UNIPROT:P31749 - FACTA Search

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Query: UNIPROT:P31749 (AKT)
22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to learn more on the role of chemokines in the regulation of human megakryopoiesis. Normal human megakaryoblasts were expanded in serum-free liquid cultures and subsequently (1) phenotyped for expression of various chemokine receptors, (2) evaluated if chemokine receptors which they express are functional after stimulation by chemokines (calcium flux assay, chemotaxis, phosphorylation of MAPK-p42/44 and AKT proteins), and (3) investigated for expression and secretion of selected chemokines by employing RT-PCR and ELISA assays, respectively. In addition we also phenotyped peripheral blood platelets for expression of chemokine receptors and chemokines. We found that while human megakaryoblasts express several chemokine receptors (CXCR4, CCR6, CCR8, CCR5, CCR2 and CXCR3), CXCR4 was the only receptor detectable by FACS on human platelets. Moreover, among various chemokines tested, only SDF-1 (CXCR4 ligand) stimulated calcium flux and chemotaxis in normal human megakaryoblasts and phosphorylated MAPK-p42/44 and AKT in these cells. Although mRNAs for several chemokines were detectable by RT-PCR in normal human megakaryoblasts, only RANTES, IL-8, MCP-1 and PF-4 were found to be secreted by these cells. Finally we noticed that no chemokine tested in this study affected CFU-Meg colony formation by human CD34+ cells in serum-free cultures. We conclude that from all the chemokine receptor-chemokine axes tested, only SDF-1-CXCR4 axis was functional in assays employed in our studies, which further support the view that this axis plays a privileged role in regulating normal human megakaryopoiesis.
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PMID:Biological significance of chemokine receptor expression by normal human megakaryoblasts. 1153 79

To better define the role HIV-related chemokine receptor-chemokine axes play in human hematopoiesis, we investigated the function of the CXCR4 and CCR5 receptors in human myeloid, T- and B-lymphoid cell lines selected for the expression of these receptors (CXCR4(+), CXCR4(+) CCR5(+), and CCR5(+) cell lines). We evaluated the phosphorylation of MAPK p42/44, AKT, and STAT proteins and examined the ability of the ligands for these receptors (stromal-derived factor-1 [SDF-1] and macrophage inflammatory protein-1beta [MIP-1beta]) to influence cell growth, apoptosis, adhesion, and production of vascular endothelial growth factors (VEGF), matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in these cell lines. We found that A) SDF-1, after binding to CXCR4, activates multiple signaling pathways and that in comparison with the MIP-1beta-CCR5 axis, plays a privileged role in hematopoiesis; B) SDF-1 activation of the MAPK p42/44 pathway and the PI-3K-AKT axis does not affect proliferation and apoptosis but modulates integrin-mediated adhesion to fibronectin, and C) SDF-1 induces secretion of VEGF, but not of MMPs or TIMPs. Thus the role of SDF-1 relates primarily to the interaction of lymphohematopoietic cells with their microenvironment and does not directly influence their proliferation or survival. We conclude that perturbation of the SDF-1-CXCR4 axis during HIV infection may affect interactions of hematopoietic cells with the hematopoietic microenvironment.
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PMID:The SDF-1-CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lymphohematopoietic cells. 1155 54

