Dataset Information

Glia Maturation Factor-? Regulates Monocyte Migration through Modulation of ?1-Integrin.

ABSTRACT: Monocyte migration requires the dynamic redistribution of integrins through a regulated endo-exocytosis cycle, but the complex molecular mechanisms underlying this process have not been fully elucidated. Glia maturation factor-? (GMFG), a novel regulator of the Arp2/3 complex, has been shown to regulate directional migration of neutrophils and T-lymphocytes. In this study, we explored the important role of GMFG in monocyte chemotaxis, adhesion, and ?1-integrin turnover. We found that knockdown of GMFG in monocytes resulted in impaired chemotactic migration toward formyl-Met-Leu-Phe (fMLP) and stromal cell-derived factor 1? (SDF-1?) as well as decreased ?5?1-integrin-mediated chemoattractant-stimulated adhesion. These GMFG knockdown impaired effects could be reversed by cotransfection of GFP-tagged full-length GMFG. GMFG knockdown cells reduced the cell surface and total protein levels of ?5?1-integrin and increased its degradation. Importantly, we demonstrate that GMFG mediates the ubiquitination of ?1-integrin through knockdown or overexpression of GMFG. Moreover, GMFG knockdown retarded the efficient recycling of ?1-integrin back to the plasma membrane following normal endocytosis of ?5?1-integrin, suggesting that the involvement of GMFG in maintaining ?5?1-integrin stability may occur in part by preventing ubiquitin-mediated degradation and promoting ?1-integrin recycling. Furthermore, we observed that GMFG interacted with syntaxin 4 (STX4) and syntaxin-binding protein 4 (STXBP4); however, only knockdown of STXBP4, but not STX4, reduced monocyte migration and decreased ?1-integrin cell surface expression. Knockdown of STXBP4 also substantially inhibited ?1-integrin recycling in human monocytes. These results indicate that the effects of GMFG on monocyte migration and adhesion probably occur through preventing ubiquitin-mediated proteasome degradation of ?5?1-integrin and facilitating effective ?1-integrin recycling back to the plasma membrane.

SUBMITTER: Aerbajinai W

PROVIDER: S-EPMC4861427 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Glia Maturation Factor-γ Regulates Monocyte Migration through Modulation of β1-Integrin.

Aerbajinai Wulin W Liu Lunhua L Zhu Jianqiong J Kumkhaek Chutima C Chin Kyung K Rodgers Griffin P GP

The Journal of biological chemistry 20160219 16

Monocyte migration requires the dynamic redistribution of integrins through a regulated endo-exocytosis cycle, but the complex molecular mechanisms underlying this process have not been fully elucidated. Glia maturation factor-γ (GMFG), a novel regulator of the Arp2/3 complex, has been shown to regulate directional migration of neutrophils and T-lymphocytes. In this study, we explored the important role of GMFG in monocyte chemotaxis, adhesion, and β1-integrin turnover. We found that knockdown o ...[more]

PMID: 26895964

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Project description:Adhesive and migratory behavior can be cell type, integrin, and substrate dependent. We have compared integrin and substrate differences using three integrin receptors: ?5?1, ?6?1, and ?L?2 expressed in a common cell type, CHO.B2 cells, which lack integrin ? subunits, as well as in different cell types that express one or more of these integrins. We find that CHO.B2 cells expressing either ?6?1 or ?L?2 integrins migrate and protrude faster and are more directionally persistent on laminin or ICAM-1, respectively, than CHO.B2 cells expressing ?5?1 on fibronectin. Despite rapid adhesion maturation and the presence of large adhesions in both the ?6?1- and ?L?2-expressing cells, they display robust tyrosine phosphorylation. In addition, whereas myosin II regulates adhesion maturation and turnover, protrusion rates, and polarity in cells migrating on fibronectin, surprisingly, it does not have comparable effects in cells expressing ?6?1 or ?L?2. This apparent difference in the integration of myosin II activity, adhesion, and migration arises from alterations in the ligand-integrin-actin linkage (molecular clutch). The elongated adhesions in the protrusions of the ?6?1-expressing cells on laminin or the ?L?2-expressing cells on ICAM-1 display a novel, rapid retrograde flux of integrin; this was largely absent in the large adhesions in protrusions of ?5?1-expressing cells on fibronectin. Furthermore, the force these adhesions exert on the substrate in protrusive regions is reduced compared to similar regions in ?5-expressing cells, and the adhesion strength is reduced. This suggests that intracellular forces are not efficiently transferred from actomyosin to the substratum due to altered adhesion strength, that is, avidity, affinity, or the ligand-integrin-actin interaction. Finally, we show that the migration of fast migrating leukocytes on fibronectin or ICAM-1 is also largely independent of myosin II; however, their adhesions are small and do not show retrograde fluxing suggesting other intrinsic factors determine their migration differences.

Project description:BackgroundGlia maturation factor-γ (GMFG) regulates actin cytoskeletal organization and promotes the invasion of cancer cells. However, its expression pattern and molecular function in gliomas have not been clearly defined.MethodsIn this study, public datasets comprising 2,518 gliomas samples were used to explore GMFG expression and its correlation with malignancy in gliomas. Immunohistochemistry (IHC) staining was performed to determine the expression of GMFG in gliomas using an in-house cohort that contained 120 gliomas samples. Gene ontology enrichment analysis was conducted using the DAVID tool. The correlation between GMFG expression and immune cell infiltration was evaluated using TIMER, Tumor Immune Single-Cell Hub (TISCH) database, and IHC staining assays. The Kaplan-Meier analysis was performed to determine the prognostic role of GMFG and its association with temozolomide (TMZ) response in gliomas.ResultsThe GMFG expression was higher in gliomas compared with non-tumor brain tissues both in public datasets and in-house cohort. High expression of GMFG was significantly associated with WHO grade IV, IDH 1/2 wild-type, and mesenchymal (ME) subtypes. Bioinformatic prediction and IHC analysis revealed that GMFG expression obviously correlated with the macrophage marker CD163 in gliomas. Moreover, both lower grade glioma (LGG) and glioblastoma multiforme (GBM) patients with high GMFG expression had shorter overall survival than those with low GMFG expression. These results indicate that GMFG may be a therapeutic target for the treatment of such patients. Patients with low GMFG expression who received chemotherapy had a longer survival time than those with high GMFG expression. For patients who received ion radiotherapy (IR) only, the GMFG expression level had no effect on the overall survival neither in CGGA and TCGA datasets.ConclusionThe GMFG is a novel prognostic biomarker for patients with both LGG and GBM. Increased GMFG expression is associated with tumor-associated macrophages (TAMs) infiltration and with a bad response to TMZ treatment.

Dataset Information

Glia Maturation Factor-? Regulates Monocyte Migration through Modulation of ?1-Integrin.

Publications

Glia Maturation Factor-γ Regulates Monocyte Migration through Modulation of β1-Integrin.

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