Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mitochondria-mediated apoptotic pathway is regulated by members of the Bcl-2 family. Epidermal growth factor (EGF) induces Bad phosphorylation at Ser112 via mitogen-activated protein kinase (MAPK), impairing its binding to Bcl-2 and Bcl-xL and interfering with their anti-apoptotic functions. In the current study, we utilized Western blot, immunofluorescence, flow cytometry, and confocal microscopy to examine the effects of CMTM8 overexpression on apoptosis. Our data indicated levels of Bad-S112 phosphorylation were lower in CMTM8-transfected cells compared to pCDB-transfected cells. Caspase-dependent and independent mediated apoptosis, induced by CMTM8 overexpression, was facilitated by the mitochondria and inhibited by knockdown of Bad or overexpression of Bcl-xL. Previous research in our laboratory also demonstrated CMTM8 attenuated EGFR-mediated signaling pathways by decreasing ERK1/2 phosphorylation levels. These data implicate CMTM8 as a negative regulator of EGF-induced signaling, with potential use as a novel therapeutic gene for EGFR-targeted anticancer gene therapy.
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PMID:CMTM8 induces caspase-dependent and -independent apoptosis through a mitochondria-mediated pathway. 1714 3

Recently, several genome-wide association studies (GWAS) on bipolar disorder (BPD) suggested novel risk genes. However, only few of them were followed up and further, the specificity of these genes is even more elusive. To address these issues, we genotyped SNPs in ANK3, CACNA1C, CMTM8, DGKH, EGFR, and NPAS3, which were significantly associated with BPD in previous GWAS, in a sample of 380 BPD patients. Replicated SNPs were then followed up in patients suffering from unipolar depression (UPD; n=387) or adult attention-deficit/hyperactivity disorder (aADHD; n=535). While we could not confirm an association of ANK3, CACNA1C, and EGFR with BPD, 10 SNPs in DGKH, CMTM8, and NPAS3 were nominally associated with disease, with two DGKH markers surviving correction for multiple testing. When these were followed up in UPD and aADHD, seven DGKH SNPs were also associated with UPD, while one SNP each in NPAS3 and CMTM8 and four in DGKH were linked to aADHD. Furthermore, a DGKH haplotype consisting of rs994856/rs9525580/rs9525584 GAT was associated with all disorders tested, while the complementary AGC haplotype was protective. The corresponding haploblock spans a 27-kb region covering exons coding for amino acids 65-243, and thus might include functional variants yet to be identified. We demonstrate an association of DGKH with BPD, UPD, and aADHD by applying a two-stage design. These disorders share the feature of mood instability, so that this phenotype might be associated with genetic variation in DGKH.
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PMID:Cross-disorder analysis of bipolar risk genes: further evidence of DGKH as a risk gene for bipolar disorder, but also unipolar depression and adult ADHD. 2165 38

The acquisition of an invasive phenotype is a critical turning point for malignant tumor cells. CMTM8, a potential tumor suppressor, is frequently down-regulated in solid tumors, and its overexpression induces tumor cell apoptosis. Here, we identify a new role for CMTM8 in regulating tumor cell migration. Reducing CMTM8 expression in HepG2 hepatocellular carcinoma cells results in the acquisition of epithelial-to-mesenchymal transition (EMT) features, including a morphological change from organized epithelial sheets to scattered fibroblast-like shapes, reduction of the epithelial marker E-cadherin, and an increased invasive and migratory ability. These phenotypic changes are mediated in large part by the ERK-MAPK pathway, as the MEK inhibitor U0126 and shRNA-mediated knockdown of ERK2 significantly reversed these phenotypes. Hepatocyte growth factor binding to the c-MET receptor is known to induce EMT in HepG2 cells. We found that CMTM8 knockdown in HepG2 cells induced c-MET signaling and ERK activation. Inhibition of c-MET signaling with the small molecule inhibitor SU11274 or c-MET RNAi blocked the EMT-like changes following CMTM8 knockdown. CMTM8 overexpression in HepG2 cells inhibited hepatocyte growth factor-induced EMT-like morphological changes and cell motility. Down-regulation of CMTM8 also promoted an EMT-like change in MCF-10A cells, indicating a broader role for CMTM8 in regulating cellular transformation.
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PMID:Down-regulation of CMTM8 induces epithelial-to-mesenchymal transition-like changes via c-MET/extracellular signal-regulated kinase (ERK) signaling. 2233 76

Osteosarcoma is an aggressive bone tumor that preferentially develops in adolescents. The tumor is characterized by an abundance of genomic aberrations, which hampers the identification of the driver genes involved in osteosarcoma tumorigenesis. Our study aims to identify these genes by the investigation of focal copy number aberrations (CNAs, <3 Mb). For this purpose, we subjected 26 primary tumors of osteosarcoma patients to high-resolution single nucleotide polymorphism array analyses and identified 139 somatic focal CNAs. Of these, 72 had at least one gene located within or overlapping the focal CNA, with a total of 94 genes. For 84 of these genes, the expression status in 31 osteosarcoma samples was determined by expression microarray analysis. This enabled us to identify the genes of which the over- or underexpression was in more than 35% of cases in accordance to their copy number status (gain or loss). These candidate genes were subsequently validated in an independent set and furthermore corroborated as driver genes by verifying their role in other tumor types. We identified CMTM8 as a new candidate tumor suppressor gene and GPR177 as a new candidate oncogene in osteosarcoma. In osteosarcoma, CMTM8 has been shown to suppress EGFR signaling. In other tumor types, CMTM8 is known to suppress the activity of the oncogenic protein c-Met and GPR177 is known as an overexpressed upstream regulator of the Wnt-pathway. Further studies are needed to determine whether these proteins also exert the latter functions in osteosarcoma tumorigenesis.
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PMID:Focal chromosomal copy number aberrations identify CMTM8 and GPR177 as new candidate driver genes in osteosarcoma. 2555 57