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)

Desensitization to the effects of acetylcholine (ACh) or carbachol (CCh) on ACh-regulated potassium current (IK(ACh)) and the voltage-dependent L-type, calcium current (ICa(L)) was studied in single guinea-pig atrial cells under voltage clamp at room temperature (22-24 degrees C). At a holding potential of -40 mV, CCh (100 microM) activated IK(ACh) repeatedly and reproducibly when applied for 15-s periods with 60-s intervals between applications. Prolonged (10 min) exposure to CCh caused a time-dependent decline of IK(ACh) and a marked reduction (desensitization) of the response to subsequent application of CCh. In the absence of guanosine triphosphate (GTP) in the pipette, only partial resensitization occurred within 20 min after CCh washout. The desensitization to CCh could also be obtained when adenosine (20 microM) was used to activate this current. Therefore, this desensitization must be heterologous. In the presence of isoproterenol (ISO, 3 microM), ICa(L) increased. Acetylcholine continued to inhibit this current at a time when its activation of IK(ACh) had become desensitized. Muscarinic inhibition of ICa(L) eventually desensitized but only after IK(ACh) desensitization had occurred. Because of its heterologous nature, as well as of the ability of ACh to desensitize in the presence of intrapipette dextran, which is reported to inhibit beta-adrenergic receptor kinase (beta ARK), it seems unlikely that beta ARK-dependent phosphorylation of the muscarinic receptor (mAChR) accounted for desensitization. The differential desensitization time course is consistent with the hypothesis that different subunits of Gi, the inhibitory guanine nucleotide binding protein, not only transduce the agonist effects of ACh on IK(ACh) and ICa(L) but are also subjected to different inactivation/regulation processes.
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PMID:Muscarinic agonist-induced actions on potassium and calcium channels in atrial myocytes: differential desensitization. 166 56

Hormones, neurotransmitter and autacoid receptors, localized on the plasma membrane, do not interact directly with their respective downstream effector (i.e., an ion channel and/or an enzyme that synthesizes a second messenger), but control their target systems via activation of an intermediary guanine nucleotide binding protein on G protein, which serves as signal transducer. Traffic of these pathways is regulated via a GTP (on)-GDP (off) switch, which is triggered by the receptor. The combination of classical biochemistry and recombinant DNA technology has resulted in the discovery of many members of the G protein family. Receptor desensitization is a main criterion of G protein-coupled receptors with important pharmacological implications. Multiple mechanisms are responsible for the loss of sensitivity that follows against exposure. The process is initiated by uncoupling the receptor from its G protein, which is due to receptor phosphorylation by specific kinases. In the case of the beta-adrenergic receptor, two particular kinases - beta-adrenergic receptor kinase (beta ARK) and protein kinase A--are involved. Further steps of desensitization are receptor sequestration or internalization, an event as rapid and transient as receptor uncoupling, and receptor downregulation, which requires more prolonged agonist exposure. Finally, antagonists are able to induce a receptor-G protein interaction in a reverse manner to agonists. Whereas agonists stimulate both, the GDP dissociation from the G protein and the association of GTP, antagonists markedly decrease GTP association. Moreover, in the turkey erythrocyte adenylyl cyclase system antagonists decrease the GTP-stimulated adenylyl cyclase activity almost at basal levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Role of G protein-mediated signal transduction in molecular pharmacodynamics]. 217 69

EDG-1, encoded by the endothelial differentiation gene-1, is a heterotrimeric guanine nucleotide binding protein-coupled receptor (GPCR) for sphingosine-1-phosphate (SPP) that has been shown to stimulate angiogenesis and cell migration in cultured endothelial cells. Unexpectedly, EDG-1 knockout embryos had a normal blood vessel network, vasculogenesis and angiogenesis, but died in utero owing to massive haemorrhaging as a result of failure of smooth muscle cells and pericytes to migrate around the circumference and reinforce endothelial tubes [Liu, Wada, Yamashita, Mi, Deng, Hobson, Rosenfeldt, Nava, Chae, Lee, et al. (2000) J. Clin. Invest. 106, 951-961]. This vascular maturation defect is similar to the phenotype of mice homozygous for disrupted alleles of platelet-derived growth factor B-subunit homodimer (PDGF-BB) or its receptor PDGFR-beta. We found that fibroblasts from EDG-1 null embryos did not migrate toward PDGF or SPP, and inhibition of motility correlated with defective activation of the small guanosine triphosphatase Rac, which is required for lamellipodia formation and directional locomotion [Hobson, Rosenfeldt, Barak, Olivera, Poulton, Caron, Milstien, and Spiegel (2001) Science 291, 1800-1803]. Moreover, we showed that PDGF-directed cell migration requires both sphingosine kinase activation and expression of EDG-1, suggesting a functional link between PDGF signalling and EDG-1. Indeed, treatment of wild-type cells with PDGF transactivated EDG-1 as determined by translocation of beta-arrestin and phosphorylation of EDG-1. These findings reveal a new paradigm for receptor cross-communication in which activation of a GPCR by a receptor tyrosine kinase is critical for cell motility. Our observations might also clarify the role of EDG-1 in vascular maturation and angiogenesis.
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PMID:The sphingosine-1-phosphate receptor EDG-1 is essential for platelet-derived growth factor-induced cell motility. 1170 84

