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

---

Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dyrk is a dual specific protein kinase thought to be involved in normal embryo neurogenesis and brain development. Defects/imperfections in this kinase have been suggested to play an important role in the mental retardation of patients with Down's syndrome. The transcriptional factor cAMP response element-binding protein (CREB) has been implicated in the formation of many types of synaptic plasticity, such as learning and memory. In the present study we show that Dyrk1 activity is markedly induced during the differentiation of immortalized hippocampal progenitor (H19-7) cells. The addition of a neurogenic factor, basic fibroblast growth factor, to the H19-7 cells results in an increased specific binding of Dyrk1 to active CREB. In addition, Dyrk1 directly phosphorylates CREB, leading to the stimulation of subsequent CRE-mediated gene transcription during the neuronal differentiation in H19-7 cells. Blockade of Dyrk1 activation significantly inhibits the neurite outgrowth as well as CREB phosphorylation induced by basic fibroblast growth factor. These findings suggest that Dyrk1 activation and subsequent CREB phosphorylation is important in the neuronal differentiation of central nervous system hippocampal cells.
...
PMID:Protein kinase Dyrk1 activates cAMP response element-binding protein during neuronal differentiation in hippocampal progenitor cells. 1151 9

Although Down Syndrome (DS, trisomy 21) is the most frequent isolated cause of mental retardation, information on brain protein expression and in particular protein expression of signaling-related proteins is limited. Impaired signaling in DS involving different signaling systems has been proposed and the availability of fetal brain along with recent proteome technologies unambiguously identifying individual brain proteins made us study individual signaling factors in the brain. We studied fetal brain cortex of controls (n = 7) and DS (n = 9) from early second trimester of gestation by two-dimensional gel electrophoresis with subsequent matrix-assisted laser/desorption ionization (MALDI) identification followed by quantification with specific software. Four 14-3-3 protein isoforms, mitogen-activated protein kinase 1, receptor for activited kinase 1 (RACK1), constitutive photomorphogenesis (COP9) complex subunit 4 and cAMP-dependent protein kinase type II have been identified. Quantification showed that protein 14-3-3 gamma (means +/- standard deviation of controls: 10.18+/-2.30 and of DS 4.20+/-1.19) and two spots assigned to RACK1 (controls spot 1: 4.15+/-2.45 and DS 1.95+/-0.93; controls spot 2: 5.08+/-2.4 vs. DS: 2.56+/-1.19) were significantly decreased in DS cortex. Reduced 14-3-3 gamma may represent impaired neuronal differentiation, synaptic plasticity and impaired signaling by PKC and Raf while decreased RACK1 (anchoring protein receptor for activated C-kinase) may reflect or generate deranged beta-II- protein kinease C (PKC) function with the putative biological meaning of aberrant migration and neuritic outgrowth in DS early in life.
...
PMID:Aberrant expression of signaling-related proteins 14-3-3 gamma and RACK1 in fetal Down syndrome brain (trisomy 21). 1182 16

The Coffin-Lowry syndrome (CLS) is a syndromic form of X-linked mental retardation characterised in male patients by psychomotor and growth retardation, and various skeletal anomalies. CLS is caused by mutations in a gene located in Xp22.2 and encoding RSK2, a growth-factor regulated protein kinase. Mutations are extremely heterogeneous and lead to premature termination of translation and/or to loss of phosphotransferase activity. No correlation between the type and location of mutation and the clinical phenotype is evident. However, in one family (MRX19), a missense mutation was associated solely with mild mental retardation and no other clinical feature. Screening for RSK2 mutations is essential in most cases to confirm the diagnosis as well as for genetic counseling.
...
PMID:X-linked Coffin-Lowry syndrome (CLS, MIM 303600, RPS6KA3 gene, protein product known under various names: pp90(rsk2), RSK2, ISPK, MAPKAP1). 1189 50

