Degradation of pro-insulin-receptor proteins by proteasomes.
BACKGROUND
Type-2 diabetes is characterized by hyperinsulinemia, peripheral insulin resistance, and diminished tyrosine phosphorylation activity. It has been recently shown that proteasomes are implicated in the degradation of the insulin receptor substrate-1 (IRS-1) but not in that of the insulin receptor (IR). However, it is unknown whether proteasomes are involved in pro-IR degradation.


METHODS
We used CHO-IR and the 3T3-L1 cells treated with insulin at different concentrations and compared the proteasome activity of IRS-1, IR, and pro-IR degradation either in presence or in absence of lactacystin.


RESULTS
A total of 100 nM of insulin allowed degradation of IRS-1 after 6 h of incubation. At 1,000 nM of insulin, pro-IR degradation began at 1 h of incubation, similar to IRS-1 degradation. Surprisingly, at a higher concentration (10 microM) of insulin, a drastic decrease of proteins was observed from the first minute of incubation. This activity was blocked by lactacystin, a specific proteasome inhibitor.


CONCLUSIONS
According to these results, we propose that pro-IR is degraded by proteasomes.
Cruz
Miguel
M
Unidad de Investigación Medica en Bioquímica, Hospital de Especialidades, Centro Medico Nacional Siglo XXI (CMNSXXI), Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico. mcruzl@yahoo.com
Velasco
Eduardo
E
Kumate
Jesús
J
D016475:3T3 Cells; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D051379:Mice; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011498:Protein Precursors / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D009097:Multienzyme Complexes; D010750:Phosphoproteins; D011498:Protein Precursors; D011972:Receptor, Insulin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex