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β1Pix induces Cell Proliferation through p66Shc/FOXO3a Signaling pathway independently of Akt.
Author(s) -
Chahdi Ahmed,
Sorokin Andrey
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a617-c
Subject(s) - phosphorylation , protein kinase b , rac1 , microbiology and biotechnology , downregulation and upregulation , guanine nucleotide exchange factor , cell growth , chemistry , serine , pi3k/akt/mtor pathway , kinase , small hairpin rna , signal transduction , biology , gene knockdown , biochemistry , apoptosis , gene
The phosphorylation of forkhead transcription factor FOXO3a in cells stimulated with reactive oxygen species requires the activation of Akt and p66Shc. We report here that the expression of the Rac1/Cdc42 guanine nucleotide exchange factor β1Pix induces serine 36 phosphorylation of p66Shc through Rac1 and ERK1/2 activation. Knocking down Akt by its specific shRNA completely abolished serum‐induced FOXO3a phosphorylation but did not inhibit β1Pix‐induced FOXO3a phosphorylation. The depletion of p66Shc by RNA interference inhibited β1Pix‐mediated FOXO3a phosphorylation, without affecting the cyclin‐dependent kinase inhibitor p27kip1 protein level. β1Pix‐induced p27kip1 downregulation was blocked by ERK1/2 inhibition. Both endogenous p66Shc and FOXO3a bind to the amino acids sequence 603–608 of β1Pix. Deletion of amino acids 603–608 prevented the formation of β1Pix/p66Shc/FOXO3a complex and impaired the ability of β1Pix to induce p27kip1 downregulation as well as cell proliferation. Our results identify p66Shc and FOXO3a as novel partners of β1Pix and represent the first direct evidence of β1Pix in inducing cell proliferation via an Akt‐independent mechanism.