Coffin-Lowry syndrome (CLS) is a syndromic form of X-linked mental retardation that is characterized, in male patients, by psychomotor and growth retardation and various skeletal anomalies. Typical facial changes and specific clinical and radiological hand aspects exhibited by patients are essential clues for the diagnosis. CLS is caused by mutations in a gene that is located in Xp22.2 and that encodes RSK2, a growth-factor-regulated protein kinase. RSK2 mutations are extremely heterogeneous and lead to premature termination of translation and/or loss of phosphotransferase activity. Surprisingly, among a series of 250 patients screened by single-strand conformation polymorphism (SSCP) analysis, in whom a clinical diagnosis of CLS was made, no mutations were detected in 66% (165) of the patients. To determine what proportion of these latter patients have a RSK2 mutation that has not been detected and what proportion have different disorders that are phenotypically similar to CLS, we have, in the present article, investigated, by western blot analysis and in vitro kinase assay, cell lines from 26 patients in whom no mutation was previously identified by SSCP analysis. This approach allowed us to identify seven novel RSK2 mutations: two changes in the coding sequence of RSK2, one intragenic deletion, and four unusual intronic nucleotide substitutions that do not affect the consensus GT or AG splice sites. We have also determined the nucleotide sequence of the promoter region of the RSK2 gene, and we have screened it for mutations. No disease-causing nucleotide change was identified, suggesting that mutations affecting the promoter region are unlikely to account for a large number of patients with CLS. Finally, our results provide evidence that some patients have a disease that is phenotypically very similar to CLS, which is not caused by RSK2 defects. This suggests that there are defects in either additional genes or combinations of genes that may result in a CLS-like phenotype.
...
PMID:Unusual splice-site mutations in the RSK2 gene and suggestion of genetic heterogeneity in Coffin-Lowry syndrome. 1199 50

The ribosomal S6 kinase family members RSK2 (RPS6KA3) and RSK4 (RPS6KA6) belong to the group of X chromosomal genes, in which defects cause unspecific mental retardation (MRX) in humans. In this study, we investigated the spatiotemporal expression pattern of these genes during mouse development with emphasis to midgestation stages. Additionally, we analyzed the expression of the phosphoinositide-dependent protein kinase-1 gene, Pdk1 (Pspk1), which is essential for the activation of Rsk family members and thus regulates their function. During midgestation we observed specifically enhanced expression of Rsk2 first in somites, later restricted to the dermatomyotome of the somites, then in the sensory ganglia of cranial nerves and in the dorsal root ganglia of the spinal nerves. High Rsk2 expression in the cranial nerve ganglia persists throughout development and is correlated with Pdk1 expression. In the brain of 2-day-old mice, Pdk1 is expressed in the cortical plate of the cerebral cortex and in the stratum pyramidale of the hippocampus, whereas Rsk2 expression is lower in these structures. For Rsk4 ubiquitous expression at lower levels was observed throughout development.
...
PMID:Expression pattern of the Rsk2, Rsk4 and Pdk1 genes during murine embryogenesis. 1271 46

Dual-specificity tyrosine(Y) regulated kinase 1A (DYRK1A) is a serine/threonine protein kinase implicated in mental retardation resulting from Down syndrome. In this study, we carried out yeast two-hybrid screening to find proteins regulating DYRK1A kinase activity. We identified 14-3-3 as a Dyrk1A interacting protein, which is consistent with the previous finding of the interaction between the yeast orthologues Yak1p and Bmh1/2p. We showed the interaction between Dyrk1A and 14-3-3 in vitro and in vivo. The binding required the N-terminus of Dyrk1A and was independent of the Dyrk1A phosphorylation status. Functionally, 14-3-3 binding increased Dyrk1A kinase activity in a dose dependent manner in vitro. In vivo, a small peptide inhibiting 14-3-3 binding, sc138, decreased Dyrk1A kinase activity in COS7. In summary, these results suggest that DYRK1A kinase activity could be regulated by the interaction of 14-3-3.
...
PMID:Regulation of Dyrk1A kinase activity by 14-3-3. 1536 79

Recently, we showed that truncation of the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene caused mental retardation and severe neurological symptoms in two female patients. Here, we report that de novo missense mutations in CDKL5 are associated with a severe phenotype of early-onset infantile spasms and clinical features that overlap those of other neurodevelopmental disorders, such as Rett syndrome and Angelman syndrome. The mutations are located within the protein kinase domain and affect highly conserved amino acids; this strongly suggests that impaired CDKL5 catalytic activity plays an important role in the pathogenesis of this neurodevelopmental disorder. In view of the overlapping phenotypic spectrum of CDKL5 and MECP2 mutations, it is tempting to speculate that these two genes play a role in a common pathogenic process.
...
PMID:Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation. 1549 49

