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)

The EphA2 receptor tyrosine kinase signals through two distinct mechanisms, one regulated by tyrosine phosphorylation and the other by serine/threonine phosphorylation. Serine 892 (S892) is one of the major serine/threonine phosphorylation sites in EphA2, but little is known about its regulation and function. S892 is located in the linker connecting the EphA2 kinase and SAM domains, and is part of a cluster of five phosphorylated residues that includes the well characterized S897. EphA2 can be phosphorylated on S897 by the RSK, AKT and PKA kinases to promote a non-canonical form of signaling that plays an important role in cancer malignancy. Here we show that the Protein Kinase C (PKC) family phosphorylates the EphA2 S892 motif in vitro and in cells. By using a newly developed phosphospecific antibody, we detected EphA2 S892 phosphorylation in a variety of cell lines. As expected for a PKC target site, the PKC activator 12-O-tetradecanoylphorbol-13-acetate (TPA) increases S892 phosphorylation whereas the broad-spectrum PKC inhibitor Go 6983 inhibits both basal and TPA-induced S892 phosphorylation. Besides phosphorylating S892, PKC can also increase EphA2 phosphorylation on S897 through the MEK kinase, which regulates the ERK-RSK signaling axis. We also found that S892 and S897 phosphorylation induced by PKC activation can be downregulated by ephrin ligand-induced EphA2 canonical signaling. Our data reveal that the PKC family contributes to the phosphorylation cluster in the EphA2 kinase-SAM linker, which regulates EphA2 non-canonical signaling and cancer malignancy.
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PMID:Protein kinase C phosphorylates the EphA2 receptor on serine 892 in the regulatory linker connecting the kinase and SAM domains. 3241 52

OPCML is a highly conserved glycosyl phosphatidylinositol (GPI)-anchored protein belonging to the IgLON family of cell adhesion molecules. OPCML functions as a tumor suppressor and is silenced in over 80% of ovarian cancers by loss of heterozygosity and by epigenetic mechanisms. OPCML inactivation is also observed in many other cancers suggesting a conservation of tumor suppressor function. Although epigenetic silencing and subsequent loss of OPCML expression correlate with poor progression-free and overall patient survival, its mechanism of action is only starting to be fully elucidated. Recent discoveries have demonstrated that OPCML exerts its tumor suppressor effect by inhibiting several cancer hallmark phenotypes in vitro and abrogating tumorigenesis in vivo, by downregulating/inactivating a specific spectrum of Receptor Tyrosine Kinases (RTKs), including EphA2, FGFR1, FGFR3, HER2, HER4, and AXL. This modulation of RTKs can also sensitize ovarian and breast cancers to lapatinib, erlotinib, and anti-AXL therapies. Furthermore, OPCML has also been shown to function in synergy with the tumor suppressor phosphatase PTPRG to inactivate pro-metastatic RTKs such as AXL. Recently, the identification of inactivating point mutations and the elucidation of the crystal structure of OPCML have provided valuable insights into its structure-function relationships, giving rise to its potential as an anti-cancer therapeutic.
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PMID:Emerging roles for the GPI-anchored tumor suppressor OPCML in cancers. 3259 15

Cell division is a tightly regulated, essential process for cell proliferation. Very recently, we reported that EphA2 is phosphorylated at Ser897, via the Cdk1/MEK/ERK/RSK pathway, during M phase and contributes to proper M-phase progression by maintaining cortical rigidity via the EphA2pSer897/ephexin4/RhoG pathway. Here, we show that EphA2 kinase activity is dispensable for M-phase progression. Although EphA2 knockdown delayed this progression, the delay was rescued by an EphA2 mutant expression with an Asp739 to Asn substitution, as well as by wild-type EphA2. Western blotting analysis confirmed that the Asp739Asn mutant lost its EphA2 kinase activity. Like wild-type EphA2, the Asp739Asn mutant was localized to the plasma membrane irrespective of cell cycle. While RhoG localization to the plasma membrane was decreased in EphA2 knockdown cells, it was rescued by re-expression of wild-type EphA2 but not via the mutant containing the Ser897 to Ala substitution. This confirmed our recent report that phosphorylation at Ser897 is responsible for RhoG localization to the plasma membrane. In agreement with the M-phase progression's rescue effect, the Asp739Asn mutant rescued RhoG localization in EphA2 knockdown cells. These results suggest that EphA2 regulates M-phase progression in a manner independent of its kinase activity.
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PMID:Kinase activity-independent role of EphA2 in the regulation of M-phase progression. 3275 Mar 31

The volumes of waste electrical and electronic equipment are rapidly increasing worldwide. While the relationship between e-waste generation and economic growth has previously been studied, mismanaged e-waste has received little attention. This study examines the environmental Kuznets curve (EKC) hypothesis between economic growth and mismanagement e-waste for 27 European countries over the period 2008-2016. Previous studies on ECK employed waste generation as a proxy for environmental degradation, while this work uses mismanaged e-waste, namely uncollected and non-recycled/non-reused e-waste. Two different econometric methods (dynamic and static) are applied; the first method uses Fully Modified Ordinary Least Square (FMOLS) and Dynamic Ordinary Least Square (DOLS) as panel integration estimation, while the second method employs traditional Pooled Ordinary Least Square (OLS) and Robust Least Squares (MM-estimation). The advantages of the first method are its ability to avoid the problems of endogeneity and serial correlation, while the second method is applied to check the robustness of the results and to disclose whether the data set suffers from outliers. All estimators used consistently identified the inverted U-shaped relationship between economic growth and mismanaged e-waste, as postulated by the EKC hypothesis: quantities of mismanaged e-waste increase along economic growth up to a certain economic development stage (turning point), but then mismanaged e-waste quantities decline while economy continues to grow. A unidirectional causality relationship running from economic growth to uncollected and non-recycled/non-reused e-waste was found. Furthermore, the results reveal that mismanaged e-waste increases with higher credit to private sector.
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PMID:Relationship between economic growth and mismanaged e-waste: Panel data evidence from 27 EU countries analyzed under the Kuznets curve hypothesis. 3328 77


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