Cells that display chemokine receptors are capable of responding to a gradient of chemokine with a motility response that can translate into a chemotactic response. This continuous response to the chemokine sometimes requires that the chemokine receptor be internalized and recycled back to the membrane. We have shown that ligand activation of the CXC chemokine receptor, CXCR2, results in movement of the receptor into clathrin coated pits, followed by movement into the early endosome, the sorting endosome, then on to the recycling endosome prior to trafficking back into the plasma membrane compartment. Prolonged exposure to saturating concentrations of the ligand results in movement of a large percentage of the receptor into the late endosome and on to the lysosome for degradation. Mutation of the receptor in a manner which impairs receptor internalization by altering the binding of adaptor proteins AP-2 or beta arrestin to CXCR2, results in a marked reduction in the chemotactic response. Chemokine receptors also activate multiple intracellular signals that lead to the activation of the transcription factor, nuclear factor kappa beta (NF-kappaB). Transformation is often associated with a constitutive activation of NF-kappaB, leading to endogenous expression of chemokines and their receptors. This creates an autocrine loop with NF-kappaB in the activated state, and altered cxpression of factors that promote tumour angiogenesis and escape from apoptosis. We have shown that the constitutive activation of NF-kappaB in human melanoma tumours is accompanied by constitutive activation of the NF-kappaB inducing kinase (NIK) as well as the constitutive activation of AKT. As these factors that modulate the expression of anti-apoptotic factors work together, the tumour cells exhibit enhanced survival and growth. This never ending cycle of activation of NF-kappaB, leading to enhanced production of chemokines, enhanced activation of AKT and NF-kappaB, and enhanced transcription of inhibitors of apoptosis and chemokines, is one that has been used to foster the growth of the tumour to the disadvantage of the host. Thus we propose that blocking CXCR2 and/or NF-kappaB offers potential therapeutic promise for a number of chronic inflammatory conditions and cancers, including malignant melanoma.
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PMID:How do chemokine/chemokine receptor activations affect tumorigenesis? 1502 84

In this study, we show that IFNalpha increases the chemotaxis of human B cells to CCL20, CCL21 and CXCL12 in a dose- and time-dependent manner. The effect was maximal with 2000 IU ml(-1) IFNalpha. It peaked at 24 h and decreased thereafter. At 24 h, IFNalpha had increased B-cell chemotaxis to CCL20 by 20 +/- 6.2% (n = 9, P < 0.002), to CCL21 by 20 +/- 8.5% (n = 14, P < 0.0001) and to CXCL12 by 16.3 +/- 4.2% (n = 12, P < 0.003) without changing CCR6, CCR7 or CXCR4 expression. IFNalpha enhanced the migration of memory B cells to CCL20, CCL21 and CXCL12 2.6-fold more strongly than that of naive B cells. The triggering of chemokine receptors by their ligands resulted in the activation of phosphatidylinositide-3 kinase (PI3K)/protein kinase B (PKB), inhibitory NF-kappaB (IkappaBalpha) RhoA and extracellular signal-regulated protein kinase 1/2 (ERK1/2). All these effectors except ERK1/2 are crucial for B-cell chemotaxis. IFNalpha modulated the requirements for B-cell chemotaxis, which became dependent on ERK1/2, more dependent on PI3K, RhoA and nuclear factor-kappaB but less dependent on Gbetagamma and phospholipase C activation. IFNalpha also decreased ligand-induced chemokine receptor internalization in a manner dependent on PI3K/AKT and RhoA but not on IkappaBalpha and ERK1/2. Our data characterize chemokine receptor signaling in human B cells and clarify the relevance of downstream pathways in B-cell chemotaxis and chemokine receptor internalization. They also suggest that non-class I PI3K are involved in B-cell chemotaxis.
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PMID:IFN{alpha} enhances human B-cell chemotaxis by modulating ligand-induced chemokine receptor signaling and internalization. 1574 30

Host defense against viruses probably depends on targeted death of infected host cells and then clearance of cellular corpses by macrophages. For this process to be effective, the macrophage must presumably avoid its own virus-induced death. Here we identify one such mechanism. We show that mice lacking the chemokine Ccl5 are immune compromised to the point of delayed viral clearance, excessive airway inflammation and respiratory death after mouse parainfluenza or human influenza virus infection. Virus-inducible levels of Ccl5 are required to prevent apoptosis of virus-infected mouse macrophages in vivo and mouse and human macrophages ex vivo. The protective effect of Ccl5 requires activation of the Ccr5 chemokine receptor and consequent bilateral activation of G(alphai)-PI3K-AKT and G(alphai)-MEK-ERK signaling pathways. The antiapoptotic action of chemokine signaling may therefore allow scavengers to finally stop the host cell-to-cell infectious process.
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PMID:CCL5-CCR5 interaction provides antiapoptotic signals for macrophage survival during viral infection. 1620 18

