Differential localization of ATM is correlated with activation of distinct downstream signaling pathways.
ATM, the gene mutated in the genetic disease ataxia telangiectasia (AT), is a well-known protein involved in the DNA double-strand break response, where it plays an important role in sensing damage and signaling to DNA repair machinery and cell cycle checkpoints. However, a number of recent papers, including ours have found that ATM also plays important roles outside of the nucleus, which may explain some of the phenotypic features seen in AT patients. Our research into mechanisms of TSC2 regulation helped uncover a pathway upstream of TSC2 that is regulated by cytoplasmic ATM in response to ROS initiated by ATM activation of LKB1 and AMPK. We found that TSC2 activation results in mTORC1 repression and subsequent induction of autophagy. Elucidation of this stress response pathway provides a molecular mechanism for ATM signaling in the cytoplasm and lays the groundwork for further studies on how ATM activity is regulated beyond DNA damage in different cellular compartments.
Alexander
Angela
A
Department of Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Smithville, TX, USA.
Walker
Cheryl L
CL
D000091162:AMP-Activated Protein Kinase Kinases; D064007:Ataxia Telangiectasia Mutated Proteins; D001343:Autophagy; D018797:Cell Cycle Proteins / Q000032:analysis* / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000032:analysis* / Q000378:metabolism; D006801:Humans; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000032:analysis* / Q000378:metabolism; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000032:analysis* / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D017382:Reactive Oxygen Species; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases