Dataset Information

SDF-1?/CXCR4 Signaling in Lipid Rafts Induces Platelet Aggregation via PI3 Kinase-Dependent Akt Phosphorylation.

ABSTRACT: Stromal cell-derived factor-1? (SDF-1?)-induced platelet aggregation is mediated through its G protein-coupled receptor CXCR4 and phosphatidylinositol 3 kinase (PI3K). Here, we demonstrate that SDF-1? induces phosphorylation of Akt at Thr308 and Ser473 in human platelets. SDF-1?-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the CXCR4 antagonist AMD3100 or the PI3K inhibitor LY294002. SDF-1? also induces the phosphorylation of PDK1 at Ser241 (an upstream activator of Akt), GSK3? at Ser9 (a downstream substrate of Akt), and myosin light chain at Ser19 (a downstream element of the Akt signaling pathway). SDF-1?-induced platelet aggregation is inhibited by pretreatment with the Akt inhibitor MK-2206 in a dose-dependent manner. Furthermore, SDF-1?-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the raft-disrupting agent methyl-?-cyclodextrin. Sucrose density gradient analysis shows that 35% of CXCR4, 93% of the heterotrimeric G proteins G?i-1, 91% of G?i-2, 50% of G? and 4.0% of PI3K?, and 4.5% of Akt2 are localized in the detergent-resistant membrane raft fraction. These findings suggest that SDF-1?/CXCR4 signaling in lipid rafts induces platelet aggregation via PI3K-dependent Akt phosphorylation.

SUBMITTER: Ohtsuka H

PROVIDER: S-EPMC5224795 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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SDF-1α/CXCR4 Signaling in Lipid Rafts Induces Platelet Aggregation via PI3 Kinase-Dependent Akt Phosphorylation.

Ohtsuka Hiroko H Iguchi Tomohiro T Hayashi Moyuru M Kaneda Mizuho M Iida Kazuko K Shimonaka Motoyuki M Hara Takahiko T Arai Morio M Koike Yuichi Y Yamamoto Naomasa N Kasahara Kohji K

PloS one 20170110 1

Stromal cell-derived factor-1α (SDF-1α)-induced platelet aggregation is mediated through its G protein-coupled receptor CXCR4 and phosphatidylinositol 3 kinase (PI3K). Here, we demonstrate that SDF-1α induces phosphorylation of Akt at Thr308 and Ser473 in human platelets. SDF-1α-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the CXCR4 antagonist AMD3100 or the PI3K inhibitor LY294002. SDF-1α also induces the phosphorylation of PDK1 at Ser241 (an upstream ...[more]

PMID: 28072855

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Project description:Metastasis is the primary cause of mortality in patients with advanced gastric carcinoma, and multiple signaling pathways promote the development of this condition. Stromal cell-derived factor-1 (SDF-1α/CXCL12), the main ligand for CXC chemokine receptor-4 (CXCR4), serves an important role in gastric cancer cell migration. Previous studies have demonstrated that CXCL12 could also stimulate the secretion of epidermal growth factor receptor (EGFR) ligands, including amphiregulin and heparin-binding epidermal growth factor-like growth factor, from gastric cancer cells, resulting in an increase in the ability of migration. However, it remains to be elucidated whether CXCL12 activates EGFR intracellular signaling and therefore stimulates migration in gastric cancer. The present study demonstrated that three gastric cancer cell lines, SGC-7901, MGC-803 and BGC-823, all expressed CXCR4. The increased chemotactic migratory ability stimulated by CXCL12 was effectively abrogated by the CXCR4 antagonist, AMD3100. Furthermore, a rapid phosphorylation of Akt/extracellular signal-regulated kinase (ERK)/EGFR was demonstrated to be involved in CXCL12/CXCR4-induced gastric cancer cell migration. Knockdown of EGFR gene or the use of a monoclonal antibody against EGFR (C225) blocked the activation of ERK/Akt and partially prevented the ability of migration induced by CXCL12, which indicated that EGFR signaling is located downstream of CXCL12. In addition, it was also revealed that the activation of non-receptor tyrosine kinase c-steroid receptor co-activator (SRC) and the formation of the SRC/EGFR heterodimer are promoted by CXCL12, whereas the SRC inhibitor, PP2, blocks the SRC/EGFR heterodimer and the activation of EGFR, as well as CXCR4-meditated migration induced by CXCL12. The present results indicated that SRC mediates a potential CXCR4-EGFR cross-talk, and thereby utilizes the EGFR-Akt/ERK axis to promote cellular migration. The present study provided a novel insight into the underlying regulatory mechanisms of the CXCL12/CXCR4 pathway in gastric cancer cell migration.

Project description:BackgroundOne of the most frequent disorders is liver fibrosis. An improved understanding of the different events during the process of liver fibrosis & its reversibility could be helpful in its staging and in finding potential therapeutic agents.AimThe goal of this research was to evaluate the relationship among CD34 + HPSCs, SDF-1α, and CXCR4 receptor expression with the percentage of the area of hepatic fibrosis.Materials and methodsThirty-six male Sprague-Dawley rats were separated into the control group, liver injury group & spontaneous reversion group. The liver injury was induced by using 2 ml/kg CCl4 twice a week. Flow cytometric examination of CD34 + cells in the blood & liver was performed. Bone marrow & liver samples were taken for evaluation of the SDF-1α mRNA by PCR. Liver specimens were stained for histopathological and CXCR4 immuno-expression evaluation.ResultsIn the liver injury group, the hepatic enzymes, fibrosis area percentage, CXCR4 receptor expression in the liver, CD34 + cells in the blood and bone marrow & the level SDF-1α in the liver and its concentration gradient were statistically significantly elevated with the progression of the liver fibrosis. On the contrary, SDF-1α in the bone marrow was statistically significantly reduced with the development of liver fibrosis. During the spontaneous reversion group, all the studied parameters apart from SDF-1α in the bone marrow were statistically substantially decreased compared with the liver injury group. We found a statistically substantial positive correlation between fibrosis area and all of the following: liver enzymes, CXCR4 receptor expression in the liver, CD34 + cells in the blood and liver, and SDF- 1α in the liver and its concentration gradient. In conclusion, in CCl4 rat model, the fibrosis area is significantly correlated with many parameters in the blood, bone marrow, and liver, which can be used during the process of follow-up during the therapeutic interventions.

Dataset Information

SDF-1?/CXCR4 Signaling in Lipid Rafts Induces Platelet Aggregation via PI3 Kinase-Dependent Akt Phosphorylation.

Publications

SDF-1α/CXCR4 Signaling in Lipid Rafts Induces Platelet Aggregation via PI3 Kinase-Dependent Akt Phosphorylation.

Similar Datasets

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