Several reports have recently documented that CXCR7/RDC1 functions as a chemokine receptor for SDF-1/CXCL12, which regulates a spectrum of normal and pathological processes. In this study, the role of CXCR7/RDC1 in prostate cancer (PCa) was explored. Staining of high density tissue microarrays demonstrates that the levels of CXCR7/RDC1 expression increase as the tumors become more aggressive. In vitro and in vivo studies with PCa cell lines suggest that alterations in CXCR7/RDC1 expression are associated with enhanced adhesive and invasive activities in addition to a survival advantage. In addition, it was observed that CXCR7/RDC1 levels are regulated by CXCR4. Among the potential downstream targets of CXCR7/RDC1 are CD44 and cadherin-11, which are likely to contribute to the invasiveness of PCa cells. CXCR7/RDC1 also regulates the expression of the proangiogenic factors interleukin-8 or vascular endothelial growth factor, which are likely to participate in the regulation of tumor angiogenesis. Finally, we found that signaling by CXCR7/RDC1 activates AKT pathways. Together, these data demonstrate a role for CXCR7/RDC1 in PCa metastasis and progression and suggest potential targets for therapeutic intervention.
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PMID:The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. 1805 3

Recent studies demonstrate that cyclooxygenase-2 (COX-2) expression is frequently associated with lymph node metastasis. However, the mechanism by which COX-2 increases the invasion of cancer cells to lymph node is unclear. CCR7 is a chemokine receptor that plays important roles in the mediation of migration of leukocytes and dendritic cells toward lymphatic endothelial cells (LECs) that express receptor ligand CCL21. We found that treatment of prostaglandin E(2) or ectopic expression of COX-2 in MCF-7 cells up-regulated CCR7 expression. On the contrary, knockdown of COX-2 by small hairpin RNA reduced CCR7 in COX-2-overexpressing MDA-MB-231 cells. Interaction of CCR7 and CCL21 was important for the migration of breast cancer cells toward LECs because antibodies against these two molecules inhibited the migration. We also found that COX-2 increased CCR7 expression via the EP2 and EP4 receptor in breast cancer cells. EP2 and EP4 agonists stimulated CCR7 in MCF-7 cells, whereas antagonists or small hairpin RNA of EP2 and EP4 attenuated CCR7 in MDA-MB-231 cells. Protein kinase A and AKT kinase were involved in COX-2-induced CCR7. Pathological analysis demonstrated that COX-2 overexpression was associated with CCR7, EP2, and EP4 expressions in breast tumor tissues. In addition, CCR7 expression in COX-2-overexpressing tumors was significantly correlated with lymph node metastasis. Collectively, we suggest that CCR7 is a down-stream target for COX-2 to enhance the migration of breast cancer cells toward LECs and to promote lymphatic invasion.
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PMID:Cyclooxygenase-2 up-regulates CCR7 via EP2/EP4 receptor signaling pathways to enhance lymphatic invasion of breast cancer cells. 1831 53

Brain metastasis confers an extremely unfavorable prognosis upon melanoma patients. The mechanisms underlying the homing of metastatic melanoma to the brain and survival of metastatic melanoma cells in the brain are unknown. Tumor cells, including melanoma, use chemokine receptor-ligand axes to home to specific organ sites. To identify chemokine receptors that might be involved in brain-targeted melanoma metastasis, we first established a chemokine receptor profile of cultured melanoma cells (3 cell lines of cutaneous melanoma and 5 cell lines of melanoma brain metastasis). The expression of the membrane-bound chemokine CX3CL1 by these lines was also determined. We show that out of 19 receptors tested, cultured melanoma cells express CCR3, CCR4, CXCR3, CXCR7, CX3CR1 and membrane CX3CL1. Utilizing cells from newly created variants of human melanoma xenografts, we found that the expression of CCR4 was significantly higher in one brain metastatic variant compared to its expression in the corresponding local variant. Local and metastatic variants stimulated with the CCR4 ligand, CCL22, showed a differential AKT phosphorylation pattern. These findings may suggest the involvement of CCR4 in the process of brain metastasis in human melanoma, and that CCR4 may be a novel molecular biomarker for the identification of melanoma cells likely to metastasize to the brain.
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PMID:Chemokine-chemokine receptor axes in melanoma brain metastasis. 2000 2

