title: Insulin-like growth factor type-I receptor internalization and recycling mediate the sustained phosphorylation of Akt.
abstract: Previously we demonstrated that insulin-like growth factor-I mediates the sustained phosphorylation of Akt, which is essential for long term survival and protection of glial progenitors from glutamate toxicity. These prosurvival effects correlated with prolonged activation and stability of the insulin-like growth factor type-I receptor. In the present study, we investigated the mechanisms whereby insulin-like growth factor-I signaling, through the insulin-like growth factor type-I receptor, mediates the sustained phosphorylation of Akt. We showed that insulin-like growth factor-I stimulation induced loss of receptors from the cell surface but that surface receptors recovered over time. Blocking receptor internalization inhibited Akt phosphorylation, whereas inhibition of receptor trafficking blocked receptor recovery at the cell surface and the sustained phosphorylation of Akt. Moreover the insulin-like growth factor type-I receptor localized with the transferrin receptor and Rab11-positive endosomes in a ligand-dependent manner, further supporting the conclusion that this receptor follows a recycling pathway. Our results provide evidence that ligand stimulation leads to internalization of the insulin-like growth factor type-I receptor, which mediates Akt phosphorylation, and that receptor recycling sustains Akt phosphorylation in glial progenitors. Mathematical modeling of receptor trafficking further supports these results and predicts an additional kinetic state of the receptor consistent with sustained Akt phosphorylation.
authors.affiliation: Department of Neurology and Neurosciences, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Romanelli
authors.forename: Andrew P
authors.initials: AP
authors.lastname: LeBeau
authors.forename: Clifton G
authors.initials: CG
authors.lastname: Fulmer
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Lazzarino
authors.forename: Alan
authors.initials: A
authors.lastname: Hochberg
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Wood
mesh_terms: D000818:Animals; D019921:Biotinylation; D016895:Culture Media, Serum-Free / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D008962:Models, Theoretical; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D016895:Culture Media, Serum-Free; D005971:Glutamates; D007334:Insulin-Like Growth Factor I; D008024:Ligands; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins