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)

p58, also referred to as the lamin B receptor, is an intrinsic protein of the inner nuclear membrane that binds in vitro to lamin B. Previous studies have demonstrated that p58 is phosphorylated in vivo and removal of its phosphate moieties affects lamin B binding. Using affinity-purified antipeptide antibodies, we have now immunoisolated p58 from bird erythrocyte lysates under isotonic, non-denaturing conditions. Analysis of the immunopurified material shows that five distinct proteins are tightly and specifically associated with p58. Two of these polypeptides can be identified as nuclear lamins A and B. The immunoisolate also contains a kinase activity that phosphorylates p58 in vivo and in vitro, exclusively at serine residues, as indicated by phosphoamino acid analysis and two-dimensional phosphopeptide mapping. Cell fractionation experiments and in vitro phosphorylation assays demonstrate that the p58 kinase resides in the nuclear envelope and is distinct from protein kinase A and cdc2 kinase, for both of which p58 is an in vitro substrate. These data suggest that p58 is interacting in vivo with a p58 kinase and the nuclear lamins.
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PMID:The inner nuclear membrane protein p58 associates in vivo with a p58 kinase and the nuclear lamins. 132 55

Protein kinases are important signaling molecules that are known constituents of cellular pathways critical for normal cellular growth and development. We have recently identified a new protein kinase, p58, which contains a large domain that is highly homologous to the cell division control p34cdc2 protein kinase. This new cell division control-related protein kinase was originally identified as a component of semipurified galactosyltransferase; thus, it has been denoted galactosyltransferase-associated protein kinase. In vitro, this protein kinase has been shown to phosphorylate a number of substrates, including histone H1, casein, and galactosyltransferase. In vivo, we have found that this protein kinase affects galactosyltransferase enzyme activity and that it is apparently involved in some aspect of normal cell cycle regulation. In this report, we find that the p58 gene is evolutionarily well conserved and expressed ubiquitously, but to varying extents, in adult tissues. In developmentally staged embryos, p58 expression was elevated early in embryogenesis and then decreased dramatically. In the murine submandibular gland, p58 expression was elevated between day 14 and day 16 post coitus. Expression in the submandibular gland appeared to parallel the proliferation and differentiation of specific cell types as judged by in situ hybridization. These studies indicate that the p58 protein kinase may have a critical function during normal embryonic development and that this protein kinase continues to be expressed in differentiated adult tissues.
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PMID:Regulated expression of a cell division control-related protein kinase during development. 206 72

We have isolated and characterized cDNA encoding a human 58-kDa protein kinase that is homologous to the cell division control (CDC) protein kinases. This protein kinase also contains a unique N-terminal domain that may potentially regulate its function. Due to its relatedness to p34CDC2, the human p58 cDNA was overexpressed in CHO cells to determine the effect on the cell cycle. Elevated expression of p58 in these cells resulted in prolonged late telophase and early G1 phase of the cell cycle. These p58 overexpressors showed a significantly increased frequency of tubulin midbodies as well as significant increases in mitotic abnormalities. Thus, proper regulation of p58 protein kinase is essential for normal cell cycle progression in these cells.
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PMID:Increased expression of a 58-kDa protein kinase leads to changes in the CHO cell cycle. 221 77

Lymphocyte membrane fractions from both normal and neoplastic sources exhibit tyrosine-specific protein kinase activity. The molecular weights of the endogenous substrates phosphorylated on tyrosine residues differ in B and T cells. To further characterize membrane tyrosine phosphorylation in the two major classes of lymphocytes, the tryptic phosphopeptides of their endogenous substrates were compared and the sensitivity of the kinases to inhibition by N alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK) was determined. The two major B cell substrates (61,000 and 55,000 daltons, p61 and p55) were gel purified after phosphorylation and exhaustively digested with trypsin. Separation by reverse phase high pressure liquid chromatography demonstrated that these two substrates had two identical phosphotyrosine containing tryptic phosphopeptides. p61 had an additional phosphotyrosine site. Parallel analysis of the two T cell substrates (64,000 and 58,000 daltons, p64 and p58) showed that they also contained two phosphotyrosine sites that were identical. However, the tryptic phosphopeptides from the B and T cell substrate pairs were clearly distinct suggesting that they arise from different gene products. When B and T cell membrane fractions were preincubated with TLCK (21 degrees C, 30 min) a dose-dependent decrease in p64 and p58 phosphorylation resulted. p61 and p55 phosphorylation was not affected at concentrations up to 10 mM TLCK. Tyrosine-specific kinase activity was also assessed by measuring phosphorylation of a tyrosine containing synthetic peptide. The kinase activity of T cell plasma membrane fractions was inhibited by TLCK; the B cell activity was unaffected. The results suggest that membrane fractions from normal and some neoplastic B and T cells have at least two different tyrosine-specific kinases.
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PMID:Characterization of distinct tyrosine-specific protein kinases in B and T lymphocytes. 388 8

