Discrete region of the insulin receptor carboxyl terminus plays key role in insulin action

Abstract

In the present study, we attempted to determine the importance of a 23-amino-acid sequence within the carboxyl terminus of the human insulin receptor (IR) molecule in modulating insulin action in Chinese hamster ovary cells. Stable expression of a minigene encoding the receptor fragment led to an increase in insulin-induced IR autophosphorylation that was 2.4-fold higher when compared to that of IR-expressing cells transfected with empty vector. Insulin-stimulated downstream signaling was also significantly elevated in cells expressing the minigene. It was found that expression of the minigene had no effect toward insulin-like growth factor I receptor kinase activity and function. These results indicate that the IR carboxyl terminus contains a motif that acts as a physiologic modulator of insulin signaling. J. Cell. Biochem. 78:160-169, 2000. Published 2000 Wiley-Liss, Inc.

Signal Protein-Derived Peptides as Functional Probes and Regulators of Intracellular Signaling

“…The most pronounced influence of N-stearyl derivatives of peptides 1142–1153 and 1293–1307 on insulin-induced IR autophosphorylation and function, compared with unmodified analogs, suggests that the intrinsic activity of IR undergoes modulation, depending on the presence of a fatty acid-acylated receptor fragment in cells. The expression of a minigene encoding 23-mer peptide 1292–1315, the longest analog of peptide 1293–1307, has no effect on the basal receptor tyrosine phosphorylation level but leads to an increase in insulin-activated IR autophosphorylation that in minigene-transfected CHO cells is about twice as high as in control cells [121]. The stimulating effects of insulin on PI3-K and MAPK activities and thymidime incorporation into DNA are also significantly elevated in cells expressing the minigene.…”

“…These data indicate that peptides 1142–1153 and 1293–1307 and minigene-expressed peptide 1292–1315 bind to the regions in IR β subunit responsible for the intrinsic activity of the receptor and functional coupling with downstream signaling proteins, such as IRS and Shc proteins, PI3-K and MAPK. The action of the peptides and their lipophilic derivatives is highly specific since the latter are not capable of inhibiting dephosphorylation of EGF receptor and do not influence ligand-induced phosphorylation of both EGF receptor and insulin-like growth factor-1 receptor which functionally and structurally resembles IR [67, 68, 121]. …”