• Recently, we isolated a novel negative regulator of epidermal growth factor receptor (EGFR), termed EGFR-related protein (ERRP), whose expression attenuates EGFR activation. (aacrjournals.org)
  • In the current study, we examined the effects of recombinant ERRP on the growth and ligand-induced activation of multiple members of erbB family in three pancreatic cancer cell lines that express varying levels of EGFR and other member(s) of its family, specifically HER-2. (aacrjournals.org)
  • ERRP also inhibited ligand-induced activation of EGFR, HER-2, and HER-3 (ErbB3). (aacrjournals.org)
  • In contrast, Erbitux and Herceptin only partially or modestly inhibited activation of EGFR, HER-2, and HER-3. (aacrjournals.org)
  • The ErbB/HER family of receptor tyrosine kinases (RTKs) consists of four family members: the epidermal growth factor receptor (EGFR/ErbB1), HER2 (ErbB2/Neu), HER3 (ErbB3), and HER4 (ErbB4). (plos.org)
  • ErbB receptors comprise a family of four RTKs (EGFR/ErbB1, Her2/ErbB2, Her3/ErbB3 and Her4/ErbB4) with important roles in normal cell physiology and in cancer 1 . (nature.com)
  • Here we exploit the multiplexing capabilities of Exchange-PAINT, a multiplexed variant of DNA-PAINT 14 , to image simultaneously five RTKs (EGFR, ErbB2, ErbB3, IGF-1R and Met) at endogenous levels of expression in BT20 cancer cells and to examine how receptor distribution changes following ligand stimulation. (nature.com)
  • Mutations in epidermal growth factor receptor ( EGFR ), KRAS, and anaplastic lymphoma kinase ( ALK ) are mutually exclusive in patients with NSCLC, and the presence of one mutation in lieu of another can influence response to targeted therapy. (medscape.com)
  • Initial studies with the EGFR tyrosine kinase inhibitors (TKIs) gefitnib (Iressa) and erlotinib (Tarceva) demonstrated biologic and clinical activity in only a relatively limited subset of lung cancers. (medscape.com)
  • [ 9 ] Most importantly, patients with KRAS mutations seem to have a poorer prognosis and seem to be resistant to EGFR-TKIs, although the extent to which this might influence treatment selection remains somewhat unclear. (medscape.com)
  • This approach has made significant headway in a number of cancers, such as breast and lung carcinoma, where alterations in the EGFR/ERBB pathways proved to be the main drivers that could be targeted with specific small molecules [ 11 , 12 ]. (biomedcentral.com)
  • This family, which includes epidermal growth factor receptor (EGFR), plays a pivotal role in normal cell growth, lineage determination, repair, and functional differentiation. (medscape.com)
  • Selective compounds have been developed that target either the extracellular ligand-binding region of the EGFR (including a number of monoclonal antibodies [MAbs], immunotoxins, and ligand-binding cytotoxic agents) or the intracellular tyrosine kinase region (including various small-molecule inhibitors). (medscape.com)
  • Subsequently, lapatinib, an orally bioavailable small molecule dual HER2- and EGFR/HER1-specific tyrosine kinase inhibitor, received Food and Drug Administration (FDA) approval in combination with capecitabine for patients with advanced HER2+ breast cancer. (carcinogenesis.com)
  • For NSCLC, much of the work in the last decade has been focussed on mutations of the epidermal growth factor receptor (EGFR) and on the abnormal fusion of the anaplastic lymphoma kinase (ALK) being inhibited successfully with EGFR tyrosine kinase inhibitors (TKI) and crizotinib respectively. (amegroups.org)
  • Activation of MAPK is initiated by one of the four ErbB receptors (ErbB1/epidermal growth factor receptor (EgfR), ErbB2-4), which leads to signaling through Raf (RAF proto-oncogene serine/threonine-protein kinase), Mek (mitogen-activated protein kinase kinase 1/2) and Erk. (biomedcentral.com)
  • The assay detected signal across at least 3 orders of magnitude of lysate input with a linear range spanning 1-2 orders and a low femtomole limit of detection for EGFR phosphotyrosine. (biomedcentral.com)
  • Lung cancer with epidermal growth factor receptor (EGFR)-activating mutations responds favorably to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. (aacrjournals.org)
  • Gene amplification, overexpression and hyperactivity of the epidermal growth factor receptor (EGFR) is frequently observed in non-small cell lung cancer (NSCLC), head and neck cancer (HNSCC), breast and colorectal cancer (CRC). (wisc.edu)
