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

Williams syndrome (WS) is a multisystem developmental disorder caused by the deletion of contiguous genes at 7q11.23. Hemizygosity of the elastin (ELN) gene can account for the vascular and connective tissue abnormalities observed in WS patients, but the genes that contribute to features such as infantile hypercalcemia, dysmorphic facies, and mental retardation remain to be identified. In addition, the size of the genomic interval commonly deleted in WS patients has not been established. In this study we report the characterization of a 500-kb region that was determined to be deleted in our collection of WS patients. A detailed physical map consisting of cosmid, P1 artificial chromosomes, and yeast artificial chromosomes was constructed and used for gene isolation experiments. Using the techniques of direct cDNA selection and genomic DNA sequencing, three known genes (ELN, LIMK1, and RFC2), a novel gene (WSCR1) with homology to RNA-binding proteins, a gene with homology to restin, and four other putative transcription units were identified. LIMK1 is a protein kinase with two repeats of the LIM/double zinc finger motif, and it is highly expressed in brain. RFC2 is the 40-kDa ATP-binding subunit of replication factor C, which is known to play a role in the elongation of DNA catalyzed by DNA polymerase delta and epsilon. LIMK1 and WSCR1 may be particularly relevant when explaining cognitive defects observed in WS patients.
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PMID:Identification of genes from a 500-kb region at 7q11.23 that is commonly deleted in Williams syndrome patients. 881 60

We have isolated human and rat clones of the LIM motif-containing protein kinase, termed LIMK-2. LIMK-2 is related to the neuronally expressed LIM-kinase, whose hemizygous deletion appears to result in cognitive impairment in patients with Williams syndrome. The hallmark of this protein family is the presence of 1 or 2-terminal LIM motifs and an atypical C-terminal protein kinase domain. LIMK-2 mRNA was detected by Northern blot analysis in human tissues, most abundantly in placenta, lung, liver, and pancreas, and also in a variety of cell lines including neuronal, glioblastoma, and mammary carcinoma lines. The LIMK-2 transcript was also induced upon neuroectodermal differentiation of mouse P19 embryonal carcinoma cells. A 65 kDa recombinant LIMK-2 protein was identified in 293 cells stably transfected with a LIMK-2 expression vector. An in vitro kinase assay demonstrates LIMK-2 is autophosphorylated and exhibits serine/threonine kinase activity towards the exogenous substrate MBP. The endogenous 65 kDa LIMK-2 protein was detected in a variety of cell lines, and coprecipitates with a 140 kDa tyrosine phosphorylated protein, but was not itself tyrosine phosphorylated. At the subcellular level, LIMK-2 is localized in both the nucleus and in a Triton X-100 soluble fraction.
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PMID:Cloning and biochemical characterization of LIMK-2, a protein kinase containing two LIM domains. 908 16

LIM-kinase 1 and 2 (LIMK1 and LIMK2) are members of a novel class of protein kinases with structures composed of two LIM motifs at the N-terminus and an unusual protein kinase domain at the C-terminus. The cellular functions of the LIMK family proteins have remained unknown. In the present study, we examined effects of LIMKs on neuronal differentiation of PC12 pheochromocytoma cells. Transient expression analyses revealed that LIMK1, in itself, had no apparent effect on PC12 cells, but the oncogenic Ras-induced differentiation of PC12 cells was notably inhibited by co-expression with LIMK1 or LIMK2. A mutant of LIMK1 lacking a protein kinase domain (delta K) similarly inhibited Ras-induced differentiation of PC12 cells, but a mutant lacking a LIM domain (delta LIM) failed to do so, indicating that a LIM domain but not a protein kinase domain is required for the inhibitory activity. This notion was further supported by the finding that mutation, changing conserved cysteines involved in zinc coordination to glycines in both of two LIM motifs, abolished the inhibitory activity of delta K. Additionally, we also found that the constitutively activated MAP kinase kinase (MAPKK)-induced differentiation of PC12 cells was inhibited by co-expression with delta K. Furthermore, AK did not inhibit the kinase activity of MAP kinase (MAPK) stimulated by MAPKK, when co-expressed in COS7 cells. These findings suggest that LIMK1 inhibits neuronal differentiation of PC12 cells, through its LIM domain and by interfering with events downstream of MAPK activation.
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PMID:Inhibition of activated Ras-induced neuronal differentiation of PC12 cells by the LIM domain of LIM-kinase 1. 915 Mar 88

