Posttranslational modifications of CXCR4: implications in cancer metastasis

CXCR4, the most widely expressed chemokine receptor in solid malignancies, has been implicated in cancer metastasis. However, how the activity of CXCR4 is regulated during carcinogenesis especially at the metastatic stage remains largely unknown. As with other G protein-coupled receptors, CXCR4 is subjected to posttranslational medications such as phosphorylation, ubiquitination, glycosylation, and sulfation. These posttranslational modifications contribute significantly to the heterogeneity of CXCR4 in terms of intracellular location, signaling, and functionality. We have shown that the difference in the sulfation level of CXCR4 is responsible for, if not all, the difference in the activities of CXCR4 between the highly metastatic and non-metastatic nasopharyngeal carcinoma (NPC) cell lines. Molecular mechanistic studies revealed that the Epstein-Barr virus-encoded oncoprotein LMP1 induces the expression of tyrosylprotein sulfotransferase 1 (TPST-1) through nuclear translocation of the epidermal growth factor receptor. This LMP1-regulated TPST-1 expression accounts for tyrosine sulfation of CXCR4 and is associated with the metastatic phenotype of NPC cell lines. Finally, in NPC patient specimens, there was a positive correlation between the expression of LMP1 and TPST-1 and the metastatic potential of NPC. Our findings provide the first evidence that the posttranslational modification of a chemokine receptor plays a role in cancer metastatic progression. Understanding the role of posttranslational modifications of chemokine receptors in cancer biology may provide new insights for developing attractive therapeutic targets in cancer therapy

AuPt/3DOM CoCr2O4: Highly Active Catalysts for the Combustion of Methane

 Three-dimensionally ordered macroporous (3DOM) CoCr2O4 and its supported bimetallic Auy Pt nanocatalysts (xAuyPt/3DOM CoCr2O4, x = 0.49, 0.98, and 1.92 wt%; Au/Pt molar ratio (y) = 0.99, 0.98, and 1.01) were prepared using the polymethyl methacrylate-templating and polyvinyl alcohol-protected reduction methods, respectively. Physicochemical properties of the samples were characterized by means of various techniques. Catalytic activities of the xAuyPt/3DOM CoCr2O4 samples were evaluated for methane combustion. It is found that the 3DOM CoCr2O4 support possessed a single-phase and cubic spinel-type crystal structure, the xAuyPt/3DOM CoCr2O4 samples displayed a high-quality 3DOM architecture and a surface area of 32-33 m2/g, and the AuyPt nanoparticles (NPs) with a size of 3-5 nm were well dispersed on the 3DOM CoCr2O4 surface. The loading of an appropriate amount of AuyPt NPs could enhance the adsorbed oxygen species concentration and low-temperature reducibility of the sample. Among all of the samples, 0.98Au0.98Pt/3DOM CoCr2O4 showed the best catalytic performance: the T10%, T50%, and T90% (temperatures required for achieving methane conversion of 10, 50, and 90 %, respectively) were 253, 315, and 354 oC at a space velocity of 20,000 mL/(g h). It is concluded that the good activity of 0.98Au0.98Pt/3DOM CoCr2O4 was associated with its highly dispersed Au0.98Pt NPs, high adsorbed oxygen species concentration, good low-temperature reducibility, and strong interaction between Au0.98Pt NPs and 3DOM CoCr2O4

KCTD10 is involved in the cardiovascular system and Notch signaling during early embryonic development.

As a member of the polymerase delta-interacting protein 1 (PDIP1) gene family, potassium channel tetramerisation domain-containing 10 (KCTD10) interacts with proliferating cell nuclear antigen (PCNA) and polymerase δ, participates in DNA repair, DNA replication and cell-cycle control. In order to further investigate the physiological functions of KCTD10, we generated the KCTD10 knockout mice. The heterozygous KCTD10(+/-) mice were viable and fertile, while the homozygous KCTD10(-/-) mice showed delayed growth from E9.0, and died at approximately E10.5, which displayed severe defects in angiogenesis and heart development. Further study showed that VEGF induced the expression of KCTD10 in a time- and dose-dependent manner. Quantitative real-time PCR and western blotting results revealed that several key members in Notch signaling were up-regulated either in KCTD10-deficient embryos or in KCTD10-silenced HUVECs. Meanwhile, the endogenous immunoprecipitation (IP) analysis showed that KCTD10 interacted with Cullin3 and Notch1 simultaneously, by which mediating Notch1 proteolytic degradation. Our studies suggest that KCTD10 plays crucial roles in embryonic angiogenesis and heart development in mammalians by negatively regulating the Notch signaling pathway

Tyrosylprotein sulfotransferase-1 and tyrosine sulfation of chemokine receptor 4 are induced by Epstein-Barr virus encoded latent membrane protein 1 and associated with the metastatic potential of human nasopharyngeal carcinoma.