Dendritic cell (DC)-based cancer vaccines have become important as an immunotherapeutics in generating anti-tumor immune responses. Due to a short lifespan of DCs, however, clinical application of current DC vaccines has been limited. Recently, activation of AKT/protein kinase B (PKB), a major effector of phosphatidylinositol 3-kinase (PI3K), has been reported as a critical factor in both activation and survival of DCs. We here improved the potency of a DC vaccine with a small interfering RNA (siRNA) targeting phosphatase and tensin homologue (PTEN), which is known to be a central negative regulator of the PI3K/AKT signal transduction cascade. Down-regulation of PTEN in DCs resulted in AKT dependent maturation, which in turn caused a significant up-regulation of surface expression in co-stimulatory molecules and the chemokine receptor, CCR7, leading to an increase of in vitro T cell activation activity and in vivo migration to a draining lymph node, respectively. Moreover, these PTEN siRNA-transfected DCs (DC/siPTEN) acquired an increased survival from the apoptotic death caused by GM-CSF deprivation or antigen-specific CD8(+) T cell killing. Most importantly, DC/siPTEN generated more tumor antigen-specific CD8(+) T cells and stronger anti-tumor effects in vaccinated mice than did control DCs (DC/siGFP). Thus, our data indicate that manipulation of the PI3K/AKT pathway via siRNA system could improve the efficacy of a DC-based tumor vaccine.
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PMID:Enhancement of DC vaccine potency by activating the PI3K/AKT pathway with a small interfering RNA targeting PTEN. 2072 12

Up-regulation of cyclooxygenase-2 (COX-2) is frequently found in human cancers and is significantly associated with tumor metastasis. Our previous results demonstrate that COX-2 and its metabolite prostaglandin E2 (PGE2) stimulate the expression of CCR7 chemokine receptor via EP2/EP4 receptors to promote lymphatic invasion in breast cancer cells. In this study, we address the underlying mechanism of COX-2/PGE2-induced CCR7 expression. We find that COX-2/PGE2 increase CCR7 expression via the AKT signaling pathway in breast cancer cells. Promoter deletion and mutation assays identify the Sp1 site located at the -60/-57 region of CCR7 gene promoter is critical for stimulation. Chromatin immunoprecipitation (ChIP) assay confirms that in vivo binding of Sp1 to human CCR7 promoter is increased by COX-2 and PGE2. Knockdown of Sp1 by shRNA reduces the induction of CCR7 by PGE2. We demonstrate for the first time that AKT may directly phosphorylate Sp1 at S42, T679, and S698. Phosphorylation-mimic Sp1 protein harboring S42D, T679D, and S698D mutation strongly activates CCR7 expression. In contrast, change of these three residues to alanine completely blocks the induction of CCR7 by PGE2. Pathological investigation demonstrates that CCR7 expression is strongly associated with phospho-AKT and Sp1 in 120 breast cancer tissues. Collectively, our results demonstrate that COX-2 up-regulates CCR7 expression via AKT-mediated phosphorylation and activation of Sp1 and this pathway is highly activated in metastatic breast cancer.
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PMID:Cyclooxygenase-2 up-regulates CCR7 expression via AKT-mediated phosphorylation and activation of Sp1 in breast cancer cells. 2271 98

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