Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A mechanism for the upregulation of EGF receptor levels in glioblastomas.

ABSTRACT: Tissue transglutaminase (tTG) is a GTP-binding protein/acyltransferase whose expression is upregulated in glioblastoma and associated with decreased patient survival. Here, we delineate a unique mechanism by which tTG contributes to the development of gliomas by using two glioblastoma cell lines, U87 and LN229, whose growth and survival are dependent on tTG. We show that tTG significantly enhances the signaling activity and lifespan of EGF receptors (EGFRs) in these brain cancer cells. Moreover, overexpressing tTG in T98G glioblastoma cells that normally express low levels of tTG caused a marked upregulation of EGFR expression and transforming activity. Furthermore, we show that tTG accentuates EGFR signaling by blocking c-Cbl-catalyzed EGFR ubiquitylation through the ability of tTG to bind GTP and adopt a specific conformation that enables it to interact with c-Cbl. These findings demonstrate that tTG contributes to gliomagenesis by interfering with EGFR downregulation and, thereby, promoting transformation.

SUBMITTER: Zhang J

PROVIDER: S-EPMC3742030 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

A mechanism for the upregulation of EGF receptor levels in glioblastomas.

Zhang Jingwen J Antonyak Marc A MA Singh Garima G Cerione Richard A RA

Cell reports 20130613 6

Tissue transglutaminase (tTG) is a GTP-binding protein/acyltransferase whose expression is upregulated in glioblastoma and associated with decreased patient survival. Here, we delineate a unique mechanism by which tTG contributes to the development of gliomas by using two glioblastoma cell lines, U87 and LN229, whose growth and survival are dependent on tTG. We show that tTG significantly enhances the signaling activity and lifespan of EGF receptors (EGFRs) in these brain cancer cells. Moreover, ...[more]

PMID: 23770238

Similar Datasets

YAP modulates TGF-?1-induced simultaneous apoptosis and EMT through upregulation of the EGF receptor.

Project description:YAP is a transcriptional co-regulator that plays important roles in various patho-physiological processes, including the survival and death of cells. However, the effect of YAP on apoptosis and EMT, simultaneously mediated by TGF-?1, is not known. In this study, we demonstrate that YAP can modulate cell fate of apoptosis versus EMT by acting as a surviving factor. Overexpression of YAP in mouse mammary epithelial (NMuMG) cells suppressed TGF-?1-induced apoptosis, which shifted the cellular response predominantly toward EMT. In contrast, knockdown of YAP induced spontaneous apoptosis and enhanced TGF-?1-induced apoptosis, leading to a sharp decrease in the proportion of surviving cells that underwent EMT. These data suggest that YAP is an essential factor for modulating cellular responses to TGF-?1. Further investigation showed that YAP could regulate the expression level and activation of EGFR. Knockdown or inhibition of EGFR abolished the suppressive effect of YAP on apoptosis, whereas activation of EGFR by EGF significantly reduced apoptosis caused by the knockdown of YAP. The results indicate that EGFR and its activation are critical for YAP-mediated suppression of TGF-?1-induced apoptosis. This study provides a new understanding of the regulatory mechanism underlying the determination of cell fate in response to TGF-?1-mediated simultaneous apoptosis and EMT.

| S-EPMC5397873 | biostudies-other

Hypoxia promotes ligand-independent EGF receptor signaling via hypoxia-inducible factor-mediated upregulation of caveolin-1.

Project description:Caveolin-1 (CAV1) is an essential structural constituent of caveolae, specialized lipid raft microdomains on the cell membrane involved in endocytosis and signal transduction, which are inexplicably deregulated and are associated with aggressiveness in numerous cancers. Here we identify CAV1 as a direct transcriptional target of oxygen-labile hypoxia-inducible factor 1 and 2 that accentuates the formation of caveolae, leading to increased dimerization of EGF receptor within the confined surface area of caveolae and its subsequent phosphorylation in the absence of ligand. Hypoxia-inducible factor-dependent up-regulation of CAV1 enhanced the oncogenic potential of tumor cells by increasing the cell proliferative, migratory, and invasive capacities. These results support a concept in which a crisis in oxygen availability or a tumor exhibiting hypoxic signature triggers caveolae formation that bypasses the requirement for ligand engagement to initiate receptor activation and the critical downstream adaptive signaling during a period when ligands required to activate these receptors are limited or are not yet available.

| S-EPMC3323978 | biostudies-literature

Structure and mechanism of activity-based inhibition of the EGF receptor by Mig6.

