Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proline-, glutamic acid-, and leucine-rich protein-1 (PELP1) is a novel estrogen receptor coactivator that plays an important role in the genomic and nongenomic actions of estrogen receptor by interacting with histones and src-mitogen-activated protein kinase pathway, respectively. A great deal of information has emerged in recent years about the possible role of PELP1 in estrogen receptor signaling. However, the participation and significance of PELP1 in other cellular signaling pathways remains unknown. Using a yeast two-hybrid screen, we identified PELP1 as a novel interacting protein of signal transducers and activators of transcription 3 (STAT3) and found evidence of physiologic interaction between PELP1 and STAT3. We also found that these interactions played a mechanistic role in the positive regulation of STAT3 transcription from synthetic promoters and endogenous target genes such as cyclin D1, c-myc, and c-fos. Overexpression of PELP1 enhanced phosphorylation of STAT3 at Ser727 in a src-mitogen-activated protein kinase-sensitive manner and, conversely, down-regulation of PELP1 compromised growth factor-mediated induction of STAT3 target genes. We also discovered that PELP1 interacts with STAT3 in the nuclear compartment and down-regulation of PELP1 interfered with the recruitment of STAT3 to its target gene promoters. In summary, our results highlight a novel role for PELP1 in growth factor signaling and indicate that PELP1-mediated genomic and nongenomic functions play a role in the growth factor-mediated STAT3 transactivation functions. Such regulatory interactions of PELP1 may have important functional implications in the cross-talk of estrogen receptor and growth factor signaling.
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PMID:Proline-, glutamic acid-, and leucine-rich protein-1 is essential in growth factor regulation of signal transducers and activators of transcription 3 activation. 1599 29

It is increasingly accepted that steroidal receptor co-regulators may also function in the cytoplasmic compartment. Proline-, glutamic acid-, and leucine-rich protein-1 (PELP1) is a novel coregulator that plays a role in both the genomic and extranuclear actions of estrogen receptors (ER) in hormonally responsive tissues. In this study using breast tumor arrays, we found that PELP1 was localized only in the cytoplasm in 58% of the PELP1-positive breast tumors. To help explain the significance of the cytoplasmic localization of PELP1 in human breast tumors, we created a mutant protein that was expressed only in the cytoplasm (PELP1-cyto) and then generated a model system wherein MCF-7 breast cancer cells were engineered to specifically express this mutant. We found that PELP1-cyto cells were hypersensitive to estrogen but resistant to tamoxifen. PELP1-cyto cells, but not parental MCF-7 cells, formed xenograft tumors in nude mice. In addition, PELP1-cyto cells exhibited increased association of PELP1 with Src, enhanced mitogen-activated protein kinase (MAPK) activation, and constitutive activation of AKT. The altered localization of PELP1 was sufficient to trigger the interaction of PELP1 with the p85 subunit of phosphatidylinositol-3-kinase (PI3K), leading to PI3K activation. In addition, PELP1 interacted with epidermal growth factor receptors and participated in growth factor-mediated ER transactivation functions. Our results suggest that the altered localization of PELP1 modulates sensitivity to antiestrogens, potentiates tumorigenicity, presumably via the stimulation of extranuclear estrogen responses, such as the activation of MAPK and AKT, and also enhance cross-regulation of ER transactivation activity by growth factors.
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PMID:Functional implications of altered subcellular localization of PELP1 in breast cancer cells. 1614 Sep 40

The EGFR/Ras/Raf/MEK/ERK pathway is a major pathway involved in the control of growth signals, cell survival and differentiation. Mutations of signaling components, such as EGFR (c-erbB1), Ras, and B-Raf, have been shown to play roles in the genesis of human cancer, while point mutation of ERK has not been reported. In this study, we present evidence for a mutation in an oral squamous cell carcinoma cell line, HSC6. PCR-amplification of cDNA, cloning and sequencing resulted in the identification of glutamic acid to lysine substitution at codon 322 (E322K) that occurred in the common docking (CD) domain of ERK2. The mutant protein contributed towards faster-migration in SDS-PAGE, and constitutive phosphorylation in a MEK-dependent manner. The transient transfection of the mutant ERK2 in 293T cells resulted in the expression of the same faster-migrating band in SDS-PAGE as was detected in HSC6 cells, which was preferentially phosphorylated relative to endogenous wild-type ERK2. The present study is the first to report ERK2 substitution mutation in a human cancer cell line which resulted in constitutive phosphorylation.
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PMID:A mutation in the common docking domain of ERK2 in a human cancer cell line, which was associated with its constitutive phosphorylation. 1627 4

