The Mechanism of Insulin-induced Signal Transduction Mediated by the Insulin Receptor Substrate Family.
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Accession number;99A0391887
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| Title;The Mechanism of Insulin-induced Signal Transduction Mediated by the Insulin Receptor Substrate Family. |
| Author;
KABURAGI Y
(Univ. Tokyo, Tokyo, Jpn)
YAMAUCHI T
(Univ. Tokyo, Tokyo, Jpn)
YAMAMOTO-HONDA R
(Univ. Tokyo, Tokyo, Jpn)
UEKI K
(Univ. Tokyo, Tokyo, Jpn)
TOBE K
(Univ. Tokyo, Tokyo, Jpn)
AKANUMA Y
(Asahi Life Foundation, Tokyo, Jpn)
YAZAKI Y
(Univ. Tokyo, Tokyo, Jpn)
KADOWAKI T
(Univ. Tokyo, Tokyo, Jpn)
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Journal Title;Endocr J
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Journal Code:F0625A
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ISSN:0918-8959
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VOL.46;NO.Supplement;PAGE.S25-S34(1999)
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| Figure&Table&Reference;FIG.9, REF.49 |
| Pub. Country;Japan |
| Language;English |
| Abstract;Distinct from other growth factor receptors, insulin and insulin-like growth factor-I (IGF-I) receptors phosphorylate endogenous substrates on tyrosine residues which in turn associate with the SH2 domain-containing proteins transducing signals to downstream pathways. Among the cellular substrates of insulin and IGF-I receptors, insulin receptor substrate (IRS)-1 has been shown to play an important role in mediating the actions of these hormones. Recently, several proteins with similar structures and different tissue distributions were cloned as IRS-2, -3 and -4. To study the roles of these IRSs in mediating insulin actions, we analyzed liver, muscle and adipocytes, the major targets of insulin actions, from IRS-1 null mice which we previously generated, and showed that: 1) insulin-stimulated activation of PI 3-kinase, mitogen-activated protein kinase and glucose transport were impaired in muscles from IRS-1 null mice which was in contrast to the grossly normal signaling and actions in livers from these mice; 2) the difference in the degree of insulin resistance in these two major insulin targets appeared to depend on the amount of tyrosine phosphorylation of IRS-2 compensating for IRS-1 deficiency; 3) insulin-induced activation of PI 3-kinase, glucose transport and GLUT4 translocation were impaired but not abolished in adipocytes from these mice in which IRS-3 was the major tyrosine-phosphorylated protein activating PI 3-kinase and at least partially mediating some residual insulin actions in the absence of IRS-1. These data suggest that the members of the IRS family redundantly regulate insulin actions in each target organ in a distinct fashion. (author abst.) |
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