The LIM double zinc finger motif locates in several developmentally functioning and cytoskeletal proteins, and is considered to act as a specific motif for protein-protein interactions. LIM kinase (LIMK) is a novel protein kinase containing two LIM motifs at the N-terminal, the function of which has yet to be clearly defined. In this study, we cloned a cDNA encoding Xenopus counterpart of human LIMK1 gene by RT-PCR mediated cloning, and designated in Xlimk1. Xlimk1 is highly homologous to mammalian LIMK1 in each structural domain, particularly in LIM and protein kinase domains. In Northern blot analysis, two distinct Xlimk1 transcripts of 9.0 Kb and 3.7 Kb were present in early cleavage stages of the embryo. Both mRNA species were subsequently decreased at the gastrula stages. The 9.0 Kb of Xlimk1 mRNA again appeared in late neurula stage, then the expression level gradually increased in later stages of the embryo. Whole-mount in situ hybridization analysis showed the localization of Xlimk1 transcripts in the animal half of the blastula embryo. In post-neurula stages, specific signals for Xlimk1 were predominant in the anterior (head) region of the embryo, including developing brain, hyoid and branchial arches, and anlagen of sensory organs. These results indicate that Xlimk1 may play an important role in neural development and formation of anterior (head) structures in the Xenopus embryo.
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PMID:Xenopus LIM motif-containing protein kinase, Xlimk1, is expressed in the developing head structure of the embryo. 918 54

Expression of many components of the secretory pathway in peptidergic neuroendocrine cells is precisely controlled in response to secretagogues. Regulated endocrine-specific protein (RESP18) was identified as a dopamine-regulated intermediate pituitary transcript. Although the amino acid sequence of RESP18 initially suggested that it might be a novel preprohormone, its widespread expression in peptide-producing neurons and endocrine cells and its localization to the lumen of the endoplasmic reticulum suggested that it subserves a unique function. Subtractive hybridization of a pituitary corticotrope AtT-20 cell line engineered for inducible RESP18 expression demonstrated a RESP18-dependent induction of several transcripts. Regulation of RESP18 expression in vitro and in vivo was accompanied by changes in the same transcripts. Several cDNAs encoding transcripts up-regulated by RESP18 were analyzed by DNA sequencing, searching the GenBank databases for homologous proteins, and Northern blotting. One novel clone showed a tissue distribution nearly identical to that of RESP18. One clone was identical to rat LIMK2, a protein kinase containing modular protein-protein interaction LIM (lin-11, isl-1, mec-3) domains. Another clone was similar to monomeric bacterial isocitrate dehydrogenases. Like the unfolded protein response, these data demonstrate a novel signaling pathway from the secretory pathway lumen to the nucleus. RESP18 acts as a lumicrine peptide (an intracellular luminal autocrine hormone) inducing this pathway.
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PMID:A novel neuroendocrine intracellular signaling pathway. 936 52

LIM-kinase 1 and LIM-kinase 2 (LIMK1 and LIMK2) are members of a novel protein kinase subfamily containing LIM motifs at the N-terminus. There are two isoforms of Limk2 transcripts coding proteins with distinct N-terminal structures: LIMK2a, containing two LIM motifs, and LIMK2b, with one and one-half LIM motifs. Here we report the cDNA and genomic structures of mouse LIMK2. The deduced 638-aminoacid sequence of mouse LIMK2a shows 98% identity with that of rat LIMK2a. The mouse Limk2a gene consists of at least 16 exons and spans more than 50 kb. Exon/intron boundaries of the mouse Limk2a gene are exactly conserved with those of the mouse Limk1 gene. An additional exon encoding the Limk2b-specific 5'-terminal sequence was found to be located between exons 2 and 3, suggesting that Limk2a and 2b mRNAs are transcribed from a single Limk2 gene by an alternative usage of exons near the 5' end of the gene. Limk2a and Limk2b transcripts were expressed at different ratios in a variety of mouse tissues.
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PMID:Mouse LIM-kinase 2 gene: cDNA cloning, genomic organization, and tissue-specific expression of two alternatively initiated transcripts. 944 59

LIM-kinase 1 (LIMK1) and LIM-kinase 2 (LIMK2) are members of a novel serine/threonine kinase subfamily with structural features composed of N-terminal two LIM domains, an internal PDZ-like domain, and a C-terminal protein kinase domain. We recently identified and characterized the mouse Limk2 gene and two Limk2 transcripts (Limk2a and Limk2b) coding for proteins with distinct N-terminal LIM structures. Here we describe two additional transcripts of the mouse Limk2 gene. One is a 1.7-kb transcript, termed Limk2t, which is specifically expressed in the testis and codes for an N-terminally truncated form of LIMK2 consisting of only a part of a PDZ-like domain and a protein kinase domain. The other is a transcript, termed Limk2c, which is specifically expressed in the brain and codes for a protein with a 6-amino-acid insert within the protein kinase domain. Exons specific to the 5'-terminal extra sequence of Limk2t and the insert sequence of Limk2c locate between exons 5-6 and exons 8-9 in the mouse Limk2 gene, respectively. Testis- and brain-specific expression of Limk2t and Limk2c suggests specific roles in these tissues.
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PMID:Identification of testis-specific (Limk2t) and brain-specific (Limk2c) isoforms of mouse LIM-kinase 2 gene transcripts. 961 Mar 54

