Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 HER family of receptor tyrosine kinase couples binding of extracellular growth factor ligands to intracellular signal transduction pathways, contributing in this fashion to the ability of the cell to respond correctly to its environment. The HER family and its ligands are critically involved in the carcinogenesis of the mammary gland. Abnormal function of the members of HER family resulting in receptor hyper-activation (due to gene amplification, protein overexpression or abnormal transcriptional regulation) has been linked with breast cancer prognosis. It is also extensively studied as the predictive factor and target for therapy. There are clinical indications supporting the concept that none of the receptors: EGFR, HER2, HER3 and HER4 can be considered as the stand-alone receptor in breast cancer development and clinical course of the disease. There is a growing body of evidence that cooperation between them contributes to more aggressive tumor phenotype and influences the response to therapy. This underlines the importance of quantification of all HER family members and indicates the urgent need for implementation of methods that can efficiently and reliably examine four HER receptors as a whole panel in breast cancer patients.
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PMID:The diverse signaling network of EGFR, HER2, HER3 and HER4 tyrosine kinase receptors and the consequences for therapeutic approaches. 1594 51

The human epidermal growth factor (EGF) receptor (HER) family of receptor tyrosine kinases has frequently been implicated in cancer. Apart from overexpression or mutation of these receptors, also the aberrant autocrine or paracrine activation of HERs by EGF-like ligands may be important in cancer progression. Neuregulins constitute a family of EGF-like ligands that bind to HER3 or HER4, preferably forming heterodimers with the orphan receptor HER2. Mesenchymal neuregulin typically serves as a pro-survival and pro-differentiation signal for adjacent epithelia. Disruption of the balance between proliferation and differentiation, because of autocrine production by the epithelial cells, increased sensitivity to paracrine signals or disruption of the spatial organization, may lead to constitutive receptor activation, in the absence of receptor overexpression. Consequently, the analysis of ligand expression and/or activated receptors in tumor samples may broaden the group of patients that can benefit from targeted therapies.
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PMID:Roles for neuregulins in human cancer. 1603 12

The epidermal growth factor (EGF) system is ubiquitous in humans and plays fundamental roles in embryogenesis, development, proliferation and differentiation. As the endometrium of fertile women is characterized by proliferation and differentiation, we hypothesize a role for the EGF system. Fourteen premenopausal women had endometrial samples removed on day 6 +/- 1 and day 6 +/- 1 and 12 +/- 1 after ovulation during one menstrual cycle. RNA was extracted and analysed by real-time PCR, and immunohistochemistry was performed to localize the components of the EGF system. Human EGF Receptor 1 (HER1) showed highest expression during the proliferative phase, HER2 and HER4 during the early and HER3 during the late secretory phase. Amphiregulin (AR) and transforming growth factor alpha (TGFalpha) expression is highest in proliferative phase. Heparin binding (HB)-EGF and betacellulin (BCL) show no variation. Epiregulin (EP) is detectable in some samples. EGF is undetectable. HER1, HER2, HER3 and HER4 were localized to the epithelium and glands HER3 and HER4 solely in the secretory phase. Amphiregulin was seen in leucocytes and stromal cells, TGFalpha and betacellulin in the epithelial lining, epiregulin in stromal cells whereas HB-EGF and EGF are undetectable. In conclusions, we observed cyclical expression of the four EGF receptors and two ligands and localized all four receptors and four ligands in endometrial biopsies. This suggests a role for the EGF system in growth of the endometrium.
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PMID:Expression of the epidermal growth factor system in human endometrium during the menstrual cycle. 1610 Feb 39

The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases is part of a network of pathways that are involved in the development and progression of prostate cancer. HER-kinase receptors include epidermal growth factor receptor (EGFR), HER2, HER3, and HER4, which must combine as dimers to affect signaling. Different combinations of receptors produce different qualities and levels of pathway activation. Among HER-family receptors, HER2 activation is particularly important in breast cancer, as HER2 gene amplification is associated with a distinct clinical course and response to treatment with a HER2-directed therapy (trastuzumab). Although HER2 can be over-expressed in prostate cancer, there is no clinical data to support the use of trastuzumab for prostate cancer patients. Preclinical and clinical data show that the activation of the HER-kinase axis is important for the progression of prostate cancer to androgen-independent disease. Data points towards the importance of inhibiting multiple members of the HER-kinase family to achieve more complete blockade of this axis for cancers other than HER2-overexpressing breast cancer. Multiple pharmaceutical agents that block the HER-kinase axis are currently being tested for patients with prostate cancer. These include antibodies, tyrosine kinase inhibitors, and novel strategies which seek to decrease HER2 expression.
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PMID:Update on HER-kinase-directed therapy in prostate cancer. 1616 60