  • Therefore, the EGFR has been one of the most targeted receptors in all of oncology. (wisc.edu)
  • Herein, we summarized the novel agents in tyrosine kinase inhibitors especially for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitors, checkpoint inhibitors, and other potential immunotherapy aiming to provide a landscape of emerging agents for NSCLC as well as insights and perspectives for the future in anticancer treatment. (biomedcentral.com)
  • The erbB family of receptor tyrosine kinases plays critical roles in human cancers, including pancreatic cancer. (aacrjournals.org)
  • Nuclear localized HER family receptor tyrosine kinases (RTKs) have been observed in primary tumor specimens and cancer cell lines for nearly two decades. (plos.org)
  • Signal transduction by receptor tyrosine kinases (RTKs) involves complex ligand- and time-dependent changes in conformation and modification state. (nature.com)
  • We report the use of multiplexed super-resolution imaging (Exchange-PAINT) followed by mean-shift clustering and random forest analysis to measure the precise distributions of five receptor tyrosine kinases (RTKs) from the ErbB, IGF-1R and Met families in breast cancer cells. (nature.com)
  • The HER (erbB) family of transmembrane receptor tyrosine kinases is one of the cytostatic targets in tumor cell growth and survival. (medscape.com)
  • 1) We study Cbl proteins, a family of ubiquitin ligases that negatively regulate signaling by receptor tyrosine kinases. (cancer.gov)
  • Cbl proteins belong to the RING finger class of ubiquitin protein ligases (E3s) and function as E3s for activated tyrosine kinases. (cancer.gov)
  • HER2 is a member of the cErbB family of receptor tyrosine kinases, and is responsible for HER2-mediated signal transduction in the cytoplasm. (carcinogenesis.com)
  • These mutations in receptors or protein kinases can stimulate a complex cascade of cross signalling pathways such as the RAS-RAF-MEK-ERK or MAPK, PI3K-AKT-mTOR or JAK-STAT pathways ( Figure 2 ) ( 3 , 4 , 7 , 18 , 20 ). (amegroups.org)
  • My laboratory is focused on understanding mechanisms of resistance to molecular targeting agents directed against receptor tyrosine kinases. (wisc.edu)
  • Monoclonal antibody therapy has been developed over the past 30 years to target receptor tyrosine kinases (RTKs), which sit on the outer membrane of cancerous cells. (wisc.edu)
  • EphB4 is a member of the largest family of receptor tyrosine kinases and is an important regulator of fundamental physiological and pathophysiological processes such as tissue patterning during development, angiogenesis and tumour progression [ 1 ]. (oncotarget.com)
  • Discovering a specific agent, which targets multiple members of the erbB family, would be important in pancreatic cancer therapy. (aacrjournals.org)
  • The HER2 receptor does not bind to any known ligands, however, its dimerization arm is innately positioned in an open conformation. (plos.org)
  • The role of human EGFR2 (HER2), a member of the ERBB family of tyrosine kinase receptors, has been studied for NSCLC. (medscape.com)
  • The proto-oncogene designated erbB2 or HER2 encodes a 185-kilodalton transmembrane tyrosine kinase (p185erbB2), whose overexpression has been correlated with a poor prognosis in several human malignancies. (embl.de)
  • Breast cancer tumors that do not express hormone receptors or have amplification of Her2/Neu (so called triple-negative tumors) have a poor prognosis and no validated molecular targets. (cancer.gov)
  • With the addition of trastuzumab, a monoclonal antibody targeting the human epidermal growth factor receptor-2 (HER2), improvements in overall survival have been observed among patients with advanced HER2-positive disease. (carcinogenesis.com)
  • One type of breast cancer is identified by the human epidermal growth factor receptor 2 (HER2) gene amplification. (carcinogenesis.com)
  • Caco-2 cells with a high expression of both HER2 and FASN were selected for functional characterization. (biomedcentral.com)
  • Caco-2 cells were transfected with either the FASN specific RNAi plasmid or the negative control RNAi plasmid, followed by the RT-qPCR and western blot to examine the expression of FASN, HER2, PI3K and Akt. (biomedcentral.com)
