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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Identification of WNK1 as a substrate of Akt/ protein kinase B and a negative regulator of insulin-stimulated mitogenesis in 3T3-L1 cells.

Insulin signaling through protein kinase Akt/ protein kinase B ( PKB), a downstream element of the phosphatidylinositol 3-kinase ( PI3K) pathway, regulates diverse cellular functions including metabolic pathways, apoptosis, mitogenesis, and membrane trafficking. To identify Akt/ PKB substrates that mediate these effects, we used antibodies that recognize phosphopeptide sites containing the Akt/ PKB substrate motif (RXRXX(p)S/T) to immunoprecipitate proteins from insulin-stimulated adipocytes. Tryptic peptides from a 250-kDa immunoprecipitated protein were identified as the protein kinase WNK1 (with no lysine) by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, consistent with a recent report that WNK1 is phosphorylated on Thr60 in response to insulin-like growth factor I. Insulin treatment of 3T3-L1 adipocytes stimulated WNK1 phosphorylation, as detected by immunoprecipitation with antibody against WNK1 followed by immunoblotting with the anti-phosphoAkt substrate antibody. WNK1 phosphorylation induced by insulin was unaffected by rapamycin, an inhibitor of p70 S6 kinase pathway but abolished by the PI3K inhibitor wortmannin. RNA interference-directed depletion of Akt1/PKB alpha and Akt2/ PKB beta attenuated insulin- stimulated WNK1 phosphorylation, but depletion of protein kinase C lambda did not. Whereas small interfering RNA-induced loss of WNK1 protein did not significantly affect insulin-stimulated glucose transport in 3T3-L1 adipocytes, it significantly enhanced insulin-stimulated thymidine incorporation by about 2-fold. Furthermore, depletion of WNK1 promoted serum-stimulated cell proliferation of 3T3-L1 preadipocytes, as evidenced by a 36% increase in cell number after 48 h in culture. These data suggest that WNK1 is a physiologically relevant target of insulin signaling through PI3K and Akt/ PKB and functions as a negative regulator of insulin-stimulated mitogenesis.[1]


  1. Identification of WNK1 as a substrate of Akt/protein kinase B and a negative regulator of insulin-stimulated mitogenesis in 3T3-L1 cells. Jiang, Z.Y., Zhou, Q.L., Holik, J., Patel, S., Leszyk, J., Coleman, K., Chouinard, M., Czech, M.P. J. Biol. Chem. (2005) [Pubmed]
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