The EGFR family consists of 4 receptor tyrosine kinases, EGFR (ERBB1), ERBB2 (HER2), ERBB3 (HER3) and ERBB4 (HER4). Recent reports revealed that the kinase domains of both EGFR (ERBB1) and ERBB2 gene were somatically mutated in human cancers, raising the possibility that the other ERBB members possess somatic mutations in human cancers. Here, we performed mutational analysis of the ERBB4 kinase domain by polymerase chain reaction-single-strand conformation polymorphism assay in 595 cancer tissues from stomach, lung, colon and breast. We detected the ERBB4 somatic mutations in 3 of 180 gastric carcinomas (1.7%), 3 of 104 colorectal carcinomas (2.9%), 5 of 217 nonsmall cell lung cancers (2.3%) and 1 of 94 breast carcinomas (1.1%). The 12 ERBB4 mutations consisted of 1 in-frame duplication mutation and 8 missense mutations in the exons, and 3 mutations in the introns. We simultaneously analyzed the somatic mutations of EGFR, ERBB2, K-RAS, PIK3CA and BRAF genes in the 12 samples with the ERBB4 mutations and found that 1 gastric carcinoma with ERBB4 mutation also harbored K-RAS gene mutation. Our study demonstrated that in addition to EGFR and ERBB2, somatic mutation of the kinase domain of ERBB4 occurs in the common human cancers, and suggested that alterations of ERBB4-mediated signaling pathway by ERBB4 mutations may contribute to the development of human cancers.
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PMID:Somatic mutations of the ERBB4 kinase domain in human cancers. 1618 81

The human ErbB family of receptor tyrosine kinases comprises the epidermal growth factor receptor (EGFR/ErbB1/HER1), ErbB2 (HER2/Neu), ErbB3 (HER3), and ErbB4 (HER4). ErbBs play fundamental roles in cell growth and differentiation events in embryonic and adult tissues, and inappropriate ErbB activity has been implicated in several human cancers. We report here the 2.4 A crystal structure of the extracellular region of human ErbB4 in the absence of ligand and show that it adopts a tethered conformation similar to inactive forms of ErbB1 and ErbB3. This structure completes the gallery of unliganded ErbB receptors and demonstrates that all human ligand-binding ErbBs adopt the autoinhibited conformation. We also show that the binding of neuregulin-1beta to ErbB4 and ErbB3 and the binding of betacellulin to both ErbB4 and ErbB1 does not decrease at low pH, unlike the binding of epidermal growth factor and transforming growth factor-alpha to ErbB1. These results indicate an important role for ligand in determining pH-dependent binding and may explain different responses observed when the same ErbB receptor is stimulated by different ligands.
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PMID:The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand. 1620 64

An important recent advance in anticancer therapy was the development of molecular-targeting drugs, such as the epidermal growth-factor receptor (EGFR)-targeting drug ZD1839 (Iressa) and the HER2-trageting anti-HER2 monoclonal antibody trastuzumab (Herceptin). ZD1839 and trastuzumab are reported to improve the therapeutic efficacy of treatment for non-small-cell lung cancer (NSCLC) and breast cancer, respectively, although the effectiveness of either drug alone is not satisfactory. NSCLC cells often express both EGFR and HER2. We therefore investigated whether a combination of ZD1839 and trastuzumab had an additive or synergistic antitumor effect. In culture ZD1839 inhibited the growth of four NSCLC cell lines (A549, NCI-H23, NCI-H727, and NCI-H661) that expressed various levels of EGFR, HER2, HER3, and HER4. A significant cytotoxic effect was observed when ZD1839 was combined with trastuzumab in A549 cells. However, this combination had no apparent effect in NCI-H23 cells. Significant G(1)-phase arrest, increased p27 expression and decreased cyclin E or D1 levels were detected in A549 cells treated with ZD1839 and trastuzumab. No significant effects were detected in NCI-H23 cells examined. The combination treatment significantly inhibited the phosphorylation of EGFR, HER2, retinoblastoma, extracellular signal-regulated kinase-1/2, and protein kinase B/Akt in A549 cells, but not in NCI-H23 cells. Our results indicated that increased levels of constitutive EGFR/HER2 heterodimers were formed in A549 cells in the presence of ZD1839, whereas no heterodimer formation was detected in NCI-H23 cells. We therefore suggest that combination treatment with ZD1839 and trastuzumab might have improved therapeutic efficacy against NSCLC cells expressing both EGFR and HER2.
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PMID:Cooperative cell-growth inhibition by combination treatment with ZD1839 (Iressa) and trastuzumab (Herceptin) in non-small-cell lung cancer. 1625 59

