IGF-I receptor signalling: lessons from the somatotroph.
Insulin-like growth factor 1 (IGF-I) is a major feedback regulator of pituitary GH secretion, with defined actions occurring at both the hypothalamus and pituitary. The IGF-I gene is expressed in the anterior pituitary in a GH-dependent manner thus providing for both endocrine-as well as autocrine-mediated GH regulation. In turn, IGF-I selectively and specifically inhibits GH gene transcription and secretion, its attenuating effects on nascent GH mRNA synthesis being demonstrable within 1 h. Binding of IGF-I to its pituitary cell surface receptor is followed by rapid activation of the intrinsic tyrosine kinase activity of the receptor beta-subunit and phosphorylation of insulin receptor substrate 1 (IRS-1). Structure-function studies of the human IGF-I receptor were performed in stable, GH-secreting transfectants expressing either the cDNA encoding the wild-type (WT) human IGF receptor and exhibiting enhanced IGF-I responsiveness, or cDNAs encoding IGF-I receptor mutants and a truncated, kinase-deficient receptor (952STOP). 950Tyr situated on the submembrane receptor domain was found to be critical for transducing the IGF-I signal to the GH gene. IGF-I failed to suppress GH secretion by signalling endogenous rat IGF-I receptors when hybrid receptors were formed with kinase-deficient human receptors and rat hemi-receptors. This dominant negative effect on hormone secretion was also evidenced when mitogenic IGF-I signals were blocked in vitro and in vivo by these hybrid receptors. Using similar doses of IGF-I, the IGF-I receptor cell transfectants also demonstrated ligand-dependent activation of ERKs in pituitary cells. In conclusion, the pituitary IGF-I receptor mediates the negative feedback regulation of GH. Thus, IGF-I receptor mass may determine GH responses to malnutrition, pregnancy, and refeeding. IGF-I receptor mutations may also prove useful to abrogate the growth of IGF-I-dependent tumors. These structure-function studies of the human IGF-I receptor provide mechanistic insights into both metabolic control of the GH axis, as well as target tissue proliferative characteristics.
Melmed
S
S
Department of Medicine, Cedars-Sinai Research Institute-UCLA School of Medicine 90048, USA.
Yamashita
S
S
Yamasaki
H
H
Fagin
J
J
Namba
H
H
Yamamoto
H
H
Weber
M
M
Morita
S
S
Webster
J
J
Prager
D
D
D000818:Animals; D005260:Female; D015870:Gene Expression; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D009154:Mutation; D010902:Pituitary Gland / Q000378:metabolism*; D011247:Pregnancy; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection
D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D017526:Receptor, IGF Type 1