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. 1992 Nov;90(5):2117–2122. doi: 10.1172/JCI116096

Human insulin-like growth factor I receptor function in pituitary cells is suppressed by a dominant negative mutant.

D Prager 1, H Yamasaki 1, M M Weber 1, S Gebremedhin 1, S Melmed 1
PMCID: PMC443280  PMID: 1430235

Abstract

Hybrid receptors were studied in GC rat pituitary cells overexpressing either wild-type 950Tyr (WT) human insulin-like growth factor I (IGF-I) receptors or mutant human IGF-I receptors truncated at position 952 in the beta subunit transmembrane region (952STOP). 125I-IGF-I binding was increased in both 950Tyr (WT) (14-fold) and truncated human IGF-I receptor (952STOP) stable transfectants (50-fold), when compared to untransfected cells that contained endogenous rat IGF-I receptors. Metabolic cell labeling followed by immunoprecipitation with monoclonal alpha and beta subunit-specific antibodies revealed the presence of hybrid rat/truncated human receptors, truncated transfected human receptors, and WT human IGF-I holotetramers. Both mutant and hybrid receptors were degraded slower than 950Tyr (WT) receptors (> 16 h). Despite their markedly increased ligand binding and prolonged receptor half-life, 952STOP transfectants failed to transduce the IGF-I signal to suppress growth hormone (GH). Also, they neither underwent autophosphorylation nor phosphorylated endogenous proteins. The expected suppression of GH by endogenous rat IGF-I receptors was completely abrogated in 952STOP transfectants (P < 0.001 compared to untransfected cells). Mutant 952STOP cells were therefore completely devoid of biological signaling to GH despite the presence of endogenous rat IGF-I receptors. Thus mutant IGF-I receptors block ligand-mediated endogenous rat IGF-I signaling by functioning as a dominant negative forming nonfunctional human/rat hybrid receptors. Defective IGF-I receptors may function therefore as dominant negative phenotypes which suppress normal receptor responses in pituitary cells.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

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