Rat somatotroph insulin-like growth factor-II (IGF-II) signaling: role of the IGF-I receptor.
The anterior pituitary contains insulin-like growth factor-II (IGF-II) and expresses abundant IGF-II-binding sites, but the IGF-II signaling pathway in the pituitary has not been defined. We, therefore, tested the effects of recombinant human IGF-II on pituitary function by assessing the GH responsiveness of the primary rat somatotroph to IGF-II. IGF-II (3.3 nM) suppressed GH secretion by 50%, similar to the effect elicited by equimolar doses of IGF-I. In contrast, a low concentration of IGF-II (0.2 nM) did not attenuate GH secretion, while a similar IGF-I dose was sufficient to produce 50% inhibition of basal GH secretion. Fifty percent competition for [125I]IGF-I binding by IGF-I and IGF-II in GC rat pituitary cells demonstrated a 14-fold lesser affinity of the IGF-II ligand for the IGF-I receptor compared to IGF-I; therefore, the binding affinity of IGF-II for the IGF-I receptor correlates with the concentration of IGF-II required for 50% GH inhibition. Transfected GH-secreting cell lines derived from GC cells overexpressing intact human IGF-I receptors exhibited enhanced responsiveness to IGF-II. In contrast, cells transfected with a truncated IGF-I receptor cDNA lacking the cytoplasmic receptor beta-subunit (952STOP) failed to transduce the IGF-II signal, indicating that functional IGF-I receptors are required for IGF-II signaling. In addition, a mutant IGF ligand, [Leu27]IGF-II, which selectively exhibits high affinity for the type II receptor, but only minimal binding to the IGF-I receptor, did not attenuate GH secretion. However, the analog [Arg54,Arg55]IGF-II, which exhibits high affinity to the IGF-I receptor, but no binding to the type II receptor, appropriately suppressed GH secretion. This unique model of somatotroph signaling provides evidence for IGF-II regulation of polypeptide hormone secretion mediated by the IGF-I receptor.
Weber
M M
MM
Department of Medicine, Cedars-Sinai Medical Center-University of California School of Medicine, Los Angeles 90048.
Melmed
S
S
Rosenbloom
J
J
Yamasaki
H
H
Prager
D
D
D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000032:analysis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D013006:Growth Hormone / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D007457:Iodine Radioisotopes; D008024:Ligands; D008297:Male; D009154:Mutation / Q000235:genetics; D010903:Pituitary Gland, Anterior / Q000166:cytology* / Q000502:physiology* / Q000648:ultrastructure; D011863:Radioimmunoassay; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D014284:Triiodothyronine / Q000494:pharmacology
D007457:Iodine Radioisotopes; D008024:Ligands; D014284:Triiodothyronine; D007335:Insulin-Like Growth Factor II; D013006:Growth Hormone; D004247:DNA; D017526:Receptor, IGF Type 1