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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This report describes induction of HIV-1 resistance and synthesis of resistance factors in immortal CD4-positive T lymphocytes. SupT1 cells were infected by NL4-3 attenuated by a defect in the vif gene through coculture with infected primary lymphocytes. Cell lines from this infection, termed R1, expressed CD4 and CXCR4, carried low levels of HIV-1 DNA, but expressed no other detectable viral products and were resistant to infection by wild-type HIV-1. Investigation of challenge infection in resistant R1 lines demonstrated entry, reverse transcription, and integration by incoming HIV-1 but no synthesis of viral RNA. By assay of marker gene expression, we found that Tat was unable to activate LTR-driven transcription in R1 lines. HIV-1-resistant R1 lines secreted soluble factors that inhibited productive infection of primary lymphocytes by several strains of HIV-1 and blocked viral RNA synthesis in newly infected cells. Resistance factors also blocked the induction of HIV-1 transcription in ACH-2 cells as assayed by viral antigen expression and Northern blot of viral RNA. Soluble factors produced by HIV-1-resistant, immortal R1 cells may form the basis of new approaches to control HIV-1 infection.
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PMID:Induction of secreted human immunodeficiency virus type 1 (HIV-1) resistance factors in CD4-positive T lymphocytes by attenuated HIV-1 infection. 1188 60

Chemotaxis mediated by chemokine receptors such as CXCR4 plays a key role in lymphocyte homing and hematopoiesis as well as in breast cancer metastasis. We have demonstrated previously that beta-arrestin2 functions to attenuate CXCR4-mediated G protein activation and to enhance CXCR4 internalization. Here we show further that the expression of beta-arrestin2 in both HeLa and human embryonic kidney 293 cells significantly enhances the chemotactic efficacy of stromal cell-derived factor 1alpha, the specific agonist of CXCR4, whereas the suppression of beta-arrestin2 endogenous expression by antisense or RNA-mediated interference technology considerably attenuates stromal cell-derived factor 1alpha-induced cell migration. Expression of beta-arrestin2 also augmented chemokine receptor CCR5-mediated but not epidermal growth factor receptor-mediated chemotaxis, indicating the specific effect of beta-arrestin2. Further analysis reveals that expression of beta-arrestin2 strengthened CXCR4-mediated activation of both p38 MAPK and ERK, and the suppression of beta-arrestin2 expression blocked the activation of two kinases. Interestingly, inhibition of p38 MAPK activation (but not ERK activation) by its inhibitors or by expression of a dominant-negative mutant of p38 MAPK effectively blocked the chemotactic effect of beta-arrestin2. Expression of a dominant-negative mutant of ASK1 also exerted the similar blocking effect. The results of our study suggest that beta-arrestin2 can function not only as a regulator of CXCR4 signaling but also as a mediator of stromal cell-derived factor 1alpha-induced chemotaxis and that this activity probably occurs via the ASK1/p38 MAPK pathway.
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PMID:Beta-arrestin2 is critically involved in CXCR4-mediated chemotaxis, and this is mediated by its enhancement of p38 MAPK activation. 1237 Jan 87

The CXCR4 chemokine receptor is a G(i) protein-coupled receptor that triggers multiple intracellular signals in response to stromal cell-derived factor 1 (SDF-1), including calcium mobilization and p44/42 extracellular signal-regulated kinases (ERK1/2). Transduced signals lead to cell chemotaxis and are terminated through receptor internalization depending on phosphorylation of the C terminus part of CXCR4. Receptor endocytosis is also required for some receptors to stimulate ERK1/2 and to migrate through a chemokine gradient. In this study, we explored the role played by the 3 intracellular loops (ICL1-3) and the C terminus domain of CXCR4 in SDF-1-mediated signaling by using human embryonic kidney (HEK)-293 cells stably expressing wild-type or mutated forms of CXCR4. ICL3 of CXCR4 is specifically involved in G(i)-dependent signals such as calcium mobilization and ERK activation, but does not trigger CXCR4 internalization after SDF-1 binding, indicating that ERK phosphorylation is independent of CXCR4 endocytosis. Surprisingly, ICL2, with or without the aspartic acid, arginine, and tyrosine (DRY) motif, is dispensable for G(i) signaling. However, ICL2 and ICL3, as well as the C terminus part of CXCR4, are needed to transduce SDF-1-mediated chemotaxis, suggesting that this event involves multiple activation pathways and/or cooperation of several cytoplasmic domains of CXCR4.
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PMID:Role of the intracellular domains of CXCR4 in SDF-1-mediated signaling. 1239 63

