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)

Increasing evidence has supported the hypothesis of a neurodevelopmental component in the etiology of schizophrenia. Recently, several independent microarray gene expression studies have revealed downregulated expression of myelin-related genes in the postmortem brains of schizophrenia patients. Complete myelination of the cortex has been observed to occur in late adolescence and early adulthood, which is typically the age of onset of schizophrenia. ERBB3 is a gene which has not only been found to be downregulated in schizophrenia simultaneously in three microarray studies, but also is a strong candidate because of its potential role in neurodevelopment as a receptor of NRG1. Therefore, we performed association analysis of seven nonsynonymous SNPs in this gene. Two SNPs in ERBB3 (rs773123 and rs2271188) were polymorphic in our samples, neither of which showed significant evidence of association with the illness (P = 0.639 and 0.561, respectively). Because replication across such studies is notoriously difficult, the microarray evidence implicating ERBB3 still strongly supports some role of this gene in schizophrenia. However, our failure to find genetic association suggests that the differential expression of ERBB3 in schizophrenia may be environmentally driven, or involve cis- or trans-acting genetic factors beyond the boundaries of the gene itself.
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PMID:Schizophrenia is not associated with the functional candidate gene ERBB3: results from a case-control study. 1695 35

Isolated or nonsyndromic cleft lip and palate (NS CLP) is a complex disorder resulting from multiple genetic and environmental factors. NS CLP has a birth prevalence of 1 per 500 in the Philippines where large families provide an opportunity for gene localization. Genotyping of 392 microsatellite repeat markers at 10 cM intervals over the genome was performed by the Center for Inherited Disease Research (CIDR) on 220 Filipino families with 567 affected and 1,109 unaffected family members genotyped. Among the most statistically significant results from analysis of the genome-wide scan data was a 20 cM region at 8p11-23 in which markers had LODs > or =1.0. This region on 8p11-23 has not been found in any previous genome wide scan nor does it contain any of the candidate genes widely studied in CLP. Fine mapping in 8p11-23 was done in the 220 families plus an additional 51 families, using SNP markers from 10 known genes (FGFR1, NRG1, FZD3, SLC8A1, PPP3CC, EPHX2, BNIP3L, EGR3, PPP2R2A, and NAT1) within the 20 cM region of 8p11-23. Linkage and association analyses of these SNPs yield suggestive results for markers in FGFR1 (recessive multipoint HLOD 1.07) and BAG4 (recessive multipoint HLOD 1.31).
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PMID:A genome-wide linkage scan for cleft lip and cleft palate identifies a novel locus on 8p11-23. 1736 57

NRG1-ERBB signaling influences the risk for schizophrenia pathology. A recent study has reported that MAGI1, MAGI2, and protein tyrosine phosphatase, receptor-type, Z polypeptide 1 (PTPRZ1; located on 7q31.3) gene products regulate the NRG1-ERBB4 signaling pathway, and PTPRZ1 is associated with schizophrenia in a Caucasian population. By applying a gene-based association concept, we analyzed any association between PTPRZ1 tagging SNPs and schizophrenia in the Japanese population (576 schizophrenics and 768 controls). After linkage disequilibrium analysis, 29 single nucleotide polymorphisms (SNPs) were genotyped using a 5'-exonuclease allelic discrimination assay. We found a significant association of one tagging SNP in a genotype-wise analysis (P = 0.007); however, this might be resulted from type I error due to multiple testing (P = 0.17 after SNPSpD correction). No association was observed between schizophrenic patients and controls in either allelic, genotypic, or haplotypic analyses. Our results therefore suggest that PTPRZ1 is unlikely to be related to the development of schizophrenia in the Japanese population.
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PMID:No association between the protein tyrosine phosphatase, receptor-type, Z Polypeptide 1 (PTPRZ1) gene and schizophrenia in the Japanese population. 1818 75

The molecular basis of complex neuropsychiatric disorders most likely involves many genes. In recent years, specific genetic variations influencing risk for schizophrenia and other neuropsychiatric disorders have been reported. We have used custom DNA microarrays and qPCR to investigate the expression of putative schizophrenia susceptibility genes and related genes of interest in the normal human brain. Expression of 31 genes was measured in Brodmann's area 10 (BA10) in the prefrontal cortex of 72 postmortem brain samples spanning half a century of human aging (18-67 years), each without history of neuropsychiatric illness, neurological disease, or drug abuse. Examination of expression across age allowed the identification of genes whose expression patterns correlate with age, as well as genes that share common expression patterns and that possibly participate in common cellular mechanisms related to the emergence of schizophrenia in early adult life. The expression of GRM3 and RGS4 decreased across the entire age range surveyed, while that of PRODH and DARPP-32 was shown to increase with age. NRG1, ERBB3, and NGFR show expression changes during the years of greatest risk for the development of schizophrenia. Expression of FEZ1, GAD1, and RGS4 showed especially high correlation with one another, in addition to the strongest mean levels of absolute correlation with all other genes studied here. All microarray data are available at NCBI's Gene Expression Omnibus: GEO Series accession number GSE11546 (http://www.ncbi.nlm.nih.gov/geo) [corrected]
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PMID:Age-related changes in the expression of schizophrenia susceptibility genes in the human prefrontal cortex. 1847 May 33