LIM-containing protein kinase 1 (LIMK1) is a serine/threonine kinase with a structure composed of two LIM domains, a PDZ domain, and a protein kinase domain. We examined the subcellular localization of LIMK1 and its variously deleted mutants in HeLa cells by transfection with these cDNAs. Immunofluorescence analysis revealed that the full-length LIMK1 and its mutants deleted with LIM domain or protein kinase domain preferentially localized in the cytoplasm, while the mutants deleted with the PDZ domain or a 52 amino acid region (B region) within the PDZ domain localized mainly in the nucleus. When the normally nuclear cyclin A was fused with the PDZ domain or the B region of LIMK1, it was localized in the cytoplasm of transfected cells. The corresponding region of the PDZ domain of postsynaptic density protein (PSD)-95 had no such function. Additionally, the PDZ domain of LIMK1 had no potential to bind to the C-terminal S/TXV peptides, to which the PSD-95 PDZ domain can bind. Taken together these results suggest that the PDZ domain, particularly the B region, of LIMK1 has a specific function to localize the protein in the cytoplasm. When glutathione S-transferase (GST) fused with the PDZ domain of LIMK1 (GST-PDZ) or GST-PDZ deleted with the B region (GST-PDZ delta B) was microinjected into the nucleus of COS cells, GST-PDZ was almost completely excluded from the nucleus within 30 min, whereas GST-PDZ delta B remained in the nucleus. These findings suggest that the B region of LIMK1 probably has nuclear export signal activity.
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PMID:Cytoplasmic localization of LIM-kinase 1 is directed by a short sequence within the PDZ domain. 963 33

Cell division, cell motility and the formation and maintenance of specialized structures in differentiated cells depend directly on the regulated dynamics of the actin cytoskeleton. To understand the mechanisms of these basic cellular processes, the signalling pathways that link external signals to the regulation of the actin cytoskeleton need to be characterized. Here we identify a pathway for the regulation of cofilin, a ubiquitous actin-binding protein that is essential for effective depolymerization of actin filaments. LIM-kinase 1, also known as KIZ, is a protein kinase with two amino-terminal LIM motifs that induces stabilization of F-actin structures in transfected cells. Dominant-negative LIM-kinasel inhibits the accumulation of the F-actin. Phosphorylation experiments in vivo and in vitro provide evidence that cofilin is a physiological substrate of LIM-kinase 1. Phosphorylation by LIM-kinase 1 inactivates cofilin, leading to accumulation of actin filaments. Constitutively active Rac augmented cofilin phosphorylation and LIM-kinase 1 autophosphorylation whereas phorbol ester inhibited these processes. Our results define a mechanism for the regulation of cofilin and hence of actin dynamics in vivo. By modulating the stability of actin cytoskeletal structures, this pathway should play a central role in regulating cell motility and morphogenesis.
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PMID:Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. 965 88

Activation of the cAMP signaling pathway is correlated with increased secretory-related events in a wide variety of cell types including the gastric parietal cell. Within this pathway, as well as in other intracellular signaling pathways, protein phosphorylation serves as a major downstream regulatory mechanism. However, although agonist and cAMP-dependent activation of cAMP-dependent protein kinase (PKA) has been demonstrated, little is currently known about the downstream in vivo phosphoprotein substrates of this enzyme. Here we report the isolation, microsequencing, and cloning of a LIM and SH3 domain-containing, cAMP-responsive, 40-kDa phosphoprotein (pp40) from rabbit gastric parietal cells. The deduced amino acid sequence for pp40 is 93.5%, homologous with the putative protein product of the human gene lasp-1, which was recently identified based on its overexpression in some breast carcinomas. In addition to LIM and SH3 domains, the rabbit homolog contains two highly conserved PKA consensus sequences as well as two conserved SH2 binding motifs and several other putative protein kinase phosphorylation sites, including two for tyrosine kinase(s). Combined Northern and Western blot analyses indicate that pp40/lasp-1 is widely expressed (through a single 3.3-kb message) not only in epithelial tissues but also in muscle and brain. Furthermore, stimulation of isolated parietal cells, distal colonic crypts, and pancreatic cells with the adenylyl cyclase activator forskolin leads to the appearance of a higher molecular weight form of pp40/lasp-1, a finding which is consistent with an increase in protein phosphorylation. Thus pp40/lasp-1 appears to be regulated within the cAMP signaling pathway in a wide range of epithelial cell types. Because the cAMP-dependent increase in pp40 phosphorylation is correlated with secretory responses in the parietal cell and because pp40 appears to be widely distributed among various secretory tissues, this newly defined signaling protein may play an important role in modulating ionic transport or other secretory-related activities in many different cell types.
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PMID:Lasp-1 is a regulated phosphoprotein within the cAMP signaling pathway in the gastric parietal cell. 968 35


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