Neuroblastoma is a common solid tumor of childhood that is derived from the neural crest. Expression of epidermal growth factor (EGF) receptors (EGFRs) has been associated with enhanced cell growth and aggressive behavior in other tumors. Here, we examined the expression profile of EGFRs in neuroblastoma cell lines and primary tumors. We found that all 13 neuroblastoma cell lines examined expressed EGFR1 (HER1), most at readily detectable levels. Low levels of other human EGFR family receptors were also detected in almost all cell lines. All primary tumors examined expressed readily detectable levels of HER1 and HER3 and lower levels of HER2 and HER4. EGF had a significant effect on the proliferation of neuroblastoma cell lines in vitro. EGF treatment (100 ng/mL) of the cell lines SY5Y and NLF significantly increased cell number (P < 0.01). EGF stimulated more cells to enter S and G2-M phase, as suggested by flow cytometry, indicating that EGF increases cell number by increasing proliferation, with no appreciable change in apoptosis. EGF exposure resulted in receptor autophosphorylation and activation of both the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT pathways. Exposure to 0.5 micromol/L ZD1839, a HER1-specific inhibitor, caused a 40% to 50% reduction in the number of SY5Y and NLF cells grown in medium containing 10% fetal bovine serum (P < 0.01). Even at 0.01 micromol/L, ZD1839 inhibited autophosphorylation of HER1 by EGF. At 0.1 micromol/L, it also blocked phosphorylation of AKT, but not MAPK, in NLF cells. Additional studies showed that the PI3K/AKT-specific inhibitor LY294002 had a more profound effect than the MAPK-specific inhibitor U0126 in blocking EGF-induced cell proliferation. This suggests that the PI3K/AKT pathway is the main signaling pathway responsible for the proliferation effects of EGF in neuroblastomas. Our results also indicate that ZD1839 is a potent inhibitor of neuroblastoma cell proliferation; therefore, it may be a useful, biologically based therapeutic agent for these tumors.
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PMID:Proliferation of human neuroblastomas mediated by the epidermal growth factor receptor. 1626 10

Inhibition of the epidermal growth factor receptor (EGFR) represents one of the most important avenues for research and development in the field of cancer therapy. The EGFR is a member of the ErbB receptor tyrosine kinase (TK) family, which also includes ErbB-2 (HER2/neu), ErbB-3 (HER3), and ErbB-4 (HER4). Current EGFR therapies available for use include monoclonal antibodies, such as cetuximab, and small-molecule EGFR TK inhibition by agents such as erlotinib. Side effects of these agents include dermatologic manifestations without the bone marrow suppressive properties of chemotherapy. Understanding of rash and how it relates to EGFR inhibitor toxicity and, perhaps more importantly, EGFR inhibitor response must be more clearly defined with clinical trials. The optimum management of rash in patients receiving anti-EGFR therapy remains somewhat controversial; this is secondary to imprecise classification of rash as well as the lack of clinical trials to determine the most appropriate treatment algorithm for these patients. We propose a treatment strategy to help aggressively treat dermatologic side effects allowing patients to continue receiving therapy without dose interruption or drug discontinuation.
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PMID:Management of rash and other toxicities in patients treated with epidermal growth factor receptor-targeted agents. 1633 49

The Neuregulins (NRGs) are members of the epidermal growth factor (EGF) family of growth factors. EGF family members regulate the signaling of ErbB family receptor tyrosine kinases, including the epidermal growth factor receptor (EGFR/ErbB1), ErbB2/HER2/Neu, ErbB3/HER3 and ErbB4/HER4. We have previously demonstrated that the EGF family hormone NRG2beta is a potent ErbB4 agonist, whereas NRG2alpha is a weak ErbB4 agonist. We have also previously demonstrated that Phe45 of NRG2beta regulates the potency of NRG2beta. Here, we address the hypotheses that Phe45 regulates the potency of NRG2beta by regulating the affinity of NRG2beta for ErbB4. We demonstrate that Phe45 of NRG2beta indeed regulates the affinity of NRG2beta for ErbB4. Furthermore, a hydrophobic or uncharged amino acid side chain at residue 45 contributes to NRG2beta binding to ErbB4. These data indicate that Phe45 of NRG2beta may regulate the affinity of NRG2beta for ErbB4 by interacting with hydrophobic amino acids in ErbB4.
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PMID:Phe45 of NRG2beta is critical for the affinity of NRG2beta for ErbB4 and for potent stimulation of ErbB4 signaling by NRG2beta*. 1633 90


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