Project description:Mig6 is a feedback inhibitor that directly binds, inhibits and drives internalization of ErbB-family receptors. Mig6 selectively targets activated receptors. Here we found that the epidermal growth factor receptor (EGFR) phosphorylates Mig6 on Y394 and that this phosphorylation is primed by prior phosphorylation of an adjacent residue, Y395, by Src. Crystal structures of human EGFR-Mig6 complexes reveal the structural basis for enhanced phosphorylation of primed Mig6 and show how Mig6 rearranges after phosphorylation by EGFR to effectively irreversibly inhibit the same receptor that catalyzed its phosphorylation. This dual phosphorylation site allows Mig6 to inactivate EGFR in a manner that requires activation of the target receptor and that can be modulated by Src. Loss of Mig6 is a driving event in human cancer; analysis of 1,057 gliomas reveals frequent focal deletions of ERRFI1, the gene that encodes Mig6, in EGFR-amplified glioblastomas.

| S-EPMC4790445 | biostudies-literature

Mechanism for activation of the EGF receptor catalytic domain by the juxtamembrane segment.

Project description:Signaling by the epidermal growth factor receptor requires an allosteric interaction between the kinase domains of two receptors, whereby one activates the other. We show that the intracellular juxtamembrane segment of the receptor, known to potentiate kinase activity, is able to dimerize the kinase domains. The C-terminal half of the juxtamembrane segment latches the activated kinase domain to the activator, and the N-terminal half of this segment further potentiates dimerization, most likely by forming an antiparallel helical dimer that engages the transmembrane helices of the activated receptor. Our data are consistent with a mechanism in which the extracellular domains block the intrinsic ability of the transmembrane and cytoplasmic domains to dimerize and activate, with ligand binding releasing this block. The formation of the activating juxtamembrane latch is prevented by the C-terminal tails in a structure of an inactive kinase domain dimer, suggesting how alternative dimers can prevent ligand-independent activation.

| S-EPMC2814540 | biostudies-literature

Hypoxia-mediated upregulation of MCT1 expression supports the glycolytic phenotype of glioblastomas.

Project description:Glioblastomas (GBM) present a high cellular heterogeneity with conspicuous necrotic regions associated with hypoxia, which is related to tumor aggressiveness. GBM tumors exhibit high glycolytic metabolism with increased lactate production that is extruded to the tumor microenvironment through monocarboxylate transporters (MCTs). While hypoxia-mediated regulation of MCT4 has been characterized, the role of MCT1 is still controversial. Thus, we aimed to understand the role of hypoxia in the regulation of MCT expression and function in GBM, MCT1 in particular.Expression of hypoxia- and glycolytic-related markers, as well as MCT1 and MCT4 isoforms was assessed in in vitro and in vivo orthotopic glioma models, and also in human GBM tissues by immunofluorescence/immunohistochemistry and Western blot. Following MCT1 inhibition, either pharmacologically with CHC (?-cyano-4-hydroxynnamic acid) or genetically with siRNAs, we assessed GBM cell viability, proliferation, metabolism, migration and invasion, under normoxia and hypoxia conditions.Hypoxia induced an increase in MCT1 plasma membrane expression in glioma cells, both in in vitro and in vivo models. Additionally, treatment with CHC and downregulation of MCT1 in glioma cells decreased lactate production, cell proliferation and invasion under hypoxia. Moreover, in the in vivo orthotopic model and in human GBM tissues, there was extensive co-expression of MCT1, but not MCT4, with the GBM hypoxia marker CAIX.Hypoxia-induced MCT1 supports GBM glycolytic phenotype, being responsible for lactate efflux and an important mediator of cell survival and aggressiveness. Therefore, MCT1 constitutes a promising therapeutic target in GBM.

| S-EPMC5216802 | biostudies-other

Comparison of EGF and PDGF driven glioblastomas.