A minority of the reported cases of terminal 2q37 deletion clinically resemble Albright hereditary osteodystrophy (AHO)/pseudopseudohypoparathyroidism and have only mild-to-moderate mental retardation. Our molecular and cytogenetic fluorescence in situ hybridization (FISH) findings on an additional three patients further reduce the size of the minimal critical region deleted in this syndrome to about 3 Mb. This region includes the G-protein-coupled receptor 35 (GPR35), glypican 1 (GPC1), and serine/threonine protein kinase 25 (STK25) genes on 2q37.3. We have further defined several polymorphic variants within the coding region and flanking regions of GPR35 gene, which could potentially be useful for rapid detection of GPR35 gene deletion. We postulate that the absence of GPR35 may, at least partly, account for the phenotypic resemblance to the AHO. We also believe that the deletion of GPR35 could be responsible for the entity brachydactyly mental retardation syndrome (OMIM #600430), which was coined based on the above minority of patients with terminal 2q37 deletion. We recommend that every patient with AHO phenotype should undergo 2q subtelomeric FISH screen and subsequently a molecular study on the GPR35 gene. GPC1 and/or STK25 haploinsufficiency may also contribute to the AHO-like phenotype.
...
PMID:Molecular delineation of deletions on 2q37.3 in three cases with an Albright hereditary osteodystrophy-like phenotype. 1552 82

Dual specific protein kinase Dyrks are thought to play a key role in the regulation of cell growth in a variety of cellular systems. Interestingly, human Dyrk1 is mapped to the Down's syndrome (DS) critical region on chromosome 21, and thought to be a candidate gene responsible for the mental retardation of DS patients. Huntingtin-interacting protein 1 (Hip-1), a proapoptotic mediator, is implicated as a molecular accomplice in the pathogenesis of Huntington's disease. In the present study we found that Dyrk1 selectively binds to and phosphorylates Hip-1 during the neuronal differentiation of embryonic hippocampal neuroprogenitor (H19-7) cells. The Dyrk1-mediated phosphorylation of Hip-1, in response to bFGF, resulted in the blockade of Hip-1-mediated neuronal cell death as well as the enhancement of neurite outgrowth. Furthermore, the addition of etoposide to proliferating H19-7 cells caused the diminished binding of Hip-1 to Dyrk1 and the levels of phosphorylated Hip-1 remarkably decreased. Simultaneously, the dissociated Hip-1 from Dyrk1 bound to caspase-3 in response to etoposide, which led to its activation and consequently cell death in H19-7 cells. These data suggest that the phosphorylation of Hip-1 by Dyrk1 has a dual role in regulating neuronal differentiation and cell death. The interaction between Dyrk1 and Hip-1 appeared to be differentially modulated by different kinds of stimuli, such as bFGF and etoposide in H19-7 cells.
...
PMID:Regulation of the proapoptotic activity of huntingtin interacting protein 1 by Dyrk1 and caspase-3 in hippocampal neuroprogenitor cells. 1590 74

Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant neurodegenerative disorder, first described in a Japanese family, showing linkage to chromosome 19q13.4-qter. Recently, mutations have been identified in the PRKCG gene in families with SCA14. The PRKCG gene encodes the protein kinase Cgamma (PKCgamma), a member of a serine/threonine kinase family involved in signal transduction important for several cellular processes, including cell proliferation and synaptic transmission. To identify the disease-causing mutation in a large group of ataxia patients, we searched for mutations in the PRKCG gene. We ascertained 366 unrelated patients with spinocerebellar ataxia, either pure or with associated features such as epilepsy, mental retardation, seizures, paraplegia, and tremor. A C-to-G transversion in exon 4, resulting in a histidine-to-glutamine change at codon 101 of the PKCgamma protein, was identified in patients from a family with slowly progressive pure cerebellar ataxia. Functional studies performed in HEK293 cells transfected with normal or mutant construct showed that this mutation affects PKCgamma stability or solubility, verified by time-dependent decreased protein levels in cell culture. In conclusion, the H101Q mutation causes slowly progressive uncomplicated ataxia by interfering with PKCgamma stability or solubility, which consequently may cause in either case a decrease in the overall PKCgamma-dependent phosphorylation.
...
PMID:A novel H101Q mutation causes PKCgamma loss in spinocerebellar ataxia type 14. 1618 24


<< Previous 1 2 3 4 5 6 7 Next >>

---