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AKT2 suppresses GAPDH mediated-apoptosis in ovarian cancer via phosphorylating GAPDH at threonine 237 and decreasing its nuclear translocation

Department of Experimental Medicine, Fuzhou General Hospital (Dongfang Hospital), 156 North Xi-er Huan Road, Fuzhou City, Fujian Province 350025, China.
Journal of Biological Chemistry (Impact Factor: 4.57). 12/2011; 286(49):42211-20. DOI: 10.1074/jbc.M111.296905
Source: PubMed

ABSTRACT Protein kinase B (Akt) plays important roles in regulation of cell growth and survival, but while many aspects of its mechanism of action are known, there are potentially additional regulatory events that remain to be discovered. Here we detected a 36-kDa protein that was co-immunoprecipitated with protein kinase Bβ (Akt2) in OVCAR-3 ovarian cancer cells. The protein was identified to be glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by MALDI-TOF/TOF MS, and the interaction of Akt2 and GAPDH was verified by reverse immunoprecipitation. Our further study showed that Akt2 may suppress GAPDH-mediated apoptosis in ovarian cancer cells. Overexpression of GAPDH increased ovarian cancer cell apoptosis induced by H(2)O(2), which was inhibited by Akt2 overexpression and restored by the PI3K/Akt inhibitor wortmannin or Akt2 siRNA. Akt2 phosphorylated Thr-237 of GAPDH and decreased its nuclear translocation, an essential step for GAPDH-mediated apoptosis. The interaction between Akt2 and GAPDH may be important in ovarian cancer as immunohistochemical analysis of 10 normal and 30 cancerous ovarian tissues revealed that decreased nuclear expression of GAPDH correlated with activation (phosphorylation) of Akt2. In conclusion, our study suggests that activated Akt2 may increase ovarian cancer cell survival via inhibition of GAPDH-induced apoptosis. This effect of Akt2 is partly mediated by its phosphorylation of GAPDH at Thr-237, which results in the inhibition of GAPDH nuclear translocation.

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    • "However, neither mutant differed in NleB-mediated GAPDH O-GlcNAcylation (Figure 5F). GAPDH is phosphorylated by protein kinase B (AKT) on T237, which prevents GAPDH nuclear translocation and suppresses GAPDH-mediated apoptosis (Huang et al., 2011). We also mutated T237 (T237A), as well as the neighboring residues S241 (S241A), T246 (T246A), and T277 (T277A). "
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