THE B-ISOFORM OF THE INSULIN-RECEPTOR SIGNALS MORE EFFICIENTLY THAN THE A-ISOFORM IN HEPG2 CELLS

We have demonstrated previously that dexamethasone treatment of HepG2 cells caused an enhancement of insulin's metabolic effects (Kosaki, A, and Webster, N. J. (1993) J. Biol. Chem. 268, 21990-21996). This corr elated with increased expression of the mRNA encoding the B isoform of the insulin receptor (IR). In the present study, we have demonstrated that dexamethasone treatment caused in addition an enhancement in ins ulin-stimulated immediate-early gene expression (c-fos and egr-1). Dex amethasone treatment caused an increase in in vivo IR autophosphorylat ion and insulin receptor substrate-1 (IRS-1) phosphorylation both earl y events in the insulin signaling pathway. Furthermore, the IRS-1 phos phorylation was distinctly left shifted, although the level of IRS-1 p rotein was unchanged. Total cellular tyrosine phosphatase activity was unaltered when assayed with P-32-labeled IR and IRS-1. Studies in vit ro on wheat-germ agglutinin-purified receptors showed that the B isofo rm of the IR had increased kinase activity both toward itself and the exogenous substrates poly-glu(4):tyr(1) and recombinant IRS-1 protein. In addition, two dimensional tryptic phosphopeptide maps indicated th at the B isoform has an additional phosphopeptide that is not seen for the A isoform. In conclusion, it appears that the B isoform of the IR signals more efficiently than the A isoform in HepG2 cells.