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)

In mammalian cells, four protein kinases form the PI3-kinase-related protein kinase (PIK) superfamily. These four enzymes-FRAP, DNA-PK, ATM, and ATR-are distinguished by their large size (all are >2500 amino acids), their common primary sequence relatedness through the carboxy-terminal protein kinase domain, and their sequence similarity to the p110 lipid kinase subunit of PI3-kinase. FRAP (FKBP12 and rapamycin-binding protein kinase) participates in mitogenic and growth factor responses in G1 and may regulate specific mRNA translation signals. DNA-PK (DNA-dependent protein kinase), ATM (ataxia telangiectasia mutated), and ATR (ataxia telangiectasia and Rad 3 related) are thought to participate in responses to nuclear cues that activate DNA rearrangements or cell cycle arrests. Recent studies in this protein kinase family indicate an important role for ATM and ATR in a meiotic surveillance mechanism that may regulate proper chromosome transmission.
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PMID:Responses to DNA damage and regulation of cell cycle checkpoints by the ATM protein kinase family. 911 20

In response to DNA damage and replication blocks, cells prevent cell cycle progression through the control of critical cell cycle regulators. We identified Chk2, the mammalian homolog of the Saccharomyces cerevisiae Rad53 and Schizosaccharomyces pombe Cds1 protein kinases required for the DNA damage and replication checkpoints. Chk2 was rapidly phosphorylated and activated in response to replication blocks and DNA damage; the response to DNA damage occurred in an ataxia telangiectasia mutated (ATM)-dependent manner. In vitro, Chk2 phosphorylated Cdc25C on serine-216, a site known to be involved in negative regulation of Cdc25C. This is the same site phosphorylated by the protein kinase Chk1, which suggests that, in response to DNA damage and DNA replicational stress, Chk1 and Chk2 may phosphorylate Cdc25C to prevent entry into mitosis.
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PMID:Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. 983 40

The ataxia telangiectasia mutated (ATM) gene encodes a serine/threonine protein kinase that plays a critical role in genomic surveillance and development. Here, we use a peptide library approach to define the in vitro substrate specificity of ATM kinase activity. The peptide library analysis identified an optimal sequence with a central core motif of LSQE that is preferentially phosphorylated by ATM. The contributions of the amino acids surrounding serine in the LSQE motif were assessed by utilizing specific peptide libraries or individual peptide substrates. All amino acids comprising the LSQE sequence were critical for maximum peptide substrate suitability for ATM. The DNA-dependent protein kinase (DNA-PK), a Ser/Thr kinase related to ATM and important in DNA repair, was compared with ATM in terms of peptide substrate selectivity. DNA-PK was found to be unique in its preference of neighboring amino acids to the phosphorylated serine. Peptide library analyses defined a preferred amino acid motif for ATM that permits clear distinctions between ATM and DNA-PK kinase activity. Data base searches using the library-derived ATM sequence identified previously characterized substrates of ATM, as well as novel candidate substrate targets that may function downstream in ATM-directed signaling pathways.
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PMID:Utilization of oriented peptide libraries to identify substrate motifs selected by ATM. 1080 97

Nijmegen breakage syndrome (NBS) is characterized by extreme radiation sensitivity, chromosomal instability and cancer. The phenotypes are similar to those of ataxia telangiectasia mutated (ATM) disease, where there is a deficiency in a protein kinase that is activated by DNA damage, indicating that the Nbs and Atm proteins may participate in common pathways. Here we report that Nbs is specifically phosphorylated in response to gamma-radiation, ultraviolet light and exposure to hydroxyurea. Phosphorylation of Nbs mediated by gamma-radiation, but not that induced by hydroxyurea or ultraviolet light, was markedly reduced in ATM cells. In vivo, Nbs was phosphorylated on many serine residues, of which S343, S397 and S615 were phosphorylated by Atm in vitro. At least two of these sites were underphosphorylated in ATM cells. Inactivation of these serines by mutation partially abrogated Atm-dependent phosphorylation. Reconstituting NBS cells with a mutant form of Nbs that cannot be phosphorylated at selected, ATM-dependent serine residues led to a specific reduction in clonogenic survival after gamma-radiation. Thus, phosphorylation of Nbs by Atm is critical for certain responses of human cells to DNA damage.
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PMID:ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response. 1083 19

