Insulin substrates 1 and 2 are corequired for activation of atypical protein kinase C and Cbl-dependent phosphatidylinositol 3-kinase during insulin action in immortalized brown adipocytes.
Phosphatidylinositol 3-kinase (PI3K)-dependent activation of atypical protein kinase C (aPKC) is required for insulin-stimulated glucose transport. Although insulin receptor substrate-1 (IRS-1) and IRS-2, among other factors, activate PI3K, there is little information on the relative roles of IRS-1and IRS-2 during aPKC activation by insulin action in specific cell types. Presently, ... we have used immortalized brown adipocytes in which either IRS-1 or IRS-2 has been knocked out by recombinant methods to examine IRS-1 and IRS-2 requirements for activation of aPKC. We have also used these adipocytes to see if IRS-1 and IRS-2 are required for activation of Cbl, which is required for insulin-stimulated glucose transport and has been found to function upstream of both PI3K/aPKC and Crk during thiazolidinedione action in 3T3/L1 adipocytes [Miura et al. (2003) Biochemistry 42, 14335]. In brown adipocytes in which either IRS-1 or IRS-2 was knocked out, insulin-induced increases in aPKC activity and glucose transport were markedly diminished. These effects of insulin on aPKC and glucose transport were fully restored by retroviral-mediated expression of IRS-1 or IRS-2 in their respective knockout cells. Knockout of IRS-1 or IRS-2 also inhibited insulin-induced increases in Cbl binding to the p85 subunit of PI3K, which, along with IRS-1/2, may be required for activation of PI3K, aPKC, and glucose transport during insulin action in 3T3/L1 adipocytes. These findings provide evidence that directly links both IRS-1 and IRS-2 to aPKC activation in immortalized brown adipocytes, and further suggest that IRS-1 and IRS-2 are required for the activation of Cbl/PI3K during insulin action in these cells.
Mesh Terms:
Adipose Tissue, Brown, Animals, Cell Line, Transformed, Deoxyglucose, Drug Synergism, Enzyme Activation, Insulin, Insulin Receptor Substrate Proteins, Intracellular Signaling Peptides and Proteins, Isoenzymes, Mice, Mice, Knockout, Oncogene Protein v-cbl, Phosphatidylinositol 3-Kinases, Phosphoproteins, Phosphorylation, Protein Kinase C, Protein Subunits, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Retroviridae Proteins, Oncogenic, Tritium
Adipose Tissue, Brown, Animals, Cell Line, Transformed, Deoxyglucose, Drug Synergism, Enzyme Activation, Insulin, Insulin Receptor Substrate Proteins, Intracellular Signaling Peptides and Proteins, Isoenzymes, Mice, Mice, Knockout, Oncogene Protein v-cbl, Phosphatidylinositol 3-Kinases, Phosphoproteins, Phosphorylation, Protein Kinase C, Protein Subunits, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Retroviridae Proteins, Oncogenic, Tritium
Biochemistry
Date: Dec. 14, 2004
PubMed ID: 15581362
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