Ligand-mediated endocytosis is an important regulatory mechanism of epidermal growth factor (EGF) receptor (EGFR) signal transduction. Coordinated EGFR internalization and degradation function to regulate the spatial and temporal components of EGFR-effector interactions. In an effort to better understand the molecular mechanisms that control these events, we examined the role of rab5 in the endocytic trafficking of the EGFR. Rab5 is a 25-kDa guanine nucleotide binding protein that has previously been shown to be involved in the early stages of endocytic trafficking. Using adenovirally expressed dominant negative and constitutively active rab5 [rab5(S34N) and rab5(Q79L)] in cells with endogenous EGFRs, we have found that the guanine nucleotide binding state of rab5 has no bearing on the rate of EGFR endocytosis. However, expression of dominant negative rab5 affects downstream endocytic trafficking by slowing the ligand-induced disappearance of total cellular EGFR. Using confocal microscopy to examine EGF/EGFR and rab5 localization indicates that the activity of rab5 governs whether internalized EGF/EGFR and rab5 co-localize. Transferrin, which internalizes via a constitutively internalized cell surface receptor, co-sediments with rab5(WT), but not rab5(S34N) on sucrose gradients. Taken together, these data are consistent with rab5 functioning to regulate intracellular endocytic trafficking distal from the plasma membrane.
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PMID:Expression of dominant negative rab5 in HeLa cells regulates endocytic trafficking distal from the plasma membrane. 1502 38

Melanoma is an aggressive disease with few standard treatment options. The conventional classification system for this disease is based on histological growth patterns, with division into four subtypes: superficial spreading, lentigo maligna, nodular, and acral lentiginous. Major limitations of this classification system are absence of prognostic importance and little correlation with treatment outcomes. Recent preclinical and clinical findings support the notion that melanoma is not one malignant disorder but rather a family of distinct molecular diseases. Incorporation of genetic signatures into the conventional histopathological classification of melanoma has great implications for development of new and effective treatments. Genes of the mitogen-associated protein kinase (MAPK) pathway harbour alterations sometimes identified in people with melanoma. The mutation Val600Glu in the BRAF oncogene (designated BRAF(V600E)) has been associated with sensitivity in vitro and in vivo to agents that inhibit BRAF(V600E) or MEK (a kinase in the MAPK pathway). Melanomas arising from mucosal, acral, chronically sun-damaged surfaces sometimes have oncogenic mutations in KIT, against which several inhibitors have shown clinical efficacy. Some uveal melanomas have activating mutations in GNAQ and GNA11, rendering them potentially susceptible to MEK inhibition. These findings suggest that prospective genotyping of patients with melanoma should be used increasingly as we work to develop new and effective treatments for this disease.
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PMID:Treatment implications of the emerging molecular classification system for melanoma. 2134 66

Uveal melanoma represents the most common primary intraocular malignancy in adults. Although uveal and cutaneous melanomas both arise from melanocytes, uveal melanoma is clinically and biologically distinct from its more common cutaneous counterpart. Metastasis occurs frequently in this disease, and once distant spread occurs, outcomes are poor. No effective systemic therapies are currently available; however, recent advances in our understanding of the biology of this rare and devastating disease, combined with the growing availability of targeted agents, which can be used to rationally exploit these findings, hold the promise for novel and effective therapies in the foreseeable future. Herein, we review our rapidly growing understanding of the molecular biology of uveal melanoma, including the pathogenic roles of GNAQ (guanine nucleotide binding protein q polypeptide)/11, PTEN (phosphatase and tensin homolog), IGF (insulin-like growth factor)/IGF-1 receptor, MET (hepatocyte growth factor), BAP1 [breast cancer 1, early onset (BRCA1)-associated protein-1], and other key molecules, potential therapeutic strategies derived from this emerging biology, and the next generation of recently initiated clinical trials for the treatment of advanced uveal melanoma.
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PMID:Therapeutic implications of the emerging molecular biology of uveal melanoma. 2144 80

