A transforming mutation in the pleckstrin homology domain of AKT1 in cancer (Nature, 2007, 448:439-444)

報告日期: 2007/11/02
報告時間: 16:00/16:50
報告學生: 江承堯
講評老師: 王憶卿

A transforming mutation in the pleckstrin homology domain of AKT1 in cancer

Nature 448: 439-445, 2007


Speaker: 江承堯

Commentator: 王憶卿

Time: 2007/11/02

Place: 602 Room



         AKT plays a critical role in cell proliferation- and survival-related signaling pathway. However, a defect of AKT is not frequently reported in human cancer. Pervious studies have shown that pleckstrin homology domain (PHD) is a central domain in AKT activation. AKT activates through binding of PHD to phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3) on the inner cell membrane.1 In this study, the authors revealed an E17K mutation in the PHD of primary tumors of the breast, colorectal, and ovary. The E17K mutation results in alteration of PHD of AKT crystal structure, and the localization of AKT in cancer cells. After treatment with platelet-derived growth factor, wide-typed AKT translocated from nucleus to the membrane of NIH3T3 cells. However, E17K AKT translocated to cell membrane in the absence of growth factor stimulation. Moreover, E17K AKT was found to be autophosphorylated at serine 473 and threonine 308. In soft agar assay, E17K AKT also transformed the Rat1 cells. Adaptor transferring E17K AKT induced leukaemia of embryonic liver haematopoietic stem cells in the mouse model. Leukocytes isolated from these leukaemia mice have a more activated AKT in their cells. Moreover, substitution of E17K in AKT diminished the sensitivity to allosteric kinase inhibitor, implying that E17K mutation may have important role in the development of drug targeting on human AKT.



1. Vivanco I. and Sawyers C. L. The phosphatidylinositol-3-kinase-AKT pathway in human cancer. Nature Rev. 2:489-501, 2002