The DOI matches its Crossref record; 47 of the 47 references it cites were found in a registry or an index.
A Rapamycin-Sensitive Pathway Down-Regulates Insulin Signaling via Phosphorylation and Proteasomal Degradation of Insulin Receptor Substrate-1
Open accessAbstract
Insulin receptor substrate-1 (IRS-1) is a major substrate of the insulin receptor and acts as a docking protein for Src homology 2 domain containing signaling molecules that mediate many of the pleiotropic actions of insulin. Insulin stimulation elicits serine/threonine phosphorylation of IRS-1, which produces a mobility shift on SDS-PAGE, followed by degradation of IRS-1 after prolonged stimulation. We investigated the molecular mechanisms and the functional consequences of these phenomena in 3T3-L1 adipocytes. PI 3-kinase inhibitors or rapamycin, but not the MEK inhibitor, blocked both the insulin-induced electrophoretic mobility shift and degradation of IRS-1. Adenovirus-mediated expression of a membrane-targeted form of the p110 subunit of phosphatidylinositol (PI) 3-kinase (p110CAAX) induced a mobility shift and degradation of IRS-1, both of which were inhibited by rapamycin. Lactacystin, a specific proteasome inhibitor, inhibited insulin-induced degradation of IRS-1 without any effect on its electrophoretic mobility. Inhibition of the mobility shift did not significantly affect tyrosine phosphorylation of IRS-1 or downstream insulin signaling. In contrast, blockade of IRS-1 degradation resulted in sustained activation of Akt, p70 S6 kinase, and mitogen-activated protein (MAP) kinase during prolonged insulin treatment. These results indicate that insulin-induced serine/threonine phosphorylation and degradation of IRS-1 are mediated by a rapamycin-sensitive pathway, which is downstream of PI 3-kinase and independent of ras/MAP kinase. The pathway leads to degradation of IRS-1 by the proteasome, which plays a major role in down-regulation of certain insulin actions during prolonged stimulation.
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Molecular mechanisms of mTOR-mediated translational control
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Metadata
- Authors
- Haruta, T.
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2000-06-01
- Volume
- 14
- Issue
- 6
- Pages
- 783-794
- ISSN
- 0888-8809 (ISSN-L)
- OpenAlex
- W2030977583
- Cited by
- 419
- References
- 47
- FWCI
- 4.96
- Type
- journal article
- Language
- en
- Open access
- bronze
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- CoChat. (2026). Citation check: A Rapamycin-Sensitive Pathway Down-Regulates Insulin Signaling via Phosphorylation and Proteasomal Degradation of Insulin Receptor Substrate-1. https://app.cochat.ai/papers/10.1210/me.14.6.783
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- Haruta, T. (2000). A Rapamycin-Sensitive Pathway Down-Regulates Insulin Signaling via Phosphorylation and Proteasomal Degradation of Insulin Receptor Substrate-1. Molecular Endocrinology. https://doi.org/10.1210/me.14.6.783
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