Modulation of the substrate specificity of the mammalian phosphatidylinositol 3-kinase by cholesterol sulfate and sulfatide

Biochemistry
R WoscholskiP J Parker

Abstract

The substrate specificity of the purified, mammalian phosphatidylinositol 3-kinase is subject to modulation by detergents, which are able to switch substrate specificity in vitro in favor of PtdInsP2. This effect of the detergents is due to an activation of the phosphatidylinositol biphosphate 3-kinase activity, while the phosphatidylinositol 3-kinase activity is inhibited. The selective inhibition of the phosphatidylinositol 3-kinase activity (p110 alpha/p85 alpha) is shown here also to be observed by employing cholesterol sulfate or sulfatide at low micromolar concentrations, whereas cholesterol and androsterone sulfate fail to inhibit. These naturally occurring sulfated lipids have at these concentrations no effect on the phosphatidylinositol bisphosphate 3-kinase activity but inhibit the manganese-dependent intrinsic protein kinase activity, thus switching substrate specificity toward the more highly phosphorylated inositol lipids. Cholesterol sulfate and sulfatide inhibit the free catalytic subunit p110 alpha but fail to inhibit the homologous phosphatidylinositol 3-kinase from Saccharomyces cerevisiae (Vps34p), suggesting that these sulfated lipids act specifically on the mammalian phosphatidylinositol 3-kinase. Consisten...Continue Reading

Citations

Jun 12, 1998·Clinical Biochemistry·M PrzybylskaM Bryszewska
Jun 26, 1998·Progress in Lipid Research·I Ishizuka
Mar 28, 1998·Journal of Chromatography. B, Biomedical Sciences and Applications·B LinM Iwamori
Jan 9, 2016·Biochimica Et Biophysica Acta·Daniel Pastor-FloresRicardo M Biondi
Aug 18, 1997·Biochemical and Biophysical Research Communications·M IwamoriN Ito
May 6, 2003·Journal of Lipid Research·Charles A Strott, Yuko Higashi
Aug 8, 2020·British Journal of Pharmacology·Lorena Diaz SanchezIrundika H K Dias

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