Insulin-like Growth factor I Receptor (IGF-1R) signaling is essential for cell, organ, and animal growth. The C terminal tail of the IGF-1R exhibits regulatory function but the mechanism is unknown. Here we show that mutation of S1248 (S1248A) enhances IGF-1R in vitro kinase activity, autophosphorylation, Akt mTor activity and cell growth. S1248 phosphorylation is mediated by GSK-3β in a mechanism that involves a priming phosphorylation on S1252. GSK-3β knockout cells exhibit reduced IGF-1R cell surface expression, enhanced IGF-1R kinase activity, signaling and cell growth. Examination of crystallographic structures of the IGF-1R kinase domain revealed that the 1248-SFYYS-1252 motif adopts a conformation tightly packed against the kinase C-lobe when S1248 is in the unphosphorylated state that favours kinase activity. S1248A mutation is predicted to lock the motif in this position. In contrast, phosphorylation of S1248 will drive profound structural transition of the sequence, critically affecting connection of the C terminus as well as exposing potential protein docking sites therein. Decreased kinase activity of a phosphomimetic S1248E mutant and enhanced kinase activity in mutants of its predicted target residue K1081 support this auto-inhibitory model. Thus, the SFYYS motif controls the organisation of the IGF-1R C terminus relative to the kinase domain and its phosphorylation by GSK-3β restrains kinase activity and signaling output.