Project description:Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor. Epidermal growth-factor (EGF) and platelet-derived growth-factor (PDGF) receptors are frequently amplified and/or possess gain-of-function mutations in these tumors. Despite years of research into tyrosine-kinase inhibitors, clinical trials have shown disappointing efficacy. One of the underlying reasons is intra-tumor heterogeneity. To assess the effect of intra-tumor heterogeneity on gene expression, we derived a general approach to map single-cell expression profiles to sequentially-acquired mutations identified from exome sequencing. Using 288 single cells, we constructed high-resolution phylogenies of EGF-driven and PDGF-driven GBMs, modeling transcriptional kinetics during tumor evolution. A deletion in a PDGF-receptor domain involved in dimerization correlated to an up-regulation of the PI3K/AKT pathway in a proneural GBM, and ectopic expression of this mutant PDGFRA in vitro enhanced proliferation and invasiveness. Descending the phylogenetic tree of the PDGFR-driven tumor corresponded to a progressive induction of an oligodendrocyte progenitor-like cell type that expresses growth and angiogenic factors. In contrast, phylogenetic analysis of an EGFR-amplified tumor showed a gradual up-regulation of pro-invasive genes.

| EGAS00001001900 | EGA

Opposing Effects of EGF Receptor Signaling on Proliferation and Differentiation Initiated by EGF or TSH/EGF Receptor Transactivation.

Project description:Regulation of thyroid cells by thyrotropin (TSH) and epidermal growth factor (EGF) has been known but different effects of these regulators on proliferation and differentiation have been reported. We studied these responses in primary cultures of human thyroid cells to determine whether TSH receptor (TSHR) signaling may involve EGF receptor (EGFR) transactivation. We confirm that EGF stimulates proliferation and de-differentiation whereas TSH causes differentiation in the absence of other growth factors. We show that TSH/TSHR transactivates EGFR and characterize it as follows: (1) TSH-induced upregulation of thyroid-specific genes is inhibited by 2 inhibitors of EGFR kinase activity, AG1478 and erlotinib; (2) the mechanism of transactivation is independent of an extracellular EGFR ligand by showing that 2 antibodies, cetuximab and panitumumab, that completely inhibited binding of EGFR ligands to EGFR had no effect on transactivation, and by demonstrating that no EGF was detected in media conditioned by thyrocytes incubated with TSH; (3) TSH/TSHR transactivation of EGFR is different than EGFR activation by EGF by showing that EGF led to rapid phosphorylation of EGFR whereas transactivation occurred in the absence of receptor phosphorylation; (4) EGF caused downregulation of EGFR whereas transactivation had no effect on EGFR level; (5) EGF and TSH stimulation converged on the protein kinase B (AKT) pathway, because TSH, like EGF, stimulated phosphorylation of AKT that was inhibited by EGFR inhibitors; and (6) TSH-induced upregulation of thyroid genes was inhibited by the AKT inhibitor MK2206. Thus, TSH/TSHR causes EGFR transactivation that is independent of extracellular EGFR ligand and in part mediates TSH regulation of thyroid hormone biosynthetic genes.

| S-EPMC9761572 | biostudies-literature

Participation of Tom1L1 in EGF-stimulated endocytosis of EGF receptor.

Project description:Although many proteins have been shown to participate in ligand-stimulated endocytosis of EGF receptor (EGFR), the adaptor protein responsible for interaction of activated EGFR with endocytic machinery remains elusive. We show here that EGF stimulates transient tyrosine phosphorylation of Tom1L1 by the Src family kinases, resulting in transient interaction of Tom1L1 with the activated EGFR bridged by Grb2 and Shc. Cytosolic Tom1L1 is recruited onto the plasma membrane and subsequently redistributes into the early endosome. Mutant forms of Tom1L1 defective in Tyr-phosphorylation or interaction with Grb2 are incapable of interaction with EGFR. These mutants behave as dominant-negative mutants to inhibit endocytosis of EGFR. RNAi-mediated knockdown of Tom1L1 inhibits endocytosis of EGFR. The C-terminal tail of Tom1L1 contains a novel clathrin-interacting motif responsible for interaction with the C-terminal region of clathrin heavy chain, which is important for exogenous Tom1L1 to rescue endocytosis of EGFR in Tom1L1 knocked-down cells. These results suggest that EGF triggers a transient Grb2/Shc-mediated association of EGFR with Tyr-phosphorylated Tom1L1 to engage the endocytic machinery for endocytosis of the ligand-receptor complex.

| S-EPMC2756567 | biostudies-literature

Peroxisome proliferator-activated receptor gamma upregulation and dietary fat levels in laying hens.