PELP1 (proline-, glutamic acid-, and leucine-rich protein-1) (also known as the modulator of nongenomic activity of estrogen receptor) plays a role in genomic functions of the estrogen receptor via histone interactions and in nongenomic functions via its influence on the MAPK-Src pathway. However, recent studies have shown that differential compartmentalization of PELP1 could play a crucial role in modulating the status of nongenomic signaling by using molecular mechanisms that remain poorly understood. Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) is an early endosomal protein that plays a role in regulating the trafficking of growth factor-receptor complexes through early endosomes. By using a yeast two-hybrid screen, we identified HRS as a novel PELP1-binding protein providing evidence of a physiologic interaction between HRS and PELP1. The noted HRS-PELP1 interaction was accompanied by inhibition of the basal coactivator function of PELP1 upon estrogen receptor transactivation. HRS was found to sequester PELP1 in the cytoplasm, leading to the activation of MAPK in a manner that is dependent on the epidermal growth factor receptor but independent of the estrogen receptor, Shc, and Src. In addition, stimulation of MAPK and the subsequent activation of its downstream effector pathway, Elk-1, by HRS or PELP1 were found to depend on the presence of endogenous PELP1 or HRS. Furthermore, HRS was overexpressed and correlated well with the cytoplasmic PELP1, increased MAPK, and EGFR status in breast tumors. These findings highlight a novel role of HRS in up-regulating MAPK, presumably involving interaction with PELP1.
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PMID:Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) interacts with PELP1 and activates MAPK. 1635 11

Glucocorticoid hormones have complex stimulatory and inhibitory effects on skeletal metabolism. Endogenous glucocorticoid signaling is required for normal bone formation in vivo, and synthetic glucocorticoids, such as dexamethasone, promote osteoblastic differentiation in several in vitro model systems. The mechanism by which these hormones induce osteogenesis remains poorly understood. We demonstrate here that the coordinate action of dexamethasone and the osteogenic transcription factor Runx2/Cbfa1 synergistically induces osteocalcin and bone sialoprotein gene expression, alkaline phosphatase activity, and biological mineral deposition in primary dermal fibroblasts. Dexamethasone decreased Runx2 phosphoserine levels, particularly on Ser125, in parallel with the upregulation of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) through a glucocorticoid-receptor-mediated mechanism. Inhibition of MKP-1 abrogated the dexamethasone-induced decrease in Runx2 serine phosphorylation, suggesting that glucocorticoids modulate Runx2 phosphorylation via MKP-1. Mutation of Ser125 to glutamic acid, mimicking constitutive phosphorylation, inhibited Runx2-mediated osteoblastic differentiation, which was not rescued by dexamethasone treatment. Conversely, mutation of Ser125 to glycine, mimicking constitutive dephosphorylation, markedly increased osteoblastic differentiation, which was enhanced by, but did not require, additional dexamethasone supplementation. Collectively, these results demonstrate that dexamethasone induces osteogenesis, at least in part, by modulating the phosphorylation state of a negative-regulatory serine residue (Ser125) on Runx2. This work identifies a novel mechanism for glucocorticoid-induced osteogenic differentiation and provides insights into the role of Runx2 phosphorylation during skeletal development.
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PMID:Glucocorticoid-induced osteogenesis is negatively regulated by Runx2/Cbfa1 serine phosphorylation. 1644 55

Several forms of cancer are characterized by frequent activating mutations in the serine/threonine kinase, BRAF. Substitution of glutamic acid for valine at codon 600 (V600E) accounts for approximately 90% of all BRAF activating mutations and leads to stimulation of kinase activity, downstream signaling, and cell transformation. To better understand the molecular pathogenesis induced by oncogenic BRAF signaling, we used microarray gene expression profiling to comprehensively analyze the BRAF-directed transcriptional program of cells expressing a conditionally active form of BRAFV600E. Several novel genes that affect proliferation, cell survival, angiogenesis and immune surveillance were identified as possible mediators of BRAF-induced oncogenic signaling. Moreover, we show that a MAPK family member, extracellular signal-regulated kinase-3 (ERK3/MAPK6) is highly expressed in response to BRAF signaling in this system. Cellular ERK3 protein is highly unstable and pharmacological inhibition of BRAF activity resulted in rapid ERK3 degradation. In melanoma cells, RNAi-mediated knockdown of endogenous BRAF or treatment with MEK inhibitors that prevent ERK1/2 activation led to a reduction in ERK3 levels, indicating that elevated ERK3 expression is mediated through MEK1/2 signaling. These results provide strong evidence for another mode by which BRAF can regulate the ERK protein kinase family and suggest ERK3 to be a potential pharmacodynamic marker for targeting BRAF signaling in melanoma.
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PMID:Regulation of ERK3/MAPK6 expression by BRAF. 1696 79