The latent membrane protein 1 (LMP1), which is encoded by the Epstein-Barr virus (EBV), is an important oncogenic protein that is closely related to carcinogenesis and metastasis of nasopharyngeal carcinoma (NPC), a prevalent cancer in China. We previously reported that the expression of the functional chemokine receptor CXCR4 is associated with human NPC metastasis. In this study, we show that LMP1 induces tyrosine sulfation of CXCR4 through tyrosylprotein sulfotransferase-1 (TPST-1), an enzyme that is responsible for catalysis of tyrosine sulfation in vivo, which is likely to contribute to the highly metastatic character of NPC. LMP1 could induce tyrosine sulfation of CXCR4 and its associated cell motility and invasiveness in a NPC cell culture model. In contrast, the expression of TPST-1 small interfering RNA reversed LMP1-induced tyrosine sulfation of CXCR4. LMP1 conveys signals through the epidermal growth factor receptor (EGFR) pathway, and EGFR-targeted siRNA inhibited the induction of TPST-1 by LMP1. We used a ChIP assay to show that EGFR could bind to the TPST-1 promoter in vivo under the control of LMP1. A reporter gene assay indicated that the activity of the TPST-1 promoter could be suppressed by deleting the binding site between EGFR and TPST-1. Finally, in human NPC tissues, the expression of TPST-1 and LMP1 was directly correlated and clinically, the expression of TPST-1 was associated with metastasis. These results suggest the up-regulation of TPST-1 and tyrosine sulfation of CXCR4 by LMP1 might be a potential mechanism contributing to NPC metastasis

Identification of JAK2 as a mediator of FIP1L1-PDGFRA-induced eosinophil growth and function in CEL.

The Fip1-like1 (FIP1L1)-platelet-derived growth factor receptor alpha fusion gene (F/P) arising in the pluripotent hematopoietic stem cell (HSC),causes 14% to 60% of patients with hypereosinophilia syndrome (HES). These patients, classified as having F/P (+) chronic eosinophilic leukemia (CEL), present with clonal eosinophilia and display a more aggressive disease phenotype than patients with F/P (-) HES patients. The mechanisms underlying predominant eosinophil lineage targeting and the cytotoxicity of eosinophils in this leukemia remain unclear. Given that the Janus tyrosine kinase (JAK)/signal transducers and activators of transcription (Stat) signaling pathway is key to cytokine receptor-mediated eosinophil development and activated Stat3 and Stat5 regulate the expression of genes involved in F/P malignant transformation, we investigated whether and how JAK proteins were involved in the pathogenesis of F/P-induced CEL. F/P activation of JAK2, Stat3 and Stat5, were confirmed in all the 11 F/P (+) CEL patients examined. In vitro inhibition of JAK2 in EOL-1, primary F/P(+) CEL cells (PC) and T674I F/P Imatinib resistant cells(IR) by either JAK2-specific short interfering RNA (siRNA) or the tryphostin derivative AG490(AG490), significantly reduced cellular proliferation and induced cellular apoptosis. The F/P can enhance the IL-5-induced JAK2 activation, and further results indicated that JAK2 inhibition blocked IL-5-induced cellular migration and activation of the EOL-1 and PC cells in vitro. F/P-stimulation of the JAK2 suppressed cells led to a significantly reduction in Stat3 activation, but relatively normal induction of Stat5 activation. Interestingly, JAK2 inhibition also reduced PI3K, Akt and NF-κB activity in a dose-dependent manner, and suppressed expression levels of c-Myc and Survivin. These results strongly suggest that JAK2 is activated by F/P and is required for F/P stimulation of cellular proliferation and infiltration, possibly through induction of c-Myc and Survivin expression via activation of multiple signaling pathways, including NF-κB, Stat3, and PI3K/Akt