Interaction between ATM and the Tuberous Sclerosis Complex

Nuclear ATM has a well established role in response to DNA damage, however ATM has also been localized outside the nucleus where it has been demonstrated to participate in the insulin signaling pathway by phosphorylating eIF-4E binding protein (4EBP1). 4EBP1 is also phosphorylated by components of the Mammalian target of Rapamycin (mTOR) pathway in response to insulin The Tuberous Sclerosis Complex (TSC) proteins, hamartin (TSC1) and tuberin (TSC2), act as a heterodimer to regulate mTOR activity. mTOR exists as two complexes mTORC1 (rapamycin sensitive) and mTORC2 (insensitive to short term rapamycin). These complexes control many cellular functions including protein synthesis, autophagy, lipid metabolism, mitochondrial biogenesis, and cytoskeletal organisation. Mutations in either the TSC1 or TSC2 genes lead to Tuberous Sclerosis, an autosomal dominant, multisystem disorder of benign tumour growth and neurological abnormalities. Studies in our laboratory have demonstrated for the first time that ATM interacts with both tuberin and hamartin. Evidence of this interaction was obtained by mammalian two-hybrid analysis and confirmed by immunoprecipitation experiments using endogenous levels of proteins. The effects of ATM deficiency on the mTOR pathway will be described.