Regulation of insulin receptor substrate-1 expression levels by caveolin-1.
The insulin receptor substrate-1 (IRS-1), a docking protein of the type 1 insulin-like growth factor receptor (IGF-IR) plays a significant role in cell proliferation and differentiation. The expression of IRS-1 is down-regulated in mouse embryo fibroblasts (MEFs) with a deletion of caveolin-1 (cav1) genes (KO cells). Levels of IRS-1 mRNA are not affected. Re-introduction of cav1 into KO cells rescues IRS-1 expression. Stabilization of protein levels is reciprocal and a strict correlation between IRS-1 and cav1 levels was confirmed in five cell lines, and in mouse tissues. IRS-1 binds through its phosphotyrosine binding (PTB) domain to tyrosine 14 (Y14) of cav1, the residue phosphorylated by IGF-1 stimulation and by v-src. The down-regulation of IRS-1 in cav-/- cells occurs via the proteasome pathway. These results indicate a novel mechanism for the regulation of IRS-1 expression levels, an important finding in view of IRS-1 role in cell proliferation and transformation.
Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, Pennsylvania, USA.
Jia
J
Chen
Franco
F
Capozza
An
A
Wu
Tiziana
T
Deangelis
Hongzhi
H
Sun
Michael
M
Lisanti
Renato
R
Baserga
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D051242:Caveolin 1 / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D015536:Down-Regulation; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D047468:Immunoprecipitation; D055504:Insulin Receptor Substrate Proteins; D051379:Mice; D018345:Mice, Knockout; D034622:RNA Interference; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D051242:Caveolin 1; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering