Inhibition of Akt and its anti-apoptotic activities by tumor necrosis factor-induced protein kinase C-related kinase 2 (PRK2) cleavage

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Akt is stimulated by several growth factors and has a major anti-apoptotic role in the cell. Therefore, we hypothesized that a pathway leading to the inhibition of Akt might be utilized in the process of apoptosis. Accordingly, we used a yeast two-hybrid screening assay to identify the proteins that interact with and possibly inhibit Akt, We found that the C-terminal region of protein kinase C-related kinase 2 (PRK2), containing amino acids 862 to 908, specifically binds to Akt in yeast and mammalian cells. During early stages of apoptosis, the C-terminal region of PRK2 is cleaved from the inhibitory N-terminal region and can bind Akt, The protein-protein interaction between Akt and the PRK2 C-terminal region specifically down-modulates the protein kinase activities of Akt by inhibiting phosphorylation at threonine 308 and serine 473 of Akt, This inhibition of Abt leads to the inhibition of the downstream signaling of Akt in vivo. The PRK2 C-terminal fragment strongly inhibits the Akt-mediated phosphorylation of BAD, a pro-apoptotic Bcl-2 family protein, and blocks the anti-apoptotic activities of Akt in vivo. These results provide direct evidence that the products of protein cleavage during apoptosis inhibit pro-survival signalings, leading to the amplification of pro-apoptotic signalings in the cell.
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Issue Date
2000
Language
English
Article Type
Article
Keywords

NF-KAPPA-B; GLYCOGEN-SYNTHASE KINASE-3; PHOSPHATIDYLINOSITOL 3-KINASE; MOLECULAR-CLONING; SIGNAL-TRANSDUCTION; POTENTIAL EFFECTOR; IN-VITRO; ACTIVATION; PHOSPHORYLATION; INSULIN

Citation

JOURNAL OF BIOLOGICAL CHEMISTRY, v.275, no.44, pp.34451 - 34458

ISSN
0021-9258
DOI
10.1074/jbc.M001753200
URI
http://hdl.handle.net/10203/70394
Appears in Collection
BS-Journal Papers(저널논문)
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