinases play in hemocytes, it can be suggested that PI-3K and Rho GTPases can modulate hemocyte shape changes, whereas ERK, Ras and MEK cannot. In addition, PI-3K as well as Ras and MEK through ERK activation participate in LPS endocytosis. Therefore, PI-3K shares a dual role; it is involved both in cell shape changes and in LPS endocytosis. Since ERK activation appears to be independent of the integrity of actin filaments, as cytochalasin D and latrunculin A did not block ERK activation, it can be concluded that LPS endocytosis is independent of actin cytoskeleton remodeling as is the case in mammalian systems.
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PMID:Distinct LPS-induced signals regulate LPS uptake and morphological changes in medfly hemocytes. 1456 59

Integrins are found in adhesion structures, which link the extracellular matrix to cytoskeletal proteins. Here, we attempt to further define the distribution of beta1 integrins in the context of their association with matrix proteins and other cell surface molecules relevant to the endocytic process. We find that beta1 integrins colocalize with fibronectin in fibrillar adhesion structures. A fraction of caveolin is also organized along these adhesion structures. The extracellular matrix protein laminin is not concentrated in these structures. The alpha4beta1 integrin exhibits a distinct distribution from other beta1 integrins after cells have adhered for 1 h to extracellular matrix proteins but is localized in adhesion structures after 24 h of adhesion. There are differences between the fibronectin receptors: alpha5beta1 integrins colocalize with adaptor protein-2 in coated pits, while alpha4beta1 integrins do not. This parallels our earlier observation that of the two laminin receptors, alpha1beta1 and alpha6beta1, only alpha1beta1 integrins colocalize with adaptor protein-2 in coated pits. Calcium chelation or inhibition of mitogen-activated protein kinase kinase, protein kinase C, or src did not affect localization of alpha1beta1 and alpha5beta1 integrins in coated pits. Likewise, the integrity of coated-pit structures or adhesion structures is not required for integrin and adaptor protein-2 colocalization. This suggests a robust and possibly constitutive interaction between these integrins and coated pits.
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PMID:Beta1 integrins are distributed in adhesion structures with fibronectin and caveolin and in coated pits. 1456 97

Expression of the Bcr-Abl oncoprotein alters various aspects of hematopoietic cells. We investigated the effects of a Bcr-Abl tyrosine kinase inhibitor, imatinib mesylate, on the proliferation, adhesive properties, and morphology of a Bcr-Abl-transferred cell line, TF-1 Bcr-Abl, in comparison with parental TF-1. First, the factor-independent growth of TF-1 Bcr-Abl was inhibited in the presence of imatinib mesylate, but this inhibition was overcome by addition of exogenous granulocyte-macrophage colony-stimulating factor. Imatinib mesylate remarkably reduced tyrosine phosphorylation of Bcr-Abl, Cbl, and Crkl in a time-dependent manner, and their complex formation also was affected. Imatinib mesylate inhibited activation of Stat5 rather than the MEK-ERK1/2 pathway. TF-1 Bcr-Abl cells exhibited a round shape, unlike TF-1, and the adhesive property to fibronectin was much lower than that of TF-1. Although the Bcr-Abl oncoprotein may be involved negatively in cell adhesion, the decreased adhesion and altered morphology of TF-1 Bcr-Abl cells were minimally affected by imatinib mesylate and seemed independent of Bcr-Abl kinase activity. The present data indicated that the Bcr-Abl-specific kinase inhibitor cannot control Bcr-Abl-induced cell alterations other than autonomous growth.
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PMID:Effects of the tyrosine kinase inhibitor imatinib mesylate on a Bcr-Abl-positive cell line: suppression of autonomous cell growth but no effect on decreased adhesive property and morphological changes. 1460 82

Integrin-mediated adhesion and B cell antigen receptor (BCR) signaling play a critical role in B cell development and function, including antigen-specific B cell differentiation. Here we show that the BCR controls integrin alpha4beta1 (VLA-4)-mediated adhesion of B cells to vascular cell adhesion molecule-1 and fibronectin. Molecular dissection of the underlying signaling mechanism by a combined biochemical, pharmacological, and genetic approach demonstrates that this BCR-controlled integrin-mediated adhesion requires the (consecutive) activation of Lyn, Syk, phosphatidylinositol 3-kinase, Bruton's tyrosine kinase (Btk), phospholipase C (PLC)gamma2, IP3R-mediated Ca2+ release, and PKC. In contrast, activation of mitogen-activated protein kinase kinase (MEK) or extracellular signal-regulated kinase (ERK) is not required, and simultaneous activation of MEK, ERK, and PKB is not sufficient either. Furthermore, Btk is also involved in the control of integrin-mediated adhesion of preB cells. The control of integrin alpha4beta1-mediated B cell adhesion by the BCR involves cytoskeletal reorganization and integrin clustering. These results reveal a novel function for the BCR and Btk, i.e., regulation of integrin alpha4beta1 activity, thereby providing new insights into the control of B cell development and differentiation, as well as into the pathogenesis of the immunodeficiency disease X-linked agammaglobulineamia (XLA).
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PMID:The B cell antigen receptor controls integrin activity through Btk and PLCgamma2. 1461 42

