ATM Signaling Pathway (Bos taurus)

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Cell responsePPPPPPPPPIR RadiationMDMX Ubiquitination &DegradationSTRUCTURAL CHANGEOF CHROMATINInactiveDimerCellSurvivalMRN ComplexPCellSurvivalSynaptic VesicleTransportCHEK226, 52, 65, 153, 155...CDC25ADNARepairCCNB162, 66, 70, 126, 187GADD45A6, 27, 59, 112, 115...CREB1106CDKN1A4, 25, 79, 87, 132...TP73NEMO44, 49, 74, 97, 102...CDC25C84, 13717, 21, 40, 113, 138...SMC1A96Apoptosis1, 13, 69, 83, 117...AP3B2ApoptosisG2/M TransitionCDK15880, 86, 147, 178, 197...ATM3, 12, 39, 61, 143...H2AFX37, 46, 105, 107, 157...RAD9APIDD1121, 189RAD5148, 78, 116, 129, 167...2, 31, 33, 36, 134...TLK171, 101, 185CDK124, 35, 53, 90, 118BIKBARIPK163, 124CCNE192, 139, 16385, 119ABL154, 160, 184, 190CHEK1BRCA132, 103, 142, 161, 181...MAPK916, 28, 38, 55, 108...67, 172Cell DeathFANCD281, 133, 1468, 22, 56, 95, 127...Senescence5, 14, 73, 94, 120...MDM419, 20, 76, 89, 145...S PhaseArrestTP53DNA Repair10, 122, 149, 176MDM229, 30, 42, 91, 154...CDK253, 57, 77, 90, 170...MDC182, 99, 159, 192CRADDNF kappa B Pathway11, 45, 60, 100, 114...72, 137, 140, 188G2/M CheckpointArrestCASP2S PhaseProgression9, 68, 81, 88, 125...G1/S CheckpointArrest ATF2DNA Repair47, 109, 194BID241, 51, 128, 135, 19350, 75JUNTP53BP164S PhaseProgressionATM3, 12, 39, 61, 143...ATM3, 12, 39, 61, 143...ATM3, 12, 39, 61, 143...Cell CycleCheckpointActivationMRE11A23, 111, 130, 182, 186NBNRAD50DNA DAMAGE18, 93, 104, 175CDK253, 57, 77, 90, 170...MDM229, 30, 42, 91, 154...CellSurvivalRAD50MRE11ANBNPPPPPPPPPActivation pathInhibition pathTriggered DamageRecombination


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.

Comments

HomologyConvert 
This pathway was inferred from Homo sapiens pathway WP2516(79964) with a 97.0% conversion rate.

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Bibliography

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History

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81225view23:13, 5 August 2015AlexanderPicoremoving final IE-incompatible character
81222view22:54, 5 August 2015AlexanderPicoremoving more IE-incompatible character
81219view19:16, 5 August 2015AlexanderPicoremoving IE-incompatible character
80821view15:27, 30 June 2015MkutmonNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ABL1GeneProductENSBTAG00000017976 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000097007
AP3B2ProteinENSBTAG00000008495 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:Q13367
ATF2GeneProductENSBTAG00000002295 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000115966
ATMGeneProductENSBTAG00000003111 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000149311
ApoptosisPathwayWP254 (WikiPathways)
BID2ProteinENSBTAG00000013988 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:P55957
BIKBAProteinENSBTAG00000016683 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:P25963
BRCA1ProteinENSBTAG00000022520 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:P38398
CASP2GeneProductENSBTAG00000018159 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:P42575
CCNB1GeneProductENSBTAG00000014239 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:891
CCNE1GeneProductENSBTAG00000004735 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:F6KX26
CDC25AGeneProductENSBTAG00000009586 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000164045
CDC25CGeneProductENSBTAG00000005293 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000158402
CDK1GeneProductENSBTAG00000010109 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:983
CDK2ProteinENSBTAG00000004021 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:P24941
CDKN1AGeneProductENSBTAG00000008353 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000124762
CHEK1ProteinENSBTAG00000017582 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:O14757
CHEK2ProteinENSBTAG00000004956 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:O96017
CRADDGeneProductENSBTAG00000005107 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:P78560
CREB1GeneProductENSBTAG00000005474 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1385
Cell Cycle

Checkpoint

Activation
PathwayWP1775 (WikiPathways)
Cell DeathPathwayWP254 (WikiPathways)
DNA RepairPathwayWP707 (WikiPathways)
DNA DAMAGEPathwayWP707 (WikiPathways)
DNA RepairPathwayWP707 (WikiPathways)
FANCD2ProteinENSBTAG00000010077 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:Q9BXW9
G1/S Checkpoint Arrest PathwayWP45 (WikiPathways)
G2/M Checkpoint ArrestPathwayWP1859 (WikiPathways)
G2/M TransitionPathwayWP1859 (WikiPathways)
GADD45AGeneProductENSBTAG00000013860 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1647
H2AFXProteinENSBTAG00000038047 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:P16104
JUNGeneProductENSBTAG00000004037 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000177606
MAPK9GeneProductENSBTAG00000004709 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000050748
MDC1ProteinENSBTAG00000025526 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:Q14676
MDM2ProteinENSBTAG00000010422 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:Q00987
MDM4GeneProductENSBTAG00000006255 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:O15151
MRE11AProteinENSBTAG00000008925 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:P49959
NBNProteinENSBTAG00000013225 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:O60934
NEMOProtein
NF kappa B PathwayPathwayko04064 (KEGG Pathway)
PIDD1GeneProductENSBTAG00000019634 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000177595
RAD50ProteinENSBTAG00000011252 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:Q92878
RAD51GeneProductENSBTAG00000002918 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000051180
RAD9AGeneProductENSBTAG00000012141 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000172613
RIPK1GeneProductENSBTAG00000006378 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:Q13546
RecombinationPathwayWP438 (WikiPathways)
S Phase ArrestPathwayWP45 (WikiPathways)
S Phase ProgressionPathwayWP45 (WikiPathways)
SMC1AProteinENSBTAG00000017761 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:Q14683
SenescencePathwayWP615 (WikiPathways)
TLK1ProteinENSBTAG00000006918 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = S:Q9UKI8
TP53BP1GeneProductENSBTAG00000021304 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000067369
TP53GeneProductENSBTAG00000001069 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000141510
TP73GeneProductENSBTAG00000005812 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000078900

Annotated Interactions

No annotated interactions
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