Membrane fractions isolated from mouse and rat spleen expressed substantial tyrosine-specific protein kinase activity. Phosphotyrosine (P-Tyr) accumulation in endogenous membrane substrates was stimulated by vanadate or nonionic detergents. When in vitro phosphorylation was carried out at 0 degree C in the presence of 1 mM Mn2+ and Triton X-100, P-Tyr constituted up to 40-50% of the total phospho amino acid. Polyacrylamide gel electrophoresis showed that membranes from mixed lymphocyte populations have four major P-Tyr-containing proteins. Whereas nonionic detergents were potent stimuli for P-Tyr accumulation in all four substrates, tyrosine phosphorylation of two of these (p61 and p55) was markedly dependent on vanadate. These two substrates were present in membranes from surface Ig-bearing splenic lymphocytes purified by affinity chromatography and Raji, a human B-lymphoblastoid cell line. P-Tyr accumulation in the two other substrates observed in splenocyte membranes (p64 and p58) was much less dependent on vanadate. p64 and p58 were phosphorylated in membranes from mouse thymocytes and human and mouse T-lymphoma cell lines, while p61 and p55 were not. Thus it appears that in both murine and human lymphocytes, p64 and p58 served as T-cell-specific substrates, while p61 and p55 were specifically associated with B lymphocytes. Moreover, these distinct P-Tyr substrate patterns were conserved in some neoplastic cell lines derived from B and T cells.
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PMID:Membranes from T and B lymphocytes have different patterns of tyrosine phosphorylation. 620 54

The interferon-induced RNA-dependent protein kinase (PKR) is considered to play an important role in the cellular defense against viral infection and, in addition, has been suggested to be a tumor suppressor gene because of its growth-suppressive properties. Activation of PKR by double-stranded RNAs leads to the phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF-2 alpha) and a resultant block to protein synthesis initiation. To avoid the consequences of kinase activation, many viruses have developed strategies to down-regulate PKR. Recently, we reported on the purification and characterization of a cellular inhibitor of PKR (referred to as p58), which is activated during influenza virus infection. Subsequent cloning and sequencing has revealed that p58 is a member of the tetratricopeptide repeat (TPR) family of proteins. To further examine the physiological role of this PKR inhibitor, we stably transfected NIH 3T3 cells with a eukaryotic expression plasmid containing p58 cDNA under control of the cytomegalovirus early promoter. By taking advantage of a recently characterized p58 species-specific monoclonal antibody, we isolated cell lines that overexpressed p58. These cells exhibited a transformed phenotype, growing at faster rates and higher saturation densities and exhibiting anchorage-independent growth. Most importantly, inoculation of nude mice with p58-overexpressing cells gave rise to the production of tumors. Finally, murine PKR activity and endogenous levels of eIF-2 alpha phosphorylation were reduced in the p58-expressing cell lines compared with control cells. These data, taken together, suggest that p58 functions as an oncogene and that one mechanism by which the protein induces malignant transformation is through the down-regulation of PKR and subsequent deregulation of protein synthesis.
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PMID:The 58-kilodalton inhibitor of the interferon-induced double-stranded RNA-activated protein kinase is a tetratricopeptide repeat protein with oncogenic properties. 751 1

Many yeast genes that are essential for meiosis are expressed only in meiotic cells. Known regulators of early meiotic genes include IME1, which is required for their expression, and SIN3 and UME6, which prevent their expression in nonmeiotic cells. We report here the molecular characterization of the RIM11 gene, which we find is required for expression of several early meiotic genes. A close functional relationship between RIM11 and IME1 is supported by two observations. First, sin3 and ume6 mutations are epistatic to rim11 mutations; prior studies have demonstrated their epistasis to ime1 mutations. Second, overexpression of RIM11 can suppress an ime1 missense mutation (ime1-L321F) but not an ime1 deletion. Sequence analysis indicates that RIM11 specifies a protein kinase related to rat glycogen synthase kinase 3 and the Drosophila shaggy/zw3 gene product. Three partially defective rim11 mutations alter residues involved in ATP binding or catalysis, and a completely defective rim11 mutation alters a tyrosine residue that corresponds to the site of an essential phosphorylation for glycogen synthase kinase 3. Immune complexes containing a hemagglutinin (HA) epitope-tagged RIM11 derivative, HA-RIM11, phosphorylate two proteins, p58 and p60, whose biological function is undetermined. In addition, HA-RIM11 immune complexes phosphorylate a functional IME1 derivative but not the corresponding ime1-L321F derivative. We propose that RIM11 stimulates meiotic gene expression through phosphorylation of IME1.
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PMID:Analysis of RIM11, a yeast protein kinase that phosphorylates the meiotic activator IME1. 796 31

