| pubmed-article:14583092 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:14583092 | lifeskim:mentions | umls-concept:C0033640 | lld:lifeskim |
| pubmed-article:14583092 | lifeskim:mentions | umls-concept:C1519726 | lld:lifeskim |
| pubmed-article:14583092 | lifeskim:mentions | umls-concept:C0123658 | lld:lifeskim |
| pubmed-article:14583092 | lifeskim:mentions | umls-concept:C1709059 | lld:lifeskim |
| pubmed-article:14583092 | lifeskim:mentions | umls-concept:C1448132 | lld:lifeskim |
| pubmed-article:14583092 | pubmed:issue | Pt 1 | lld:pubmed |
| pubmed-article:14583092 | pubmed:dateCreated | 2004-2-5 | lld:pubmed |
| pubmed-article:14583092 | pubmed:abstractText | Non-esterified fatty acid (free fatty acid)-induced activation of the novel PKC (protein kinase C) isoenzymes PKCdelta and PKCtheta correlates with insulin resistance, including decreased insulin-stimulated IRS-1 (insulin receptor substrate-1) tyrosine phosphorylation and phosphoinositide 3-kinase activation, although the mechanism(s) for this resistance is not known. In the present study, we have explored the possibility of a novel PKC, PKCdelta, to modulate directly the ability of the insulin receptor kinase to tyrosine-phosphorylate IRS-1. We have found that expression of either constitutively active PKCdelta or wild-type PKCdelta followed by phorbol ester activation both inhibit insulin-stimulated IRS-1 tyrosine phosphorylation in vivo. Activated PKCdelta was also found to inhibit the IRS-1 tyrosine phosphorylation in vitro by purified insulin receptor using recombinant full-length human IRS-1 and a partial IRS-1-glutathione S-transferase-fusion protein as substrates. This inhibition in vitro was not observed with a non-IRS-1 substrate, indicating that it was not the result of a general decrease in the intrinsic kinase activity of the receptor. Consistent with the hypothesis that PKCdelta acts directly on IRS-1, we show that IRS-1 can be phosphorylated by PKCdelta on at least 18 sites. The importance of three of the PKCdelta phosphorylation sites in IRS-1 was shown in vitro by a 75-80% decrease in the incorporation of phosphate into an IRS-1 triple mutant in which Ser-307, Ser-323 and Ser-574 were replaced by Ala. More importantly, the mutation of these three sites completely abrogated the inhibitory effect of PKCdelta on IRS-1 tyrosine phosphorylation in vitro. These results indicate that PKCdelta modulates the ability of the insulin receptor to tyrosine-phosphorylate IRS-1 by direct phosphorylation of the IRS-1 molecule. | lld:pubmed |
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| pubmed-article:14583092 | pubmed:language | eng | lld:pubmed |
| pubmed-article:14583092 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:14583092 | pubmed:citationSubset | IM | lld:pubmed |
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| pubmed-article:14583092 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:14583092 | pubmed:month | Feb | lld:pubmed |
| pubmed-article:14583092 | pubmed:issn | 1470-8728 | lld:pubmed |
| pubmed-article:14583092 | pubmed:author | pubmed-author:MorriceNickN | lld:pubmed |
| pubmed-article:14583092 | pubmed:author | pubmed-author:RothRichard... | lld:pubmed |
| pubmed-article:14583092 | pubmed:author | pubmed-author:GarofaloRober... | lld:pubmed |
| pubmed-article:14583092 | pubmed:author | pubmed-author:GreeneMichael... | lld:pubmed |
| pubmed-article:14583092 | pubmed:issnType | Electronic | lld:pubmed |
| pubmed-article:14583092 | pubmed:day | 15 | lld:pubmed |
| pubmed-article:14583092 | pubmed:volume | 378 | lld:pubmed |
| pubmed-article:14583092 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:14583092 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:14583092 | pubmed:pagination | 105-16 | lld:pubmed |
| pubmed-article:14583092 | pubmed:dateRevised | 2009-11-19 | lld:pubmed |
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