ATM signaling (Homo sapiens)

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Cell responsePPPPPPPPPIR radiationMDMX ubiquitination & degradationSTRUCTURAL CHANGE OF CHROMATINInactive dimerCell survivalMRN ComplexPCell survivalSynaptic vesicle transportChk228, 62, 71, 87, 122...CDC25ADNA repairCyclin B49, 113, 181, 183, 189GADD45A6, 37, 89, 155, 161...CREB1p2150TP735, 63, 105, 141, 192...31, 94, 100, 110, 148...NEMOCDC25C10, 457, 66, 90, 102, 166...SMC1A46ApoptosisAP3B29, 14, 82, 86, 138...ApoptosisG2/M transitionCDK115398, 135, 137, 154, 168...ATM65, 68, 84, 99, 156...H2AX69, 74, 123, 140, 151...RAD9A171, 176PIDDRAD5111, 34, 56, 73, 79...TLK135, 41, 44, 60, 119...CDC2133, 144, 188IKBA17, 40, 77, 88, 1878, 180RIP1CCNE185, 93, 120115, 116c-Abl52, 55, 150, 205Chk14, 36, 126, 136, 146...BRCA1SAPK (MAPK9)43, 101, 114, 118, 131...Cell death117, 15759, 64, 162FANCD23, 53, 61, 108, 139...SenescenceMDMX (MDM4)1, 19, 38, 80, 81, 107...20, 23, 54, 92, 96...S phase arrestTP53DNA repair26, 76, 125, 145MDM22, 91, 177, 179, 204...CDK232, 33, 77, 88, 121...MDC116, 132, 149, 152RAIDDNF kappa B pathway42, 47, 48, 58, 67...G2/M checkpoint arrest10, 15, 21, 170Caspase 230, 97, 129, 147, 162...S phaseprogressionG1/S checkpoint arrest ATF2DNA repair29, 51, 111BID24, 75, 103, 128, 165c-Jun72, 112TP53BP1S phase progression127ATM65, 68, 84, 99, 156...ATMATM65, 68, 84, 99, 156...65, 68, 84, 99, 156...Cell cycle checkpoint activationMRE1127, 109, 142, 185, 198NBS1RAD50DNA DAMAGE39, 83, 158, 199CDK2MDM232, 33, 77, 88, 121...2, 91, 177, 179, 204...Cell survivalRAD50MRE11NBS1PPPPPPPPPActivation pathInhibition pathTriggered damageRecombinationLegend


Description

Ataxia-telangiectasia (A-T) is a highly pleiotropic, autosomal recessive disease that leads to multisystem defects and has an intricate cellular phenotype, all linked to the functional inactivation of a single gene. Extensive research on the phenotype and the recent discovery and cloning of the responsible gene point to a defect as a central biochemical locus which links several signal transduction pathways that operate under stress as well as in normal physiological conditions.

Ataxia is the first symptom in all patients and is predominantly truncal, first manifested in swaying of the head and trunk on standing and even sitting. Truncal ataxia precedes appendicular cerebellar disease. In the first years of life, certain manifestations are present such as dysarthria, muscular hypotonia, the slow initiation and performance of all voluntary movements, characteristic hypotonic facies and postures, and drooling. Dyssynergia and intention tremor of the upper extremities become a major feature after the fifth year of life. The tendon reflexes are diminished or lost, but may be normal or even hyperactive in the early stages. All these observations show a clear ataxia of cerebellar type, initially of station and gait, and later of intention. Early observations of brains from patients with A-T showed neurodegenerative changes, particularly in the Purkinje and granular cells of the cerebellum. Neuronal degeneration is also present in the brainstem, and dentate and olivary nuclei atrophy. Neuronal loss occurs in the substantial nigra and oculomotor nuclei, dorsal root ganglia, and degenerative changes are evident in spinal motor neurons, and dorsal root and sympathetic motor neurons. Moreover, multiple abnormalities in Purkinje cell development have been observed in an Atm-deficient mouse model. Misplaced Purkinje cells have been observed in both the granular and molecular cell layers. In addition, Purkinje cell dendrites tend to grow laterally instead of extending towards the surface of the cerebellum.

ATM (for Ataxia-telangiectasia mutated) has been located by restriction-fragment length polymorphism in the chromosome 11, location: 108,093,211-108,239,829. Interestingly, the site of ATM is the same or adjacent to the region occupied by CD3 (Antigen, Delta subunit), THY1 (T-Cell antigen), and NCAM (Cell Adhesion Molecule, Neural, 1) genes, all of which are members of the immunoglobulin-gene superfamily and consequently may be subject to the same defect that afflicts the T-cell receptor and immunoglobulin molecules in A-T. The ATM gene presents an open reading frame (ORF) of 9,165 kb cDNA and is constituted by 66 exons spread over 150 kb of genomic DNA which has a transcript of 12 kb. The ORF of this transcript predicts a 370-kDa protein composed of 3056 amino acids. Over 300 mutations have been found in A-T patients, distributed across the full length (150 kb of genomic DNA) of the ATM gene.

