Heat shock protein 27 controls apoptosis by regulating Akt activation.
Rane, Madhavi J, et al.
J. Biol. Chem., 278: 27828-35 (2003)
2003
Show Abstract
Activation of the serine-threonine kinase Akt by cytokines, chemokines, and bacterial products delays constitutive neutrophil apoptosis, resulting in a prolonged inflammatory response. We showed previously that Akt exists in a signaling complex with p38 MAPK, MAPK-activated protein kinase-2 (MAPKAPK-2), and heat shock protein-27 (Hsp27); and Hsp27 dissociates from the complex upon neutrophil activation. To better understand the regulation of this signaling module, the hypothesis that Akt phosphorylation of Hsp27 regulates its interaction with Akt was tested. The present study shows that Akt phosphorylated Hsp27 on Ser-82 in vitro and in intact cells, and phosphorylation of Hsp27 resulted in its dissociation from Akt. Additionally, the interaction between Hsp27 and Akt was necessary for activation of Akt in intact neutrophils. Constitutive neutrophil apoptosis was accelerated by sequestration of Hsp27 from Akt, and this enhanced rate of apoptosis was reversed by introduction of constitutively active recombinant Akt. Our results define a new mechanism by which Hsp27 regulates apoptosis, through control of Akt activity. | Kinase Assay | 12740362
 |
PDK1, one of the missing links in insulin signal transduction?
Cohen, P, et al.
FEBS Lett., 410: 3-10 (1997)
1997
Show Abstract
The initial steps in insulin signal transduction occur at the plasma membrane and lead to the activation of phosphatidylinositide (PtdIns) 3-kinase and the formation of PtdIns(3,4,5,)P3 in the inner leaflet of the plasma membrane which is then converted to PtdIns(3,4)P2 by a specific phosphatase. Inhibitors of PtdIns 3-kinase suppress nearly all the metabolic actions of insulin indicating that PtdIns(3,4,5)P3 and/or PtdIns(3,4)P2 are key 'second messengers' for this hormone. A major effect of insulin is its ability to stimulate the synthesis of glycogen in skeletal muscle. By 'working backwards' from glycogen synthesis, we have dissected an insulin-stimulated protein kinase cascade which is triggered by the activation of PtdIns 3-kinase. The first enzyme in this cascade is termed 3-phosphoinositide-dependent protein kinase (PDK1), because it is only active in the presence of PtdIns(3,4,5)P3 or PtdIns(3,4)P2. PDK1 then activates protein kinase B (PKB) which, in turn, inactivates glycogen synthase kinase-3 (GSK3), leading to the dephosphorylation and activation of glycogen synthase and hence to an acceleration of glycogen synthesis. We review the evidence which indicates that the phosphorylation of other proteins by PKB and GSK3 is likely to mediate many of the intracellular actions of insulin. | | 9247112
|