  • Membrane-bound HER receptors activate numerous tumor promoting signaling cascades via this mechanism, including the PI3K/AKT, Ras/Raf/Mek/Erk, PLCγ/PKC, and signal transducer and activator of transcription (STAT) pathways [1] , [2] . (plos.org)
  • Transcriptome analysis demonstrates the involvement of BCL6 in tumor protein p53 (TP53), erythroblastic leukemia viral oncogene homolog (ErbB), and MAPK signaling pathways. (bvsalud.org)
  • Mechanistically, we found that lycopene and sorafenib could additively inhibit the mitogen-activated protein kinase (MAPK) pathways, as shown by the protein phosphorylation of ERK1/2, JNK1/2 and p38 were reduced additively. (frontiersin.org)
  • Here, we present a mathematical model of receptor sorting into alternative pathways that explains the EGF-concentration dependent response of CIE. (biomedcentral.com)
  • Further, we describe extensibility of the model to more than two pathways which might play a role in contexts other than receptor internalization. (biomedcentral.com)
  • This is especially important since a receptor modification discriminating between the pathways has not been found experimentally. (biomedcentral.com)
  • the distribution of receptors into the two pathways was shown to be EGF-concentration dependent. (biomedcentral.com)
  • Furthermore, the effect of growth factors, hormones and their receptors on FASN expression involves a complicated downstream signaling and crosstalk between multiple signal transduction pathways. (biomedcentral.com)
  • In addition, the ErbB receptors integrate a diverse array of signals, both at the cell surface level and through cross-talk with other pathways, such as the phosphoinositide 3-kinase (Pi3k) pathway [ 11 ]. (biomedcentral.com)
  • There is a great interest in studying phosphotyrosine dependent protein-protein interactions in tyrosine kinase pathways that play a critical role in many aspects of cellular function. (biomedcentral.com)
  • These receptors are responsible for activating key pathways in cancer cells that lead to their proliferation and survival. (wisc.edu)
  • Translational research advances now allow such mutations to be inhibited by either receptor monoclonal antibodies (mAb) or small molecule tyrosine kinase inhibitors (TKI). (amegroups.org)
  • Tyrosine kinase inhibitors and immunotherapy for lung cancer are the two major areas undergoing rapid development. (biomedcentral.com)
  • Herein, we summarize emerging agents including tyrosine kinase inhibitors, checkpoint inhibitors, and other potential immunotherapy such as chimeric antigen receptor T cell for non-small cell lung cancer attempting to provide insights and perspectives of the future in anticancer treatment. (biomedcentral.com)
  • they then form homodimers or heterodimers, often consisting of ERBB2, which is thought to function as a co-receptor as it has not been observed to bind any ligand. (wikipedia.org)
  • In a second project we are investigating the induction of apoptosis by activation of death receptors for the ligand TRAIL in breast and ovarian cancer cells. (cancer.gov)
  • We have shown that most breast and ovarian cancer cell lines are resistant to the induction of apoptosis by TRAIL, the ligand for the death receptors DR4 and DR5. (cancer.gov)
  • The Epidermal Growth Factor (EGF) receptor has been shown to internalize via clathrin-independent endocytosis (CIE) in a ligand concentration dependent manner. (biomedcentral.com)
  • Ligand induced phosphorylation of EGF receptor creates docking sites for adaptor proteins, such as EPS15, epsin and AP-2 [ 6 , 7 ]. (biomedcentral.com)
  • Despite significant promiscuity between other Eph family members and the ephrin ligands, the single physiologically-relevant ligand of the EphB4 receptor is ephrin-B2 [ 2 ]. (oncotarget.com)
  • Both the receptor and the ligand are membrane-bound but usually expressed on neighbouring cells. (oncotarget.com)
  • This process leads to the activation of each receptors' tyrosine kinase and the subsequent phosphorylation of tyrosine residues located on their C-terminal tails. (plos.org)
  • NRGs bind to the ERBB receptors to promote phosphorylation of specific tyrosine residues on the C-terminal link of the receptor and the interactions of intracellular signaling proteins. (wikipedia.org)
