An Akt3 splice variant lacking the serine 472 phosphorylation site promotes apoptosis and suppresses mammary tumorigenesis

Kimita Suyama, Jiahong Yao, Huizhi Liang, Outhiriaradjou Benard, Olivier D. Loudig, Dulguun Amgalan, Wendy M. McKimpson, Greg R. Phillips, Jeffrey E. Segall, Yihong Wang, Susan A. Fineberg, Larry Norton, Richard N. Kitsis, Rachel Hazan

Research output: Contribution to journalArticle

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Abstract

The Akt pathway is a well-known promoter of tumormalignancy. 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 isoformremains 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 effectswere 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.

Original languageEnglish (US)
Pages (from-to)103-114
Number of pages12
JournalCancer Research
Volume78
Issue number1
DOIs
StatePublished - Jan 1 2018

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Serine
Protein Isoforms
Carcinogenesis
Breast
Phosphorylation
Apoptosis
Triple Negative Breast Neoplasms
Endocytosis
Caspase 3
Neoplasms
Up-Regulation
Breast Neoplasms
Survival
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

An Akt3 splice variant lacking the serine 472 phosphorylation site promotes apoptosis and suppresses mammary tumorigenesis. / Suyama, Kimita; Yao, Jiahong; Liang, Huizhi; Benard, Outhiriaradjou; Loudig, Olivier D.; Amgalan, Dulguun; McKimpson, Wendy M.; Phillips, Greg R.; Segall, Jeffrey E.; Wang, Yihong; Fineberg, Susan A.; Norton, Larry; Kitsis, Richard N.; Hazan, Rachel.

In: Cancer Research, Vol. 78, No. 1, 01.01.2018, p. 103-114.

Research output: Contribution to journalArticle

Suyama, Kimita ; Yao, Jiahong ; Liang, Huizhi ; Benard, Outhiriaradjou ; Loudig, Olivier D. ; Amgalan, Dulguun ; McKimpson, Wendy M. ; Phillips, Greg R. ; Segall, Jeffrey E. ; Wang, Yihong ; Fineberg, Susan A. ; Norton, Larry ; Kitsis, Richard N. ; Hazan, Rachel. / An Akt3 splice variant lacking the serine 472 phosphorylation site promotes apoptosis and suppresses mammary tumorigenesis. In: Cancer Research. 2018 ; Vol. 78, No. 1. pp. 103-114.
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