Heat shock protein 27 controls apoptosis by regulating Akt activation.
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.
Department of Medicine, University of Louisville, Louisville, Kentucky 40202-1764, USA.
Madhavi J
MJ
Rane
Yong
Y
Pan
Saurabh
S
Singh
David W
DW
Powell
Rui
R
Wu
Timothy
T
Cummins
Qingdan
Q
Chen
Kenneth R
KR
McLeish
Jon B
JB
Klein
D017209:Apoptosis; D015153:Blotting, Western; D002460:Cell Line; D003001:Cloning, Molecular; D004396:Coloring Agents / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D004789:Enzyme Activation; D005822:Genetic Vectors; D005982:Glutathione Transferase / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000737:chemistry* / Q000502:physiology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014343:Trypan Blue / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D004396:Coloring Agents; D018076:DNA, Complementary; D006360:Heat-Shock Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D012694:Serine; D005982:Glutathione Transferase; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D014343:Trypan Blue