Interactions between pharmacologic NF-kappaB inhibitors (eg, Bay 11-7082, SN-50) and the checkpoint abrogator UCN-01 have been examined in human multiple myeloma (MM) cells. Exposure of U266 cells to Bay 11-7082 (Bay) in combination with UCN-01 resulted in the abrogation of NF-kappaB/DNA binding activity and the synergistic induction of apoptosis. Comparable synergism was observed in other MM cell lines and patient-derived CD138+ cells and between an inhibitory peptide of NF-kappaB (SN50) and UCN-01. Bay/UCN-01-mediated lethality involved mitochondrial dysfunction, caspase cleavage, and poly adenosine diphosphate-ribose polymerase (PARP) degradation. Although Bay modestly blocked UCN-01-induced extracellular signal-regulated kinase (ERK) phosphorylation, coadministration activated c-Jun N-terminal kinase (JNK) and cdc2/cdk1 and down-regulated Mcl-1, XIAP, and Bcl-xL. Transfection with a constitutively activated mitogen-activated protein kinase kinase (MEK1)/green fluorescent protein (GFP) construct failed to block apoptosis induced by Bay/UCN-01 but significantly attenuated MEK inhibitor (U0126)/UCN-01-induced lethality. Inhibiting JNK activation with SP600125 or D-JNKI1 peptide markedly reduced Bay/UCN-01-mediated mitochondrial dysfunction and apoptosis and the down-regulation of Mcl-1, XIAP, and Bcl-xL but not of cdc2/cdk1 activation. Stable transfection of cells with dominant-negative caspase-9 dramatically diminished Bay/UCN-01 lethality without altering JNK or cdc2/cdk1 activation. Neither interleukin-6 (IL-6)- nor fibronectin-mediated adherence conferred resistance to Bay/UCN-01-induced apoptosis. Together, these findings suggest that a strategy combining UCN-01 with disruption of the IkappaB kinase (IKK)/IkappaB/NF-kappaB pathway warrants attention in MM.
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PMID:Interruption of the NF-kappaB pathway by Bay 11-7082 promotes UCN-01-mediated mitochondrial dysfunction and apoptosis in human multiple myeloma cells. 1464 3

The natriuretic peptides, including human B-type natriuretic peptide (BNP), have been implicated in the regulation of cardiac remodeling. Because transforming growth factor-beta (TGF-beta) is associated with profibrotic processes in heart failure, we tested whether BNP could inhibit TGF-beta-induced effects on primary human cardiac fibroblasts. BNP inhibited TGF-beta-induced cell proliferation as well as the production of collagen 1 and fibronectin proteins as measured by Western blot analysis. cDNA microarray analysis was performed on RNA from cardiac fibroblasts incubated in the presence or absence of TGF-beta and BNP for 24 and 48 hours. TGF-beta, but not BNP, treatment resulted in a significant change in the RNA profile. BNP treatment resulted in a remarkable reduction in TGF-beta effects; 88% and 85% of all TGF-beta-regulated mRNAs were affected at 24 and 48 hours, respectively. BNP opposed TGF-beta-regulated genes related to fibrosis (collagen 1, fibronectin, CTGF, PAI-1, and TIMP3), myofibroblast conversion (alpha-smooth muscle actin 2 and nonmuscle myosin heavy chain), proliferation (PDGFA, IGF1, FGF18, and IGFBP10), and inflammation (COX2, IL6, TNFalpha-induced protein 6, and TNF superfamily, member 4). Lastly, BNP stimulated the extracellular signal-related kinase pathway via cyclic guanosine monophosphate-dependent protein kinase signaling, and two mitogen-activated protein kinase kinase inhibitors, U0126 and PD98059, reversed BNP inhibition of TGF-beta-induced collagen-1 expression. These findings demonstrate that BNP has a direct effect on cardiac fibroblasts to inhibit fibrotic responses via extracellular signal-related kinase signaling, suggesting that BNP functions as an antifibrotic factor in the heart to prevent cardiac remodeling in pathological conditions.
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PMID:B-type natriuretic peptide exerts broad functional opposition to transforming growth factor-beta in primary human cardiac fibroblasts: fibrosis, myofibroblast conversion, proliferation, and inflammation. 1472 74

Prostaglandin E(2) (PGE(2)), a major cyclooxygenase (COX-2) metabolite, plays important roles in tumor biology and its functions are mediated through one or more of its receptors EP1, EP2, EP3, and EP4. We have shown that the matrix glycoprotein fibronectin stimulates lung carcinoma cell proliferation via induction of COX-2 expression with subsequent PGE(2) protein biosynthesis. Ligands of peroxisome proliferator-activated receptor gamma (PPARgamma) inhibited this effect and induced cellular apoptosis. Here, we explore the role of the PGE(2) receptor EP2 in this process and whether the inhibition observed with PPARgamma ligands is related to effects on this receptor. We found that human non-small cell lung carcinoma cell lines (H1838 and H2106) express EP2 receptors, and that the inhibition of cell growth by PPARgamma ligands (GW1929, PGJ2, ciglitazone, troglitazone, and rosiglitazone [also known as BRL49653]) was associated with a significant decrease in EP2 mRNA and protein levels. The inhibitory effects of BRL49653 and ciglitazone, but not PGJ2, were reversed by a specific PPARgamma antagonist GW9662, suggesting the involvement of PPARgamma-dependent and -independent mechanisms. PPARgamma ligand treatment was associated with phosphorylation of extracellular regulated kinase (Erk), and inhibition of EP2 receptor expression by PPARgamma ligands was prevented by PD98095, an inhibitor of the MEK-1/Erk pathway. Butaprost, an EP2 agonist, like exogenous PGE(2) (dmPGE(2)), increased lung carcinoma cell growth, however, GW1929 and troglitazone blocked their effects. Our studies reveal a novel role for EP2 in mediating the proliferative effects of PGE(2) on lung carcinoma cells. PPARgamma ligands inhibit human lung carcinoma cell growth by decreasing the expression of EP2 receptors through Erk signaling and PPARgamma-dependent and -independent pathways.
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PMID:Suppression of prostaglandin E2 receptor subtype EP2 by PPARgamma ligands inhibits human lung carcinoma cell growth. 1475 Dec 45


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