ATM signaling (Homo sapiens)
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Description
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 β-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.Quality Tags
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History
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External references
DataNodes
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Name | Type | Database reference | Comment |
---|---|---|---|
AP3B2 | Protein | Q13367 (Uniprot/TrEMBL) | |
ATF2 | GeneProduct | ENSG00000115966 (Ensembl) | |
ATM | GeneProduct | ENSG00000149311 (Ensembl) | |
Apoptosis | Pathway | GO:0008630 (GeneOntology) | |
Apoptosis | Pathway | GO:0042771 (GeneOntology) | |
BID | Protein | P55957 (Uniprot/TrEMBL) | |
BRCA1 | Protein | P38398 (Uniprot/TrEMBL) | |
CDC25A | GeneProduct | ENSG00000164045 (Ensembl) | |
CDC25C | GeneProduct | ENSG00000158402 (Ensembl) | |
CDC2 | GeneProduct | I6L9I5 (Uniprot/TrEMBL) | |
CDK1 | GeneProduct | ENSG00000170312 (Ensembl) | |
CDK2 | Protein | P24941 (Uniprot/TrEMBL) | |
CREB1 | GeneProduct | 1385 (Entrez Gene) | |
Caspase 2 | GeneProduct | P42575 (Uniprot/TrEMBL) | |
Cell Cycle
Checkpoint Activation | Pathway | GO:0000075 (GeneOntology) | |
Cell Death | Pathway | GO:0012501 (GeneOntology) | |
Chk1 | Protein | O14757 (Uniprot/TrEMBL) | |
Chk2 | Protein | O96017 (Uniprot/TrEMBL) | |
Cyclin B | GeneProduct | 891 (Entrez Gene) | |
Cyclin-E1 | GeneProduct | F6KX26 (Uniprot/TrEMBL) | |
DNA repair | Pathway | GO:0006281 (GeneOntology) | |
DNA DAMAGE | Pathway | GO:0042770 (GeneOntology) | |
DNA repair & Recombination | Pathway | GO:0006281 (GeneOntology) | |
DNA repair | Pathway | GO:0006281 (GeneOntology) | |
FANCD2 | Protein | Q9BXW9 (Uniprot/TrEMBL) | |
G1/S checkpoint Arrest | Pathway | GO:2000134 (GeneOntology) | |
G2/M checkpoint Arrest | Pathway | GO:0010972 (GeneOntology) | |
G2/M transition | Pathway | GO:0000086 (GeneOntology) | |
GADD45A | GeneProduct | 1647 (Entrez Gene) | |
H2AX | Protein | P16104 (Uniprot/TrEMBL) | |
IKBA | Protein | P25963 (Uniprot/TrEMBL) | |
MDC1 | Protein | Q14676 (Uniprot/TrEMBL) | |
MDM2 | Protein | Q00987 (Uniprot/TrEMBL) | |
MDMX (MDM4) | GeneProduct | O15151 (Uniprot/TrEMBL) | |
MRE11 | Protein | P49959 (Uniprot/TrEMBL) | |
NBS1 | Protein | O60934 (Uniprot/TrEMBL) | |
NEMO | Protein | Q9Y6K9 (Uniprot/TrEMBL) | |
NF kappa B Pathway | Pathway | ko04064 (KEGG Pathway) | |
PIDD | GeneProduct | ENSG00000177595 (Ensembl) | |
RAD50 | Protein | Q92878 (Uniprot/TrEMBL) | |
RAD51 | GeneProduct | ENSG00000051180 (Ensembl) | |
RAD9A | GeneProduct | ENSG00000172613 (Ensembl) | |
RAIDD | GeneProduct | P78560 (Uniprot/TrEMBL) | |
RIP1 | GeneProduct | Q13546 (Uniprot/TrEMBL) | |
S Phase Progression | Pathway | GO:0000084 (GeneOntology) | |
S phase Arrest | Pathway | GO:0045749 (GeneOntology) | |
SAPK (MAPK9) | GeneProduct | ENSG00000050748 (Ensembl) | |
SMC1A | Protein | Q14683 (Uniprot/TrEMBL) | |
Senescence | Pathway | GO:0090400 (GeneOntology) | |
TLK1 | Protein | Q9UKI8 (Uniprot/TrEMBL) | |
TP53BP1 | GeneProduct | ENSG00000067369 (Ensembl) | |
TP53 | GeneProduct | ENSG00000141510 (Ensembl) | |
TP73 | GeneProduct | ENSG00000078900 (Ensembl) | |
c-Abl | GeneProduct | ENSG00000097007 (Ensembl) | |
c-Jun | GeneProduct | ENSG00000177606 (Ensembl) | |
p21 | GeneProduct | ENSG00000124762 (Ensembl) |
Annotated Interactions
No annotated interactions