Sequence homology indicates that the atm gene product falls into a family of proteins that are related to the catalytic subunit of phosphatidylinositol 3-kinase (PI 3-kinase). This family includes TEL1, MEC1, TOR1, and TOR2 of the budding yeast Saccharomyces cerevisiae, RAD3 of the fission yeast Schizosaccharomyces pombe, and MEI-41 of Drosophila melanogaster. The mammalian family member most closely related to ATM is the ATR/FRP1 protein and, like its yeast homologs, it mediates cellular responses to unreplicated or damaged DNA. In humans the PI 3-kinase family includes the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs) and FRAP. These sequence homologies appear to reflect functional homology because many of the PI 3-kinase family members are involved in DNA repair, recombination and cell cycle control. Despite the resemblance to lipid kinases, members of this family, including ATM, possess a serine/threonine protein kinase activity, which is wortmannin sensitive.

ATM phosphoprotein is ubiquitously expressed and predominantly found in nuclei of proliferating cells, but subcellular fractionation and immunofluorescence revealed that 10-20% of the protein is present in cytoplasmic vesicles, including peroxisomes and endosomes and a prominent cytoplasmic fraction in mouse oocytes. ATM is endosome-bound in mouse neurons, suggesting molecular sorting of the protein occurs in the cytoplasm. In Purkinje cells, distribution of ATM protein is primarily in cytoplasm, and this may be related to the differentiation state of the cells. ATM mRNA is present in all human and mouse tissues. In situ hybridization shows that ATM mRNA is expressed throughout the whole mouse embryo. Furthermore, ATM has been associated with beta-adaptin in lymphoblast vesicles indicating that it may play a role in intracellular vesicle and/or protein transport mechanisms. No obvious nuclear localization signals have been detected in ATM. Neither an ectopically expressed N-terminal fragment of the protein nor a C-terminal fragment is capable of entering the nucleus.

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History

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CompareRevisionActionTimeUserComment
129687view00:47, 22 May 2024EweitzModified title
128135view14:20, 27 January 2024EweitzUse standard order of graphics and labels in legend
128134view14:18, 27 January 2024EweitzUpgrade legend
128133view14:10, 27 January 2024EweitzStandardize case
116808view10:11, 14 May 2021EweitzModified title
115323view09:15, 13 February 2021EgonwMade several pathways clickable
102220view20:49, 11 December 2018Khanspersswitched multiple interactions to segmented
102213view00:14, 11 December 2018Khanspersconverted ineractions to graphical lines in legend
90247view21:13, 26 October 2016AmanzoModification of some titles
90241view17:50, 26 October 2016AmanzoModification on titles of some paths
90240view17:29, 26 October 2016AmanzoPeriodical save, work in progress
84490view23:16, 25 February 2016KhanspersQuick edit to datanode annotation or property
81224view23:13, 5 August 2015AlexanderPicoremoving final IE-incompatible character
81223view22:54, 5 August 2015AlexanderPicoremoving more IE-incompatible character
81218view19:15, 5 August 2015AlexanderPicoremoving IE-incompatible character
79964view14:04, 28 April 2015ZariChanged Id UniProt to Entrez gene for CDC2
78531view10:30, 7 January 2015MaintBotadded missing graphIds
76317view06:53, 2 July 2014MkutmonFixed datasource of S Phase Arrest pathway datanode
72241view18:46, 29 October 2013Khanspersadded one more WP node
72240view18:45, 29 October 2013Khansperschanged pathway node xrefs from GO to WP
71697view19:44, 17 October 2013MaintBotUpdated data sources
70531view16:44, 9 August 2013AmanzoWork in progress
70530view16:42, 9 August 2013AmanzoPeriodical save, work in progress
70529view16:11, 9 August 2013AmanzoPeriodical save, work in progress
70528view16:01, 9 August 2013AmanzoPeriodical save, work in progress
70527view15:50, 9 August 2013AmanzoPeriodical save, work in progress
70458view22:04, 3 August 2013AmanzoPeriodical save, work in progress
70457view21:54, 3 August 2013AmanzoPeriodical save, work in progress
70446view19:05, 1 August 2013AmanzoPeriodical save, work in progress
70445view18:55, 1 August 2013AmanzoPeriodical save, work in progress
70444view18:44, 1 August 2013AmanzoPeriodical save, work in progress
70085view15:44, 12 July 2013AmanzoModified description
70084view15:33, 12 July 2013Amanzowork in progress
70083view15:31, 12 July 2013AmanzoIR figure fixed
70082view15:27, 12 July 2013AmanzoPeriodical save, work in progress
70081view15:13, 12 July 2013AmanzoPeriodical save, work in progress
70072view09:01, 12 July 2013Mkutmonreplaced interaction lines in radiation figure with graphical lines
70004view23:12, 11 July 2013AmanzoModified description
70003view23:11, 11 July 2013AmanzoModified description
70002view23:08, 11 July 2013AmanzoWork in progress
70000view22:57, 11 July 2013AmanzoPeriodical save, work in progress
69999view22:47, 11 July 2013AmanzoPeriodical save, work in progress
69998view22:36, 11 July 2013AmanzoPeriodical save, work in progress
69706view22:54, 9 July 2013AmanzoReferences added
69705view22:49, 9 July 2013AmanzoPeriodical save, work in progress
69704view22:39, 9 July 2013AmanzoPeriodical save, work in progress
69703view22:35, 9 July 2013Amanzowork in progress
69702view22:10, 9 July 2013AmanzoPeriodical save, work in progress
69701view21:59, 9 July 2013AmanzoPeriodical save, work in progress
69698view19:10, 9 July 2013AmanzoPeriodical save, work in progress