The human epidermal growth factor (EGF) receptor (HER) family members cooperate in malignancy. Of this family, HER2 does not bind growth factors and HER3 does not encode an active tyrosine kinase. This diversity creates difficulty in creating pan-specific therapeutic HER family inhibitors. We have identified single amino acid changes in epidermal growth factor receptor (EGFR) and HER3 which create high affinity sequestration of the cognate ligands, and may be used as receptor decoys to downregulate aberrant HER family activity. In silico modeling and high throughput mutagenesis were utilized to identify receptor mutants with very high ligand binding activity. A single mutation (T15S; EGFR subdomain I) enhanced affinity for EGF (two-fold), TGF-alpha (twenty-six-fold), and heparin-binding (HB)-EGF (six-fold). This indicates that T15 is an important, previously undescribed, negative regulatory amino acid for EGFR ligand binding. Another mutation (Y246A; HER 3 subdomain II) enhanced neuregulin (NRG)1-beta binding eight-fold, probably by interfering with subdomain II-IV interactions. Further work revealed that the HER3 subunit of an EGFR:HER3 heterodimer suppresses EGFR ligand binding. Optimization required reversing this suppression by mutation of the EGFR tether domain (G564A; subdomain IV). This mutation resulted in enhanced ligand binding (EGF, ten-fold; TGF-alpha, thirty-four-fold; HB-EGF, seventeen-fold; NRG1-beta, thirty-one-fold). This increased ligand binding was reflected in improved inhibition of in vitro tumor cell proliferation and tumor suppression in a human non-small cell lung cancer xenograft model. In conclusion, amino acid substitutions were identified in the EGFR and HER3 ECDs that enhance ligand affinity, potentially enabling a pan-specific therapeutic approach for downregulating the HER family in cancer.
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PMID:Rational optimization of a bispecific ligand trap targeting EGF receptor family ligands. 1904 33

Epimorphic regeneration is a unique and complex instance of postembryonic growth observed in certain metazoans that is usually triggered by severe injury [Akimenko et al., 2003; Alvarado and Tsonis, 2006; Brockes, 1997; Endo et al., 2004]. Cell division and migration are two fundamental biological processes required for supplying replacement cells during regeneration [Endo et al., 2004; Slack, 2007]. However, the connection between the early stimuli generated after injury and the signals regulating proliferation and migration during regeneration remain largely unknown. Here we show that the oncogenes ErbB2 and ErbB3, two members of the EGFR family, are essential for mounting a successful regeneration response in vertebrates. Importantly, amputation-induced progenitor proliferation and migration are significantly reduced upon genetic and/or chemical modulation of ErbB function. Moreover, we also found that NRG1 and PI3K functionally interact with ErbB2 and ErbB3 during regeneration and interfering with their function also abrogates the capacity of progenitor cells to regenerate lost structures upon amputation. Our findings suggest that ErbB, PI3K and NRG1 are components of a permissive switch for migration and proliferation continuously acting across the amputated fin from early stages of vertebrate regeneration onwards that regulate the expression of the transcription factors lef1 and msxB.
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PMID:ErbB2 and ErbB3 regulate amputation-induced proliferation and migration during vertebrate regeneration. 1913 54

Defects in genetic and developmental processes are thought to contribute susceptibility to autism and schizophrenia. Presumably, owing to etiological complexity identifying susceptibility genes and abnormalities in the development has been difficult. However, the importance of genes within chromosomal 8p region for neuropsychiatric disorders and cancer is well established. There are 484 annotated genes located on 8p; many are most likely oncogenes and tumor-suppressor genes. Molecular genetics and developmental studies have identified 21 genes in this region (ADRA1A, ARHGEF10, CHRNA2, CHRNA6, CHRNB3, DKK4, DPYSL2, EGR3, FGF17, FGF20, FGFR1, FZD3, LDL, NAT2, NEF3, NRG1, PCM1, PLAT, PPP3CC, SFRP1 and VMAT1/SLC18A1) that are most likely to contribute to neuropsychiatric disorders (schizophrenia, autism, bipolar disorder and depression), neurodegenerative disorders (Parkinson's and Alzheimer's disease) and cancer. Furthermore, at least seven nonprotein-coding RNAs (microRNAs) are located at 8p. Structural variants on 8p, such as copy number variants, microdeletions or microduplications, might also contribute to autism, schizophrenia and other human diseases including cancer. In this review, we consider the current state of evidence from cytogenetic, linkage, association, gene expression and endophenotyping studies for the role of these 8p genes in neuropsychiatric disease. We also describe how a mutation in an 8p gene (Fgf17) results in a mouse with deficits in specific components of social behavior and a reduction in its dorsomedial prefrontal cortex. We finish by discussing the biological connections of 8p with respect to neuropsychiatric disorders and cancer, despite the shortcomings of this evidence.
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PMID:Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer. 1920 25