Project description:The present study was conducted to investigate the effect of feeding the different levels of the dietary fat on the expression of genes encoding proteins involving energy metabolism, oxidative phosphorylation, and lipid synthesis including peroxisome proliferator-activated receptor gamma (PPARγ) of laying hens in the intestine. Birds fed diets with 3 levels of fat, that is, low (LF), medium (MF), and high fat (HF) were reared from 22 to 42 wk of age. Jejunum tissue was collected at week 42 for gene expression analysis. Dietary fat content as ether extract, net energy to AME ratio, and CP content of 3 treatment groups were as follows: LF: 25, 0.735, 187 (g/kg, DM); MF: 61, 0.739, 185 (g/kg, DM); HF: 73, 0.752, 181 (g/kg, DM). The BW, fat pad weight (g), fat pad-to-BW ratio (%) was the same for all the treatments (P > 0·05). Birds fed a diet containing HF increased the AME daily intake per metabolic BW (BW0.75) (P < 0.05). The expression of jejunal PPARγ was increased in the birds fed MF than that fed LF (P < 0.05). Dietary fat level did not affect the expression of other genes: protein kinase AMP-activated noncatalytic subunit gamma 2, NADH dehydrogenase subunit 2, succinate dehydrogenase complex flavoprotein subunit A, ubiquinol-cytochrome c reductase Rieske iron-sulfur polypeptide 1, cytochrome c oxidase subunit III, ATP synthase subunit alpha, avian adenine nucleotide translocator, and acetyl-CoA carboxylase alpha (P > 0·05). The mitochondrial count per cell showed no difference among the 3 groups with different dietary treatments (P > 0·05). The results suggest that PPARγ may be important to the energy expenditure during nutrient absorption, digestion, and metabolism, and respiratory chain complexes, and other genes involving mitochondrial energy metabolism and lipogenesis may be less responsive to dietary treatment.

| S-EPMC8005814 | biostudies-literature

Manipulating the lateral diffusion of surface-anchored EGF demonstrates that receptor clustering modulates phosphorylation levels.

Project description:Upon activation, the epidermal growth factor (EGF) receptor becomes phosphorylated and triggers a vast signaling network that has profound effects on cell growth. The EGF receptor is observed to assemble into clusters after ligand binding and tyrosine kinase autophosphorylation, but the role of these assemblies in the receptor signaling pathway remains unclear. To address this question, we measured the phosphorylation of EGFR when the EGF ligand was anchored onto laterally mobile and immobile surfaces. We found that cells generated clusters of ligand-receptor complex on mobile EGF surfaces, and displayed a lower ratio of phosphorylated EGFR to EGF when compared to immobilized EGF that is unable to cluster. This result was verified by tuning the lateral assembly of ligand-receptor complexes on the surface of living cells using patterned supported lipid bilayers. Nanoscale metal lines fabricated into the supported membrane constrained lipid diffusion and EGF receptor assembly into micron and sub-micron scale corrals. Single cell analysis indicated that clustering impacts EGF receptor activation, and larger clusters (>1 ?m(2)) of ligand-receptor complex generated lower EGF receptor phosphorylation per ligand than smaller assemblies (<1 ?m(2)) in HCC1143 cells that were engaged to ligand-functionalized surfaces. We investigated the mechanism of EGFR clustering by treating cells with compounds that disrupt the cytoskeleton (Latrunculin B), clathrin-mediated endocytosis (Pitstop2), and inhibit EGFR activation (Gefitinib). These results help elucidate the nature of large-scale EGFR clustering, thus underscoring the general significance of receptor spatial organization in tuning biochemical function.

| S-EPMC3609930 | biostudies-other

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data