The tumour-suppressor protein BRCA1 mediates its biological functions by interacting with cellular factors such as the CtIP polypeptide, a substrate for the ATM (for 'ataxia telangiectasia mutated') protein kinase. Li et al. report that the BRCA1-CtIP interaction is disrupted by ionizing radiation and by other genotoxic stresses that induce phosphorylation of CtIP by ATM kinase, and that this dissociation of the BRCA1-CtIP complex in turn modulates the transcription of DNA-damage-response genes. We have shown that the BRCA1-binding domain of CtIP (amino-acid residues 133-369) is distal to the sites that are phosphorylated by ATM kinase (residues S664 and S745). We now show that the BRCA1-CtIP complex is stable in irradiated cells, and that the phosphorylated isoforms of CtIP that are induced by ionizing radiation still interact in vivo with BRCA1. We conclude that disruption of the BRCA1-CtIP complex cannot account for induction of DNA-damage-response genes in the way proposed by Li et al.
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PMID:Effect of DNA damage on a BRCA1 complex. 1168 34

The serine/threonine protein kinase LKB1 functions as a tumour suppressor, and mutations in this enzyme lead to the inherited Peutz-Jeghers cancer syndrome. We previously found that LKB1 was phosphorylated at Thr-366 in vivo, a residue conserved in mammalian, Xenopus and Drosophila LKB1, located on a C-terminal non-catalytic moiety of the enzyme. Mutation of Thr-366 to Ala or Asp partially inhibited the ability of LKB1 to suppress growth of G361 melanoma cells, but did not affect LKB1 activity in vitro or LKB1 localization in vivo. As a first step in exploring the role of this phosphorylation further, we have generated a phosphospecific antibody specifically recognizing LKB1 phosphorylated at Thr-366 and demonstrate that exposure of cells to ionizing radiation (IR) induced a marked phosphorylation of LKB1 at Thr-366 in the nucleus. Thr-366 lies in an optimal phosphorylation motif for the phosphoinositide 3-kinase-like kinases DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated kinase (ATM) and ataxia telangiectasia-related kinase (ATR), which function as sensors for DNA damage in cells and mediate cellular responses to DNA damage. We demonstrate that both DNA-PK and ATM efficiently phosphorylate LKB1 at Thr-366 in vitro and provide evidence that ATM mediates this phosphorylation in vivo. This is based on the finding that LKB1 is not phosphorylated in a cell line lacking ATM in response to IR, and that agents which induce cellular responses via ATR in preference to ATM poorly induce phosphorylation of LKB1 at Thr-366. These observations provide the first link between ATM and LKB1 and suggest that ATM could regulate LKB1.
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PMID:Ionizing radiation induces ataxia telangiectasia mutated kinase (ATM)-mediated phosphorylation of LKB1/STK11 at Thr-366. 1223 50

Patients with the autosomal recessive disorder ataxia telangiectasia (A-T) show the biallelic inactivation of the ataxia telangiectasia mutated (ATM) gene. A-T patients exhibit a predisposition to the development of a wide range of lymphoid tumours, suggesting that the ATM protein normally plays an important role in the prevention of both T and B cell malignancies. The ATM protein is a 370 kDa protein kinase implicated in the integration of different cellular responses to particular forms of DNA damage. Several recent studies have reported the possibility that the ATM gene can act as a tumour suppressor gene in non A-T individuals. Frequent ATM inactivation was confirmed in three sporadic lymphoid tumours of mature phenotype: T cell prolymphocytic leukaemia (T-PLL), B-cell chronic lymphocytic leukaemia (B-CLL) and mantle cell lymphoma (MCL). Here, we provide a summary of the published ATM mutations in sporadic lymphoid tumours, including our own study on the role of ATM mutations in the pathogenesis of sporadic B-CLL. The published results suggest possible differences in the origin, the nature and distribution of ATM mutations between sporadic B-CLL, MCL and T-PLL. While ATM mutations in mature B cell tumours (B-CLL and MCL) represent a mixture of missense and truncating errors distributed across the whole of the ATM coding sequence, mutations in sporadic T-PLL appear to be predominantly missense, clustering in the region encoding the PI-3 kinase catalytic domain of the protein. The reason for this difference is unclear, but the difference itself supports the notion that the pathogenesis of B and T cell tumours on an ATM deficient background might be different. In addition, in both B-CLL and MCL ATM mutation carriers have been reported, raising the possibility that ATM mutation carriers may have an increased risk of developing these tumours. The existence as well as magnitude of the risk, however, remains to be established. Furthermore, our own studies indicate that the presence of ATM mutations in sporadic B-CLL causes a distinctive defect in response to DNA damaging agents, offering a possible explanation for the poor response of ATM mutant tumours to standard treatment. Therefore, one of the future challenges will be to devise strategies to bypass the existing defect in response to DNA damage and activate apoptosis in ATM mutant sporadic lymphoid tumours.
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PMID:ATM mutations in sporadic lymphoid tumours. 1240 May 98