T cells migrate into inflamed sites through the extracellular matrix (ECM) in response to chemotactic areas and are then simultaneously or sequentially exposed to multiple chemotactic ligands. We examined the responses of human peripheral blood T cells, present in an ECM-like context, to combinatorial signaling transduced by SDF-1alpha (CXCL12), and two CCR5 ligands, RANTES (CCL5) and MIP-1beta (CCL4). Separately, these chemokines, at G protein-coupled receptor (GPCR)-stimulating concentrations, induced T cell adhesion to fibronectin (FN) and T cell chemotaxis. However, the pro-adhesive and pro-migratory capacities of SDF-1alpha and RANTES or MIP-1beta were mutually suppressed by the simultaneous or sequential exposure of the cells to these CCR5 or CXCR4 ligands. This cross-talk did not involve the internalization of the SDF-1alpha receptor, CXCR4, but rather, a decrease in phosphorylation of ERK and Pyk-2, as well as inhibition of Ca(2+) mobilization. Strikingly, early CXCR4 signaling of phosphatidylinositol-3-kinase, detected by SDF-1alpha-induced AKT phosphorylation, was insensitive to RANTES-CCR5 signals. Accordingly, early chemotaxis to SDF-1alpha was not susceptible to CCR5 occupancy, whereas late stages of T cell chemotaxis were markedly down-regulated. This is an example of a specialized functional desensitization of heterologous chemokine receptors that induces GPCR interference with T cell adhesion to ECM ligands and chemotaxis within chemokine-rich extravascular contexts.
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PMID:Heterologous desensitization of T cell functions by CCR5 and CXCR4 ligands: inhibition of cellular signaling, adhesion and chemotaxis. 1250 23

While HIV has subverted the chemokine receptors CCR5 and CXCR4 for its own use as an entry co-receptor, their normal functions are to transduce signals in response to extracellular ligands. Our lab is interested in understanding how HIV-1 glycoprotein 120 (gp120) may activate intracellular signals through these receptors in primary human macrophages, and how these responses may contribute to pathogenesis. Our studies demonstrate HIV-1 gp120 elicits several different types of signals in macrophages through CXCR4 and CCR5, including calcium elevations, ionic channel activation, non-receptor protein tyrosine kinase activation, and activation of MAP kinases. Receptor activation is triggered by both monomeric gp120 and whole HIV virus. Furthermore, gp120 elicits a number of functional responses in macrophages, such as secretion of chemokines and other soluble products, and we demonstrate that specific pathways linked to the chemokine receptors are responsible. These studies help illuminate the pathways through which chemokine receptors are coupled in primary macrophages, and provide a mechanistic basis for effects that HIV has on macrophage function. These signaling responses may play a role in the pathogenesis of organ dysfunction such as HIV encephalopathy and lymphocytic interstitial pneumonitis where macrophages are the principal infected cell type and inappropriate immune activation plays a central role.
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PMID:HIV-1 Env-chemokine receptor interactions in primary human macrophages: entry and beyond. 1284 69

We studied whether signaling through CD30, a member of the TNF receptor family, affected acute infection with HIV-1, encompassing its entire replicative cycle. Several non-Hodgkin cell lines, targets of CXCR4-dependent (X4) HIV-1 infection, were positive for CD30 expression. CD30 ligation induced up-regulation of viral replication only in certain CD30+ cell lines. Enhancement of X4 virus replication by CD30 engagement inversely correlated with both CD30 surface density and constitutive NF-kappaB activation. Conversely, expression of CD30, but not of other members of the TNF receptor family, was proportional to constitutive NF-kappaB binding. Concomitantly, secretion of soluble (s) CD30 increased in all cell lines by CD30 ligation. sCD30 release was enhanced by engagement of CD30 alone and, to a greater extent, by co-engagement of CD3 also in primary gamma delta T lymphocytes, along with complementary modulations of their surface CD30 expression. sCD30-containing supernatant specifically inhibited HIV-1 expression induced by CD30 engagement in chronically infected ACH-2 T cells; thus sCD30 may act as a negative feed-back molecule. In conclusion, we have delineated novel features of CD30 biology and underline the peculiar link of CD30 expression to constitutive NF-kappaB activation which is pivotal to both HIV replication and cell survival.
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PMID:CD30 ligation differentially affects CXCR4-dependent HIV-1 replication and soluble CD30 secretion in non-Hodgkin cell lines and in gamma delta T lymphocytes. 1457 82

