ATM Signaling Pathway (Homo sapiens)

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Cell response Activation path Inhibition path Triggered Damage P MDM2 P ATM P Chk2 P PIDD P Chk1 P FANCD2 P c-Abl P IKBA P ATM IR Radiation MDMX Ubiquitination & Degradation STRUCTURAL CHANGE OF CHROMATIN Inactive Dimer Cell Survival MRN Complex P BID Cell Survival Synaptic Vesicle Transport CDC25A P DNA Repair Cyclin B GADD45A CREB1 P p21 TP73 NEMO RIP1 CDC25C P SMC1A Apoptosis AP3B2 Apoptosis G2/M Transition CDK1 H2AX RAD9A P RAD51 P TLK1 CDC2 CCNE1 CDK2 BRCA1 SAPK (MAPK9) Cell Death Senescence MDMX (MDM4) MDM2 S Phase Arrest TP53 P DNA Repair Recombination CDK2 MDC1 RAIDD NF kappa B Pathway G2/M Checkpoint Arrest Caspase 2 S Phase Progression G1/S Checkpoint Arrest ATF2 P DNA Repair c-Jun TP53BP1 S Phase Progression ATM ATM Cell Cycle Checkpoint Activation MRE11 NBS1 RAD50 DNA DAMAGE Cell Survival RAD50 MRE11 NBS1 P P Name: ATM Signaling Pathway Organism: Homo sapiens


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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RevisionActionTimeUserComment
90247view 14:13, 26 October 2016AmanzoModification of some titles
90241view 10:50, 26 October 2016AmanzoModification on titles of some paths
90240view 10:29, 26 October 2016AmanzoPeriodical save, work in progress
84490view 16:16, 25 February 2016KhanspersQuick edit to datanode annotation or property
81224view 16:13, 5 August 2015AlexanderPicoremoving final IE-incompatible character
81223view 15:54, 5 August 2015AlexanderPicoremoving more IE-incompatible character
81218view 12:15, 5 August 2015AlexanderPicoremoving IE-incompatible character
79964view 07:04, 28 April 2015ZariChanged Id UniProt to Entrez gene for CDC2
78531view 03:30, 7 January 2015MaintBotadded missing graphIds
76317view 23:53, 1 July 2014MkutmonFixed datasource of S Phase Arrest pathway datanode
72241view 11:46, 29 October 2013Khanspersadded one more WP node
72240view 11:45, 29 October 2013Khansperschanged pathway node xrefs from GO to WP
71697view 12:44, 17 October 2013MaintBotUpdated data sources
70531view 09:44, 9 August 2013AmanzoWork in progress
70530view 09:42, 9 August 2013AmanzoPeriodical save, work in progress
70529view 09:11, 9 August 2013AmanzoPeriodical save, work in progress
70528view 09:01, 9 August 2013AmanzoPeriodical save, work in progress
70527view 08:50, 9 August 2013AmanzoPeriodical save, work in progress
70458view 15:04, 3 August 2013AmanzoPeriodical save, work in progress
70457view 14:54, 3 August 2013AmanzoPeriodical save, work in progress
70446view 12:05, 1 August 2013AmanzoPeriodical save, work in progress
70445view 11:55, 1 August 2013AmanzoPeriodical save, work in progress
70444view 11:44, 1 August 2013AmanzoPeriodical save, work in progress
70085view 08:44, 12 July 2013AmanzoModified description
70084view 08:33, 12 July 2013Amanzowork in progress
70083view 08:31, 12 July 2013AmanzoIR figure fixed
70082view 08:27, 12 July 2013AmanzoPeriodical save, work in progress
70081view 08:13, 12 July 2013AmanzoPeriodical save, work in progress
70072view 02:01, 12 July 2013Mkutmonreplaced interaction lines in radiation figure with graphical lines
70004view 16:12, 11 July 2013AmanzoModified description
70003view 16:11, 11 July 2013AmanzoModified description
70002view 16:08, 11 July 2013AmanzoWork in progress
70000view 15:57, 11 July 2013AmanzoPeriodical save, work in progress
69999view 15:47, 11 July 2013AmanzoPeriodical save, work in progress
69998view 15:36, 11 July 2013AmanzoPeriodical save, work in progress
69706view 15:54, 9 July 2013AmanzoReferences added
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69704view 15:39, 9 July 2013AmanzoPeriodical save, work in progress
69703view 15:35, 9 July 2013Amanzowork in progress
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69701view 14:59, 9 July 2013AmanzoPeriodical save, work in progress
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69695view 11:15, 9 July 2013AmanzoPeriodical save, work in progress
69694view 11:05, 9 July 2013AmanzoPeriodical save, work in progress
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69691view 10:04, 9 July 2013AmanzoPeriodical save, work in progress
69690view 09:55, 9 July 2013AmanzoWork 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

<cite>No annotated interactions</cite>