  • We previously established SH2 profiling, a phosphoproteomic approach based on membrane binding assays that utilizes purified Src Homology 2 (SH2) domains as a molecular tool to profile the global tyrosine phosphorylation state of cells. (biomedcentral.com)
  • An important consequence of reversible phosphorylation of tyrosine residues on proteins is the creation of binding sites for phosphotyrosine recognizing domains such as Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains [ 1 , 2 ]. (biomedcentral.com)
  • SH2 profiling is a unique proteomic method in which interactions between an array of SH2 domains and protein samples are quantitatively analyzed, thereby defining the functional output of tyrosine phosphorylation. (biomedcentral.com)
  • Most importantly, ERRP was found to inhibit pancreatic tumor growth in a severe combined immunodeficient mouse xenograft model. (aacrjournals.org)
  • This study aimed to identify molecular determinants of sensitivity of non-small cell lung cancer (NSCLC) to anti-insulin-like growth factor receptor (IGF-IR) therapy.A total of 216 tumor samples were investigated, of which 165 consisted of retrospective analyses of banked tissue and an additional 51 were from patients enrolled in a phase II study of figitumumab, a monoclonal antibody against IGF-IR, in stage IIIb/IV NSCLC. (omicsdi.org)
  • We have identified anti-cancer effects of Huaier, and its unique characteristics of 1) no side effects or toxicity, 2) in dose dependent manner, 3) causing specific cancer cell death with simultaneous tissue regeneration, 4) miRNA-mediated transcriptional control on the rescue of multiple signal transduction, by dependent on individual genomic potential. (fortunejournals.com)
  • Phosphorylated tyrosine residues recruit various intracellular adaptor and effector molecules that result in the propagation of growth promoting signal transduction cascades [1] , [2] . (plos.org)
  • It first binds with high affinity to specific cell-surface receptors and then induces their dimerization, which is essential for activating the tyrosine kinase in the receptor cytoplasmic domain, initiating a signal transduction that results in DNA synthesis and cell proliferation. (embl.de)
  • Although the lack of estrogen receptor β (ERβ) is a risk factor for the development of inflammatory bowel disease (IBD) and psychiatric disorders, the underlying cellular and molecular mechanisms are not fully understood. (biomedcentral.com)
  • Besides estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, novel biomarkers have shown their prognostic and predictive values, complicating our understanding towards to the heterogeneity of such cancers. (jcancer.org)
  • Back to 1970s, breast cancer was divided into two subtypes according to the status of estrogen receptor (ER). (jcancer.org)
  • This family of RTKs has been highly implicated in the formation and progression of various cancers via aberrant overexpression, kinase activation, and mutation [1] , [2] . (plos.org)
  • While the classical membrane-bound functions of HER family RTKs have been extensively studied, accumulating data suggest that these receptors can be found in the cell's nucleus where they can function as co-transcriptional activators [4] , [5] . (plos.org)
  • High resolution structures are available for individual receptors dimers, but less is known about receptor clusters that form in plasma membranes composed of many different RTKs with the potential to interact. (nature.com)
  • Of the 31 genes, the 21 upregulated genes were primarily associated with cell paracrine and intracellular signaling, transcription regulation and cell adhesion and migration, and their transcriptional products included transforming growth factor-β2 (TGF-β2), insulin-like growth factor-binding protein 2 and transcriptional factor AP-2α/γ ( 11 ). (spandidos-publications.com)
  • However, the regions of each receptor that confer transcriptional potential remain poorly defined. (plos.org)
  • To understand how the B 1 and B 2 regions influenced the transcriptional functions of nuclear HER3, we performed cyclin D1 promoter-luciferase assays in which HER3 deleted of the B 1 and B 2 regions was severely hindered in regulating this promoter. (plos.org)