Blood vessel injury results in limited oxygen tension and diffusion leading to hypoxia, increased anaerobic metabolism, and elevated production of acidic metabolites that cannot be easily removed due to the reduced blood flow. Therefore, an acidic extracellular pH occurs in the local microenvironment of disrupted bone. The potential role of acidic pH and glu-leu-arg (ELR(+)) CXC chemokines in early events in bone repair was studied in human mesenchymal stem cells (hMSCs) treated with medium of decreasing pH (7.4, 7.0, 6.7, and 6.4). The cells showed a reciprocal increase in CXCL8 (interleukin-8, IL-8) mRNA levels as extracellular pH decreased. At pH 6.4, CXCL8 mRNA was induced >60x in comparison to levels at pH 7.4. hMSCs treated with osteogenic medium (OGM) also showed an increase in CXCL8 mRNA with decreasing pH; although, at a lower level than that seen in cells grown in non-OGM. CXCL8 protein was secreted into the medium at all pHs with maximal induction at pH 6.7. Inhibition of the G-protein-coupled receptor alpha, G(alphai), suppressed CXCL8 levels in response to acidic pH; whereas phospholipase C inhibition had no effect on CXCL8. The use of specific mitogen-activated protein kinase (MAPK) signal transduction inhibitors indicated that the pH-dependent increase in CXCL8 mRNA is due to activation of ERK and p38 pathways. The JNK pathway was not involved. NF-kappaB inhibition resulted in a decrease in CXCL8 levels in hMSCs grown in non-OGM. However, OGM-differentiated hMSCs showed an increase in CXCL8 levels when treated with the NF-kappaB inhibitor PDTC, a pyrrolidine derivative of dithiocarbamate.
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PMID:Acidic pH stimulates the production of the angiogenic CXC chemokine, CXCL8 (interleukin-8), in human adult mesenchymal stem cells via the extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and NF-kappaB pathways. 1827 43

Urokinase receptor (uPAR) plays a key role in physiological and pathological processes sustained by an altered cell migration. We have developed peptides carrying amino acid substitutions along the Ser(88)-Arg-Ser-Arg-Tyr(92) (SRSRY) uPAR chemotactic sequence. The peptide pyro glutamic acid (pGlu)-Arg-Glu-Arg-Tyr-NH2 (pERERY-NH(2)) shares the same binding site with SRSRY and competes with N-formyl-Met-Leu-Phe (fMLF) for binding to the G-protein-coupled N-formyl-peptide receptor (FPR). pERERY-NH(2) is a dose-dependent inhibitor of both SRSRY- and fMLF-directed cell migration, and prevents agonist-induced FPR internalization and fMLF-dependent ERK1/2 phosphorylation. pERERY-NH(2) is a new and potent uPAR inhibitor which may suggest the generation of new pharmacological treatments for pathological conditions involving increased cell migration.
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PMID:An urokinase receptor antagonist that inhibits cell migration by blocking the formyl peptide receptor. 1833 22

Bone sialoprotein (BSP) is an abundant protein in the extracellular matrix of bone that has been suggested to have several different physiological functions, including the nucleation of hydroxyapatite (HA), promotion of cell attachment and binding of collagen. Studies in our lab have demonstrated that increased expression of BSP in osteoblast cells can increase expression of the osteoblast-related genes Runx2 and Osx as well as alkaline phosphatase and osteocalcin and increase matrix mineralization. To determine the molecular mechanisms responsible for the BSP-mediated increase in osteoblastic differentiation, several functional domain mutants of BSP were expressed in primary rat bone osteoblastic cells, including the contiguous glutamic acid sequences (polyGlu) and the arginine-glycine-aspartic acid (RGD) motif. Markers of osteoblast differentiation, including matrix mineralization and alkaline phosphatase staining, were increased in cells expressing BSP mutants of the polyGlu sequences but not in cells expressing RGD-mutated BSP. We also determined the dependence on integrin-associated pathways in promoting BSP-mediated differentiation responses in osteoblasts by demonstrating the activation of focal adhesion kinase, MAP kinase-associated proteins ERK1/2, ribosomal s6 kinase 2 and the AP-1 protein cFos. Thus, the mechanism regulating osteoblast differentiation by BSP was determined to be dependent on integrin-mediated intracellular signaling pathways.
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PMID:Activation of the mitogen-activated protein kinase pathway by bone sialoprotein regulates osteoblast differentiation. 1872 50

Living organisms are subject to stress, and among these stressors, heavy metals exposure triggers accumulation of sulfur metabolites. Among these metabolites, glutathione and phytochelatins are found in several organisms, such as Euglena gracilis. Pre-exposing E. gracilis to low concentrations of Hg2+ generates a population with resistance to even 0.2 mM Cd2+, and this resistance relies partly on phytochelatins. p38 MAPK is stimulated by stress and is involved in apoptotic as well as survival mechanisms. In this study, we explored its participation in heavy metal-induced stress and its possible role in sulfur metabolite accumulation. We found that about 51% of the E. gracilis pretreated with Hg2+ becomes resistant to Cd2+ and proliferates despite the presence of this metal. The accumulation of the sulfur metabolites gamma-glu-cys, glutathione and phytochelatin 2 displayed cyclic patterns that were disturbed by a challenge with Cd2+. We observed a p38 MAPK-like activity that was stimulated by acute or chronic heavy metal exposure, and its inhibition by SB203580 slightly diminished the accumulation of sulfur compounds. p38 MAPK inhibition also affected basal levels of glutathione in either pretreated or control cells. Thus, it appears that p38 MAPK mediates redox stress component of the signal pathway induced by heavy metals.
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PMID:p38 MAPK as a signal transduction component of heavy metals stress in Euglena gracilis. 1876 12


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