To identify genes involved in the transformation of thyroid follicular cells, we explored, using DNA oligonucleotide microarrays, the transcriptional response of PC Cl3 rat thyroid epithelial cells to the ectopic expression of the RET/PTC oncogenes. We found that RET/PTC was able to induce the expression of CXCR4, the receptor for the chemokine CXCL12/SDF-1alpha/beta. We observed that CXCR4 expression correlated with the transforming ability of the oncoprotein and depended on the integrity of the RET/PTC-RAS/ERK signaling pathway. We found that CXCR4 was expressed in RET/PTC-positive human thyroid cancer cell lines, but not in normal thyroid cells. Furthermore, we found CXCR4 expression in human thyroid carcinomas, but not in normal thyroid samples by immunohistochemistry. Since CXCR4 has been recently implicated in tumor proliferation, motility and invasiveness, we asked whether treatment with SDF-1alpha was able to induce a biological response in thyroid cells. We observed that SDF-1alpha induced S-phase entry and survival of thyroid cells. Invasion through a reconstituted extracellular matrix was also supported by SDF-1alpha and inhibited by a blocking antibody to CXCR4. Taken together, these results suggest that human thyroid cancers bearing RET/PTC rearrangements may use the CXCR4/SDF-1alpha receptor-ligand pathway to proliferate, survive and migrate.
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PMID:Functional expression of the CXCR4 chemokine receptor is induced by RET/PTC oncogenes and is a common event in human papillary thyroid carcinomas. 1518 68

Infusion of different hematopoietic stem cell populations and ex vivo expanded endothelial progenitor cells augments neovascularization of tissue after ischemia and contributes to reendothelialization after endothelial injury, thereby, providing a novel therapeutic option. However, controversy exists with respect to the identification and the origin of endothelial progenitor cells. Overall, there is consensus that endothelial progenitor cells can derive from the bone marrow and that CD133/VEGFR2 cells represent a population with endothelial progenitor capacity. However, increasing evidence suggests that there are additional bone marrow-derived cell populations (eg, myeloid cells, "side population" cells, and mesenchymal cells) and non-bone marrow-derived cells, which also can give rise to endothelial cells. The characterization of the different progenitor cell populations and their functional properties are discussed. Mobilization and endothelial progenitor cell-mediated neovascularization is critically regulated. Stimulatory (eg, statins and exercise) or inhibitory factors (risk factors for coronary artery disease) modulate progenitor cell levels and, thereby, affect the vascular repair capacity. Moreover, recruitment and incorporation of endothelial progenitor cells requires a coordinated sequence of multistep adhesive and signaling events including adhesion and migration (eg, by integrins), chemoattraction (eg, by SDF-1/CXCR4), and finally the differentiation to endothelial cells. This review summarizes the mechanisms regulating endothelial progenitor cell-mediated neovascularization and reendothelialization.
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PMID:Endothelial progenitor cells: characterization and role in vascular biology. 1532 44

The receptor tyrosine kinases (RTKs) RET, MET, and RON all carry the Met(p+1loop)-->Thr point mutation (i.e., 2B mutation), leading to the formation of tumors with high metastatic potential. Utilizing a novel antibody array, we identified constitutive phosphorylation of STAT3 in cells expressing the 2B mutation but not wild-type RET. MET or RON with the 2B mutation also constitutively phosphorylated STAT3. Members of the EPH, the only group of wild-type RTK that carry Thr(p+1loop) residue, are often expressed unexpectedly in different types of cancers. Ectopic expression of wild-type but not Thr(p+1loop)-->Met substituted EPH family members constitutively phosphorylated STAT3. In both RTK(Metp+1loop) with 2B mutation and wild-type EPH members the Thr(p+1loop) residue is required for constitutive kinase autophosphorylation and STAT3 recruitment. In multiple endocrine neoplasia 2B (MEN-2B) patients expressing RET(M918T), nuclear enrichment of STAT3 and elevated expression of CXCR4 was detected in metastatic thyroid C-cell carcinoma in the liver. In breast adenocarcinoma cell lines expressing multiple EPH members, STAT3 constitutively bound to the promoters of MUC1, MUC4, and MUC5B genes. Inhibiting STAT3 expression resulted in reduced expression of these metastasis-related genes and inhibited mobility. These findings provide insight into Thr(p+1loop) residue in RTK autophosphorylation and constitutive activation of STAT3 in metastatic cancer cells.
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PMID:Central role of the threonine residue within the p+1 loop of receptor tyrosine kinase in STAT3 constitutive phosphorylation in metastatic cancer cells. 1548 8

Unlocking the mysteries of cell metastasis, a major cause of cancer mortality, is essential in the development of novel therapies. In this issue of Cancer Cell, Li et al. (2004) identify a link between HER2 and CXCR4, two receptors previously implicated in breast cancer progression and metastasis. HER2 enhances the expression of CXCR4 by stimulating CXCR4 translation and attenuating CXCR4 degradation. Importantly, coexpression of HER2 and CXCR4 occurs in approximately 22% of human breast tumors and correlates with poor survival of breast cancer patients.
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PMID:A new key in breast cancer metastasis. 1554 30


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