  • Importantly, we discover that receptor tyrosine kinase AXL is a transcriptional target of BCL6 in GBM and mediates partially the regulatory effects of BCL6 on both MEK-ERK (mitogen-activated protein/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase) and S6K-RPS6 (ribosomal protein S6 kinase-ribosomal protein S6) axes. (bvsalud.org)
  • The utmost induction of transcriptional CYP2C genes seems to become reached attributable to a cross talk with the coordination concerning drug use nuclear receptors, liver components and co-activators. (dna-pkinhibitors.com)
  • sselw Keywords CYP2C human transcriptional regulation, induction medicines, nuclear receptor liver hypoxia Introduction The cytochromes P450 are a superfamily of enzymes that catalyze the metabolism of medicines and chemical compounds, and xenobiotics a large number of Ecological compounds endogenously. (dna-pkinhibitors.com)
  • The mitogen-activated protein kinase (MAPK)/Erk pathway plays a central role in cell communication: it orchestrates signaling from external receptors to internal transcriptional machinery, which leads to changes in phenotype [ 6 , 7 ]. (biomedcentral.com)
  • Epidermal growth factor receptor, a well-known biomarker for targeted therapy at present, was first brought up with potential clinical responsiveness to tyrosine kinase inhibitor gefitinib in 2004[ 6 ]. (biomedcentral.com)
  • We are investigating the function of Cbl proteins, a family of proteins that regulate tyrosine kinase activity. (cancer.gov)
  • Via direct or indirect binding, adaptors recruit the receptor to special membrane regions which are characterized by a particular composition of cage-proteins and/or -lipids [ 8 , 9 ]. (biomedcentral.com)
  • Importantly, bortezomib treated BCR ABL transduced mice indicated a clear restoration of expression of these proteins to the levels found in control mice. (mi-rna.com)
  • The crystal structure identifies the role of Ca2+ in maintaining the conformation of the N-terminal region of the domain, but more importantly demonstrates that Ca2+ can directly mediate protein-protein contacts. (embl.de)
  • Several genes in the NRG-ERBB signaling pathway have been implicated in genetic predisposition to schizophrenia, Neuregulin 3 (NRG3) encodes a protein similar to its paralog NRG1 and both play important roles in the developing nervous system. (wikipedia.org)
  • Proteomics-Based Discovery of First-in-Class Chemical Probes for Programmed Cell Death Protein 2 (PDCD2). (stanford.edu)
  • Sustaining proliferative signaling' further differentiates cancers with positive hormone receptors. (jcancer.org)
  • Classically, HER family members function from the cell surface, where binding to cognate ligands can induce receptor homo- or hetero-dimerization with other HER family receptors [3] . (plos.org)
  • EphB4 is a membrane-bound receptor tyrosine kinase (RTK) commonly over-produced by many epithelial cancers but with low to no expression in most normal adult tissues. (oncotarget.com)
  • Cetuximab (IMC- C225, Erbitux) prevents receptor activation and dimerization and ultimately induces receptor internalization and. (wisc.edu)
  • Several mechanisms to generate this behaviour have been described theoretically, the underlying assumptions of which, however, have not been experimentally demonstrated for the EGF receptor internalization network. (biomedcentral.com)
  • The model is not restricted to EGF receptor internalization and might account for ultrasensitivity in other cellular contexts. (biomedcentral.com)
  • Importantly, therapeutic inhibition of β-secretase would decrease production of all forms of Aβ, including the pathogenic Aβ 42 . (jneurosci.org)
  • Molecular analysis of non-small cell lung cancer identifies subsets with different sensitivity to insulin-like growth factor I receptor inhibition. (omicsdi.org)
  • Moreover, targeted inhibition of BCL6/nuclear receptor corepressor 1 (NCoR) complex by peptidomimetic inhibitor not only significantly decreases AXL expression and the activity of MEK-ERK and S6K-RPS6 cascades but also displays a potent antiproliferative effect against GBM cells. (bvsalud.org)
  • Type 2 diabetes mellitus (T2D), characterised by peripheral insulin resistance, is a risk factor for dementia. (biomedcentral.com)
  • Type 2 diabetes mellitus (T2D), characterised by peripheral insulin resistance (IR), is an increasing problem in affluent societies. (biomedcentral.com)