External references

DataNodes

View all...
NameTypeDatabase referenceComment
AP3B2ProteinQ13367 (Uniprot-TrEMBL)
ATF2GeneProductENSG00000115966 (Ensembl)
ATMGeneProductENSG00000149311 (Ensembl)
ApoptosisPathwayWP254 (WikiPathways)
BIDProteinP55957 (Uniprot-TrEMBL)
BRCA1ProteinP38398 (Uniprot-TrEMBL)
CCNE1GeneProductENSG00000105173 (Ensembl)
CDC25AGeneProductENSG00000164045 (Ensembl)
CDC25CGeneProductENSG00000158402 (Ensembl)
CDC2GeneProduct983 (Entrez Gene)
CDK1GeneProductENSG00000170312 (Ensembl)
CDK2ProteinP24941 (Uniprot-TrEMBL)
CREB1GeneProduct1385 (Entrez Gene)
Caspase 2GeneProductP42575 (Uniprot-TrEMBL)
Cell cycle checkpoint activationPathwayWP1775 (WikiPathways)
Cell deathPathwayWP254 (WikiPathways)
Chk1ProteinO14757 (Uniprot-TrEMBL)
Chk2ProteinO96017 (Uniprot-TrEMBL)
Cyclin BGeneProduct891 (Entrez Gene)
DNA DAMAGEPathwayWP707 (WikiPathways)
DNA repairPathwayWP707 (WikiPathways)
FANCD2ProteinQ9BXW9 (Uniprot-TrEMBL)
G1/S checkpoint arrest PathwayWP45 (WikiPathways)
G2/M checkpoint arrestPathwayWP1859 (WikiPathways)
G2/M transitionPathwayWP1859 (WikiPathways)
GADD45AGeneProduct1647 (Entrez Gene)
H2AXProteinP16104 (Uniprot-TrEMBL)
IKBAProteinP25963 (Uniprot-TrEMBL)
MDC1ProteinQ14676 (Uniprot-TrEMBL)
MDM2ProteinQ00987 (Uniprot-TrEMBL)
MDMX (MDM4)GeneProductO15151 (Uniprot-TrEMBL)
MRE11ProteinP49959 (Uniprot-TrEMBL)
NBS1ProteinO60934 (Uniprot-TrEMBL)
NEMOProteinQ9Y6K9 (Uniprot-TrEMBL)
NF kappa B pathwayPathwayko04064 (KEGG Pathway)
PIDDGeneProductENSG00000177595 (Ensembl)
RAD50ProteinQ92878 (Uniprot-TrEMBL)
RAD51GeneProductENSG00000051180 (Ensembl)
RAD9AGeneProductENSG00000172613 (Ensembl)
RAIDDGeneProductP78560 (Uniprot-TrEMBL)
RIP1GeneProductQ13546 (Uniprot-TrEMBL)
RecombinationPathwayWP438 (WikiPathways)
S phase progressionPathwayWP45 (WikiPathways)
S phase arrestPathwayWP45 (WikiPathways)
S phase progressionPathwayWP45 (WikiPathways)
SAPK (MAPK9)GeneProductENSG00000050748 (Ensembl)
SMC1AProteinQ14683 (Uniprot-TrEMBL)
SenescencePathwayWP615 (WikiPathways)
TLK1ProteinQ9UKI8 (Uniprot-TrEMBL)
TP53BP1GeneProductENSG00000067369 (Ensembl)
TP53GeneProductENSG00000141510 (Ensembl)
TP73GeneProductENSG00000078900 (Ensembl)
c-AblGeneProductENSG00000097007 (Ensembl)
c-JunGeneProductENSG00000177606 (Ensembl)
p21GeneProductENSG00000124762 (Ensembl)

Annotated Interactions

No annotated interactions

Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP2516"
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