In the initial period after melanoma was recognised as a disease entity in the early 1800's, it was subclassified on the basis of its presumed origin (from a precursor naevus, from a melanocytic precursor lesion acquired during adult life or in previously blemish-fee skin). In 1967 the eminent American pathologist, Dr Wallace Clark, proposed a histogenetic classification for melanoma in which the disease was subdivided predominantly on the basis of histopathological features of the intra-epidermal component of the tumour adjacent to any dermal invasive component. The subtypes were superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM) and nodular melanoma (NM). Whilst additional entities, including acral lentiginous melanoma, mucosal melanoma, desmoplastic melanoma and naevoid melanoma have since been recognised, SSM, LMM and NM remain in the latest (2006) version of the WHO melanoma classification. Clark's histogenetic classification has been criticised because the criteria upon which it is based include clinical features (such as the site of the melanoma) and non-tumourous histopathological features (such as the character of the associated epidermis and the degree of solar elastosis) and also because of overlap in defining features, lack of an independent association with patient outcome and minimal relevance as a determinant of clinical management. However, such criticisms fail to acknowledge its importance in highlighting the myriad of clinical and histological guises of melanoma, which if not recognized by clinicians and pathologists will inevitably lead to a delay in diagnosis and a concomitant adverse clinical outcome. Recently, mutually exclusive oncogenic mutations in melanomas involving NRAS (15-20%), BRAF (50%), CKIT (2%), and GNAQ/GNA11 (50% of uveal melanomas) have been identified. This might herald the beginning of a new molecular classification of melanoma in which the biologically distinct subsets share a common oncogenic mechanism, behave clinically in a similar fashion and require similar clinical management. These discoveries are already being successfully exploited as therapeutic targets in clinical trials of metastatic melanoma patients with promising activity. Whilst there remains much to be discovered in this rapidly evolving field, there is already great optimism that more rational and effective therapies for melanoma patients will soon be widely available.
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PMID:Evolving concepts in melanoma classification and their relevance to multidisciplinary melanoma patient care. 2148 6

In order to identify acute myeloid leukemia (AML) CD34(+)-specific gene expression profiles, mononuclear cells from AML patients (n=46) were sorted into CD34(+) and CD34(-) subfractions, and genome-wide expression analysis was performed using Illumina BeadChip Arrays. AML CD34(+) and CD34(-) gene expression was compared with a large group of normal CD34(+) bone marrow (BM) cells (n=31). Unsupervised hierarchical clustering analysis showed that CD34(+) AML samples belonged to a distinct cluster compared with normal BM and that in 61% of the cases the AML CD34(+) transcriptome did not cluster together with the paired CD34(-) transcriptome. The top 50 of AML CD34(+)-specific genes was selected by comparing the AML CD34(+) transcriptome with the AML CD34(-) and CD34(+) normal BM transcriptomes. Interestingly, for three of these genes, that is, ankyrin repeat domain 28 (ANKRD28), guanine nucleotide binding protein, alpha 15 (GNA15) and UDP-glucose pyrophosphorylase 2 (UGP2), a high transcript level was associated with a significant poorer overall survival (OS) in two independent cohorts (n=163 and n=218) of normal karyotype AML. Importantly, the prognostic value of the continuous transcript levels of ANKRD28 (OS hazard ratio (HR): 1.32, P=0.008), GNA15 (OS HR: 1.22, P=0.033) and UGP2 (OS HR: 1.86, P=0.009) was shown to be independent from the well-known risk factors FLT3-ITD, NPM1c(+) and CEBPA mutation status.
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PMID:Gene expression profiling in the leukemic stem cell-enriched CD34+ fraction identifies target genes that predict prognosis in normal karyotype AML. 2176 May 93

Since the discovery of activating mutations in the BRAF oncogene in melanoma, there has been remarkable progress in the development of targeted therapies for unresectable and metastatic melanoma. We review the latest developments in our understanding of the role of BRAF/MEK/ERK pathway signaling in melanoma, and the development of inhibitors of this pathway. We also explore alternative mutations seen in melanoma, such as NRAS, KIT, GNAQ, and GNA11, and the drug development that is ongoing based on this biology. Strategies for the management of the vexing clinical problem of BRAF inhibitor resistance, primarily via combination therapy, are outlined. With the recent approval of the BRAF inhibitor vemurafenib for stage IV metastatic melanoma, use of this agent is expanding in the United States. Thus, management of the skin toxicities of this agent, such as squamous cell carcinomas, "acneiform" eruptions, hand-foot syndrome, and panniculitis, will be a growing problem facing dermatologists today. We discuss the toxicities of targeted agents in use for melanoma, in particular the dermatologic effects and the management of these skin toxicities.
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PMID:Targeted therapy in melanoma. 2343 83

A growing understanding of the biology and molecular mechanisms of melanoma has led to the identification of a number of driver mutations for this aggressive tumor. The most common mutations affect signaling of the Ras/Raf/MAPK (mitogen-activated protein kinase) pathway. This review will focus on mutations in genes encoding proteins that play a role in the MAPK pathway and that have been implicated in melanoma biology, such as BRAF, NRAS, and MEK (MAPK kinase), and detail the current understanding of their role in melanoma progression from a molecular biology perspective. Furthermore, this review will also consider some additional mutations in genes such as KIT, GNAQ, and GNA11, which can be seen in certain subtypes of melanoma and whose gene products interact with the MAPK pathway. In addition, the association of these molecular changes with clinical and classical histopathologic characteristics of melanoma will be outlined and their role in diagnosis of melanocytic lesions discussed. Finally, a basic overview of the current targeted therapy landscape, as far as relevant to the pathologist, will be provided.
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PMID:Ras, Raf, and MAP kinase in melanoma. 2375 84


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