Insulin-like growth factor-II enhancement of human fibroblast growth via a nonreceptor-mediated mechanism.
Deciphering the complex interactions of the various components of the insulin-like growth factor (IGF) system [IGF-I and -II peptides, type I and II IGF receptors, and IGF-binding proteins (IGFBPs)] is important for our understanding of cell growth regulation. We report here that IGF-II can enhance IGF-I-stimulated cell proliferation independent of direct IGF-II interaction with type I or II IGF receptors. Human fibroblasts cultured in serum-free medium for 40 h were relatively resistant to the mitogenic effects of added IGF-I. However, preexposure of the cultures to low concentrations of IGF-II enhanced IGF-I action several-fold. IGF-II by itself had no stimulatory effect and did not influence [Gln3,Ala4,Tyr15,Leu16]IGF-I or insulin-stimulated DNA synthesis. IGF-II did not directly interact with type I IGF receptors, as [Leu27]IGF-II, an IGF-II analog that does not bind type I IGF receptors, could mimic IGF-II's potentiating effect. Type II IGF receptors also were not involved because 1) [Gln6,Ala7,Tyr18,Leu19,Leu27]IGF-II, an analog with normal receptor binding, had no effect; and 2) beta-galactosidase, a competitive inhibitor of IGF-II receptor binding, did not influence IGF-II potentiation of IGF-I action. Enhanced cell responsiveness to IGF-I appears to be due to IGF-II-induced changes in pericellular IGFBP-3 and IGFBP-4. These data support the hypothesis that IGF-II can potentiate the action of IGF-I by disrupting the IGFBP barrier at the cell surface, thereby increasing IGF-I availability for type I IGF receptor interaction.
Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota 55905.
C A
CA
Conover
J T
JT
Clarkson
L K
LK
Bale
D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000502:physiology; D017527:Receptor, IGF Type 2 / Q000502:physiology; D012867:Skin / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D013002:Somatomedins / Q000378:metabolism
D007328:Insulin; D017527:Receptor, IGF Type 2; D013002:Somatomedins; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D004247:DNA; D017526:Receptor, IGF Type 1