This study investigates the role of RAFT1, a member of the ATM-related family of kinases, in the rapamycin-sensitive signaling pathway. The authors demonstrate that RAFT1 directly phosphorylates p70S6 kinase (p70S6K) and 4E-BP1, two key regulators of translation initiation. RAFT1 phosphorylates p70S6K on Thr-389, a residue essential for S6 kinase activity, and 4E-BP1 on Thr-36 and Thr-45, which blocks its interaction with the cap-binding protein eIF-4E. The phosphorylation of these residues is regulated by serum stimulation and is partially inhibited by FKBP12-rapamycin. The study also reveals that RAFT1 phosphorylation of p70S6K and 4E-BP1 is distinct, with little amino acid homology between the phosphorylation sites. The findings suggest that RAFT1 may act as an upstream kinase in the rapamycin-sensitive pathway, and that the 4E-BP1 pathway may differ from the S6 pathway in terms of kinase involvement. The results highlight the complex regulatory mechanisms involved in controlling protein translation initiation.This study investigates the role of RAFT1, a member of the ATM-related family of kinases, in the rapamycin-sensitive signaling pathway. The authors demonstrate that RAFT1 directly phosphorylates p70S6 kinase (p70S6K) and 4E-BP1, two key regulators of translation initiation. RAFT1 phosphorylates p70S6K on Thr-389, a residue essential for S6 kinase activity, and 4E-BP1 on Thr-36 and Thr-45, which blocks its interaction with the cap-binding protein eIF-4E. The phosphorylation of these residues is regulated by serum stimulation and is partially inhibited by FKBP12-rapamycin. The study also reveals that RAFT1 phosphorylation of p70S6K and 4E-BP1 is distinct, with little amino acid homology between the phosphorylation sites. The findings suggest that RAFT1 may act as an upstream kinase in the rapamycin-sensitive pathway, and that the 4E-BP1 pathway may differ from the S6 pathway in terms of kinase involvement. The results highlight the complex regulatory mechanisms involved in controlling protein translation initiation.