  • Several linear compartment models including an insulin receptor dynamics model are taken to illustrate the application of the proposed approach. (biomedcentral.com)
  • Figitumumab is a fully human IgG2 monoclonal antibody against IGF-1 receptor (IGF-1R). (omicsdi.org)
  • In 2005, the first-ever trial combining small molecular targeted agent known as bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, with doublet chemotherapy, had shown superiority of overall survival with this treatment modality in advanced non-squamous non-small cell lung cancer patients without brain metastasis [ 2 ]. (biomedcentral.com)
  • Human epithelial malignancies frequently display deregulated tyrosine kinase activity. (cancer.gov)
  • The EMT International Association was formed in 2002 to provide an international body for those interested in EMT and the reverse process, mesenchymal-epithelial transition, and, most importantly, to bring together those working on EMT in development, cancer, fibrosis, and pathology. (rupress.org)
  • We have demonstrated that resistance to TRAIL-induced apoptosis can be overcome by co-incubation of the cells with chemotherapeutic agents, semi-synthetic retinoids (such as 4HPR), or molecularly targeted agents (such as anti-ErbB-2 antibodies). (cancer.gov)
  • Neuronal excitation is also influenced by the amounts of neurotransmitter receptors and signaling molecules retained at particular synaptic sites. (frontiersin.org)
  • Recent studies revealed a key role for PSD- 95, a scaffolding molecule enriched at glutamatergic synapses, in modulation of clustering of several neurotransmitter receptors, adhesion molecules, ion channels, cytoskeletal elements and signaling molecules at postsynaptic sites. (frontiersin.org)
  • The postsynaptic compartment of excitatory synapses is characterized by an electron-dense region, referred to as the postsynaptic density (PSD), attributable to the high density of neurotransmitter receptors and associated molecules at these sites. (frontiersin.org)
  • Brand TM, Iida M, Luthar N, Wleklinski MJ, Starr MM, Wheeler DL (2013) Mapping C-Terminal Transactivation Domains of the Nuclear HER Family Receptor Tyrosine Kinase HER3. (plos.org)
  • Fusion between echinoderm microtubule-associated proteinlike 4 ( EML4 ) and ALK is seen in approximately 2-7% of patients with NSCLC adenocarcinomas. (medscape.com)
  • This phase I, open-label, dose-escalation study (ClinicalTrials.gov: NCT00603538) assessed the safety and tolerability of figitumumab (6, 10 and 20 mg/kg) in combination with carboplatin (area under the curve: 6 mg·min/mL) and paclitaxel (200 mg/m(2)) in Japanese patients (N = 19) with chemotherapy-naïve, advanced NSCLC. (omicsdi.org)
  • The correlation of the inflammatory profile with the severity of the disease in neoplastic patients with SARS-CoV-2 infection was addressed. (cdc.gov)
  • The prostaglandin-endoperoxide synthase 2 gene (PTGS2), which encodes cyclooxygenase-2, was found to upregulate the expression of TGF-β2 ( 14 ). (spandidos-publications.com)
  • With the technological advances, we are able to characterize molecular subtypes [2] , [3] of breast cancer which has facilitated the development of molecularly targeted therapeutics. (carcinogenesis.com)
  • Here, we identified 2 distinct MDSC subfractions with clear morphologic, molecular, and functional differences. (ashpublications.org)
  • We find that these receptors are intermixed nonhomogenously on the plasma membrane. (nature.com)
  • Importantly, these Notch pathway alterations were prognostic on multivariate analyses. (biomedcentral.com)
  • It has been shown that the growth factors, hormones and activation of their receptors increased FASN transcription in cancer cells. (biomedcentral.com)
  • The atheroma volume right after 2 many years of therapy with niacin / colestipol of intercontinental transform score and quantitative coronary evaluation yielded the following MBS: regression, no Alterations while in the composition and progress as well as a important improvement in diameter stenosis from light and % minimum by quantitative coronary angiography detected. (dna-pkinhibitors.com)
  • Our main result is that a scenario where different endocytosis routes consume the same form of receptor corroborates the observation of a clear-cut, stimulus dependent sorting. (biomedcentral.com)