Ataxia telangiectasia (AT) is a human hereditary syndrome whose underlying gene product, ataxia telangiectasia mutated (ATM) protein kinase, is involved in multiple intracellular signaling pathways. We demonstrated previously that AT fibroblasts are defective in intracellular Ca(2+) mobilization in response to both stress-inducing and mitogenic stimuli. To extend these findings, normal and AT cells were exposed to serum in the presence of different concentrations of extracellular Ca(2+) ([Ca(2+)](o)), and release of intracellular Ca(2+), activation of calmodulin-dependent protein kinase II and phosphorylation of kinases ERK1 and 2 were monitored. When maintained in high [Ca(2+)](o) (0.42 mM), normal fibroblasts responded to serum introduction more rapidly and efficiently than did AT cells. Unexpectedly, decreasing the [Ca(2+)](o) in the medium had a diametrically opposite effect. Under low [Ca(2+)](o) (0.0022 mM) conditions, normal cells were slow and inefficient in their responses, whereas AT cells showed a substantial improvement in all three end points. These findings demonstrate that loss of ATM kinase function deregulates the extracellular calcium-sensing receptor (CaR). This malfunction presumably arises from a post-transcriptional event, since CaR mRNA proved to be normal in AT cells. Together, our data suggest that ATM may mediate cell response to mitogenic factors by tightly regulating the set point of the CaR and thereby modulating the crosstalk between this metabotropic receptor and growth factor receptors. Alternatively, the faulty sensing of extracellular calcium in AT cells may be secondary to a state of chronic oxidative stress attributable to ATM deficiency.
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PMID:Aberrant sensing of extracellular Ca2+ by cultured ataxia telangiectasia fibroblasts. 1254 70

Ataxia telangiectasia is one of a group of recessive hereditary genomic instability disorders and is characterized by progressive neurodegeneration, immunodeficiency and cancer susceptibility. Heterozygotes for the mutated gene are more susceptible to cancer and to ischaemic heart disease. The affected gene, ATM (ataxia telangiectasia mutated), has been cloned and codes for a protein kinase (ATM), which orchestrates the cellular response to DNA double-strand breaks after ionising radiation. An underlying feature of ataxia telangiectasia is oxidative stress and there is chronic activation of stress response pathways in tissues showing pathology such as the cerebellum, but not in the cerebrum or liver. ATM has also been shown to be activated by insulin and to have a wider role in signal transduction and cell growth. Many, but not all, aspects of the phenotype can be attributed to a defective DNA damage response. The oxidative stress may result directly from accumulated DNA damage in affected tissues or ATM may have an additional role in sensing/modulating redox homeostasis. The basis for the observed tissue specificity of the oxidative damage in ataxia telangiectasia is not clear.
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PMID:Oxidative stress in ataxia telangiectasia. 1263 40

The human tumor suppressor gene ataxia telangiectasia mutated (ATM) encodes a 3056 amino-acid protein kinase that regulates cell cycle checkpoints. ATM is defective in the neurodegenerative and cancer predisposition syndrome ataxia-telangiectasia. ATM protein kinase is activated by DNA damage and responds by phosphorylating downstream effectors involved in cell cycle arrest and DNA repair, such as p53, MDM2, CHEK2, BRCA1 and H2AX. ATM is probably a component of, or in close proximity to, the double-stranded DNA break-sensing machinery. We have observed purified human ATM protein, ATM-DNA and ATM-DNA-avidin bound complexes by single-particle electron microscopy and obtained three-dimensional reconstructions which show that ATM is composed of two main domains comprising a head and an arm. DNA binding to ATM induces a large conformational movement of the arm-like domain. Taken together, these three structures suggest that ATM is capable of interacting with DNA, using its arm to clamp around the double helix.
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PMID:Electron microscopy and 3D reconstructions reveal that human ATM kinase uses an arm-like domain to clamp around double-stranded DNA. 1281 60


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