The p58 (PITSLRE beta 1) protein kinase (PK) is a member of a large supergene family related to the master mitotic protein kinase, p34cdc2. This PK is also a member of a sub-family itself, with at least six additional related PITSLRE PK isoforms expressed by alternative splicing and promoter utilization from three duplicated genes. Minimal overproduction of the PITSLRE beta 1 PK in Chinese hamster ovary cells results in a late mitotic delay, suggesting that this PK's function may be related to the cell cycle [Bunnell et al., Proc. Natl. Acad. Sci. USA 87 (1990) 7467-7471]. Further studies using structural and functional mutants have shown that PITSLRE PKs are involved in signaling apoptosis. The gene encoding the PITSLRE beta 1 PK has previously been isolated and structurally characterized [Eipers et al., Genomics 13 (1992) 613-621]. Here we characterize the minimal essential promoter for this gene. Analysis of a 1.18-kb stretch of DNA located upstream from the PITSLRE beta 1 start codon demonstrates that significant cat gene expression can be driven by a construct containing this sequence. Deletion studies of this DNA fragment have defined a minimal promoter that extends 144 bp 5' of the previously mapped transcription start point (tsp), and 521 bp 5' of the start codon. This region of PITSLRE beta 1 DNA does not contain canonical TATA-box sequences or G + C-rich sequences associated with many promoters, yet it has approximately 20% of the promoting activity when compared to the SV40 early promoter. This suggests that this DNA sequence is a relatively strong basal promoter of a previously uncharacterized type.
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PMID:Analysis of the 5' flanking sequences from the human protein kinase p58 (PITSLRE beta 1)-encoding gene. 805 43

The 58-kDa inhibitor of the interferon-induced double-stranded RNA-activated protein kinase (PKR) is a cellular protein that is activated during influenza virus infection to down-regulate the activity of PKR. This study was initiated to further our understanding of the inhibitor which, when overproduced, has the capacity to malignantly transform cells. We report here the isolation and characterization of cDNA clones encoding the inhibitor, designated p58, from human HeLa and mouse NIH 3T3 cells. The human and mouse p58 cDNAs were 6.5 and 1.6 kb in length, respectively. Surprisingly, the deduced amino acid sequences of the human and mouse p58 were 96% identical, indicating a remarkably high degree of conservation between species. An examination of p58 mRNA expression in human tissues revealed a 6.5-kb transcript in all tissues examined, with a particularly high level of expression present in the pancreas and liver, and also in certain leukemic cell lines. Similarly, p58 expression was detected in all mouse tissues examined, with the highest level of expression found in liver. In contrast to human tissues, three p58 transcripts of approximately 1.7, 3.3 and 5.4 kb were observed in mouse tissues, suggesting that p58 expression may be regulated differently in human and mouse cells. Western blot analysis of subcellular fractions and indirect immunofluorescence analysis of intact cells revealed that p58 was found predominantly in the cytoplasm, consistent with its function as an inhibitor of PKR, which is also a predominantly cytoplasmic protein.
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PMID:Cloning, expression, and cellular localization of the oncogenic 58-kDa inhibitor of the RNA-activated human and mouse protein kinase. 866 42

The double-stranded RNA (dsRNA)-activated protein kinase (PKR) is one of many genes induced by IFN. The PKR sequentially undergoes autophosphorylation and activation on binding to dsRNA. Previous studies have shown that PKR may be an important factor in the regulation of viral and cellular protein synthesis. Recent studies suggest that PKR may function as a tumor suppressor gene. The role of PKR in various human leukemic cells was therefore investigated. PKR mRNA levels by reverse transcription-PCR, protein expression by Western blot and FACScan analysis, and activity by phosphorylation status were studied. The expression of a known inhibitor of PKR, p58, was also investigated at mRNA and protein levels. A total of 24 samples from normal mononuclear cells (MNCs), 26 samples of acute lymphoblastic leukemia, 26 samples of acute myelogenous leukemia, 32 samples of chronic lymphocytic leukemia, and 5 samples of hairy cell leukemia was investigated. Mean mRNA levels were increased in acute lymphoblastic leukemia and acute myelogenous leukemia and decreased in chronic lymphocytic leukemia compared to normal MNCs. The mRNA levels in hairy cell leukemia were similar to those of normal MNCs. PKR protein was detectable in normal MNCs and leukemic cell extracts, and on FACScan analysis, more than 70% of cells stained positive for PKR. PKR activity was detectable in all samples investigated and was enhanced 4-23-fold in the presence of the synthetic dsRNA, poly(I) x poly(C). Protein expression of a known PKR inhibitor, p58, was barely detectable in normal MNCs and leukemic cells, with high expression in the HeLa cell line. These findings provide no evidence to support the hypothesis that PKR acts as a tumor suppressor in human leukemic cells.
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PMID:Role of double-stranded RNA-activated protein kinase in human hematological malignancies. 904 Nov 99


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