Tm. Pederson et al., Serine/threonine phosphorylation of IRS-1 triggers its degradation - Possible regulation by tyrosine phosphorylation, DIABETES, 50(1), 2001, pp. 24-31
Insulin receptor substrate (IRS)-1 protein expression is markedly reduced i
n many insulin-resistant states, although the mechanism for this downregula
tion is unclear. In this study, we have investigated the early events in th
e insulin pathway that trigger the degradation of IRS-1. Incubation of the
adipocytes with insulin induced a fast electrophoretic mobility shift of IR
S-1 and a subsequent degradation of the protein. Wortmannin and rapamycin b
locked this mobility shift of IRS-1, maintained the insulin-induced tyrosin
e phosphorylation of IRS-1, and blocked its degradation. In contrast, a gly
cogen synthase kinase 3 inhibitor, a mitogen-activated protein kinase/extra
cellular-regulated kinase inhibitor, and various protein kinase C inhibitor
s had no effect. Incubation with okadaic acid increased the serine/threonin
e phosphorylation of IRS-1 and its degradation, mimicking insulin, and its
effect was prevented by the proteasome inhibitor lactacystin, as well as by
rapamycin. Treatment of the cells with the tyrosine phosphatase inhibitor
orthovanadate in the presence of insulin or okadaic acid partially inhibite
d the degradation of IRS-1. We propose that a rapamycin-dependent pathway p
articipates as a negative regulator of IRS-1, increasing its serine/threoni
ne phosphorylation, which triggers degradation. Thus, regulation of serine/
threonine versus tyrosine phosphorylation may modulate IRS-1 degradation,
affecting insulin sensitivity.