American Association for Cancer Research
00085472can151462-sup-150420_3_supp_4304862_fxf4fm.pdf (4.84 MB)

Supplemental Figure.1 from An Akt3 Splice Variant Lacking the Serine 472 Phosphorylation Site Promotes Apoptosis and Suppresses Mammary Tumorigenesis

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journal contribution
posted on 2023-03-31, 00:00 authored by Kimita Suyama, Jiahong Yao, Huizhi Liang, Outhiriaradjou Benard, Olivier D. Loudig, Dulguun Amgalan, Wendy M. McKimpson, Greg R. Phillips, Jeffrey Segall, Yihong Wang, Susan Fineberg, Larry Norton, Richard N. Kitsis, Rachel B. Hazan

Next generation sequencing of genomic DNA isolated from Akt3/+S472 and Akt3/-S472 knockout cell lines


National Cancer Institute

Breast Cancer Research Foundation



The Akt pathway is a well-known promoter of tumor malignancy. Akt3 is expressed as two alternatively spliced variants, one of which lacks the key regulatory serine 472 phosphorylation site. Whereas the function of full-length Akt3 isoform (Akt3/+S472) is well-characterized, that of Akt3/−S472 isoform remains unknown. Despite being expressed at a substantially lower level than Akt3/+S472 in triple-negative breast cancer cells, specific ablation of Akt3/−S472 enhanced, whereas overexpression, suppressed mammary tumor growth, consistent with a significant association with patient survival duration relative to Akt3/+S472. These effects were due to striking induction of apoptosis, which was mediated by Bim upregulation, leading to conformational activation of Bax and caspase-3 processing. Bim accumulation was caused by marked endocytosis of EGF receptors with concomitant ERK attenuation, which stabilizes BIM. These findings demonstrate an unexpected function of an endogenously expressed Akt isoform in promoting, as opposed to suppressing, apoptosis, underscoring that Akt isoforms may exert dissonant functions in malignancy.Significance: These results illuminate an unexpected function for an endogenously expressed Akt isoform in promoting apoptosis, underscoring the likelihood that different Akt isoforms exert distinct functions in human cancer. Cancer Res; 78(1); 103–14. ©2017 AACR.