Schizophrenia is a complex neurodevelopmental disorder that is thought to be induced by an interaction between predisposing genes and environmental stressors. To identify predisposing genetic factors, we performed a targeted (mostly neurodevelopmental) gene approach involving the screening of 396 selected non-synonymous single-nucleotide polymorphisms (SNPs) in three independent Caucasian schizophrenia case-control cohorts (USA, Denmark and Norway). A meta-analysis revealed ten non-synonymous SNPs that were nominally associated with schizophrenia, nine of which have not been previously linked to the disorder. Risk alleles are in TRKA (rs6336), BARD1 (rs28997576), LAMA5 (rs3810548), DKK2 (rs7037102), NOD2 (rs2066844) and RELN (rs2229860), whereas protective alleles are in NOD2 (rs2066845), NRG1 (rs10503929), ADAM7 (rs13259668) and TNR (rs859427). Following correction for multiple testing, the most attractive candidate for further study concerns SNP rs6336 (q=0.12) that causes the substitution of an evolutionarily highly conserved amino acid residue in the kinase domain of the neurodevelopmentally important receptor TRKA. Thus, TRKA signaling may represent a novel susceptibility pathway for schizophrenia.
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PMID:Three-cohort targeted gene screening reveals a non-synonymous TRKA polymorphism associated with schizophrenia. 1943 34

Neuregulin (NRG) signaling through the receptor tyrosine kinase, ERBB3, is required for embryonic development, and dysregulated signaling has been associated with cancer progression. Here, we show that NRG1/ERBB3 signaling inhibits melanocyte (MC) maturation and promotes undifferentiated, migratory and proliferative cellular characteristics. Embryonic analyses demonstrated that initial MC specification and distribution were not dependent on ERBB3 signaling. However NRG1/ERBB3 signaling was both necessary and sufficient to inhibit differentiation of later stages of MC development in culture. Analysis of tissue arrays of human melanoma samples suggests that ERBB3 signaling may also contribute to metastatic progression of melanoma as ERBB3 was phosphorylated in primary tumors compared with nevi or metastatic lesions. Neuregulin 1-treated MCs demonstrated increased proliferation and invasion and altered morphology concomitant with decreased levels of differentiation genes, increased levels of proliferation genes and altered levels of melanoma progression and metastases genes. ERBB3 activation in primary melanomas suggests that NRG1/ERBB3 signaling may contribute to the progression of melanoma from benign nevi to malignancies. We propose that targeting ERBB3 activation and downstream genes identified in this study may provide novel therapeutic interventions for malignant melanoma.
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PMID:NRG1 / ERBB3 signaling in melanocyte development and melanoma: inhibition of differentiation and promotion of proliferation. 1965 70

The levels of expression of the four receptors and eleven ligands composing the epidermal growth factor family were measured using immunohistochemical staining in one hundred cases of breast cancer. All of the family were expressed to some degree in some cases; however, individual cases showed a very wide range of expression of the family from essentially none to all the factors at high levels. The highest aggregate level of expression of a receptor was HER2 followed by HER1, then HER3, then HER4. The ligands (including two splice variants of the NRG1 and NRG2 genes) broadly fell into three groups, those with the highest aggregate expression were Epigen, Epiregulin, Neuregulin 1alpha, Neuregulin 2alpha, Neuregulin 2beta, Neuregulin 4 and TGFalpha, moderate expression was seen with EGF, Neuregulin 1beta and Neuregulin 3, and relatively low levels of expression were seen of HB-EGF, Betacellulin and Amphiregulin. Statistical analysis using Spearman's Rank Correlation showed a positive correlation of expression between each of the factors. Analysing the data using the Cox Proportional Hazards model showed that, in this dataset, the most powerful predictors of relapse free interval and overall survival were the combined measurement of only Epigen and Neuregulin 4.
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PMID:The complete family of epidermal growth factor receptors and their ligands are co-ordinately expressed in breast cancer. 1976 33


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