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TOR kinase and ran are downstream from PI3K/Akt in H 2 O 2 ‐induced mitosis
Author(s) -
Radisavljevic Ziv Manasija,
GonzálezFlecha Beatriz
Publication year - 2004
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.20037
Subject(s) - pi3k/akt/mtor pathway , protein kinase b , wortmannin , rptor , microbiology and biotechnology , phosphorylation , chemistry , akt1 , biology , signal transduction
Abstract Hydrogen peroxide (H 2 O 2 ) activates signaling cascades essential for cell proliferation via phosphatidylinositol‐3‐kinase (PI3K) and Akt. Here we show that induction of mitogenic signaling by H 2 O 2 activates sequentially PI3K, Akt, mammalian target of rapamycin (mTOR), and Ran protein. Akt activation is followed by signaling through the mTOR kinase and upregulation of Ran in primary type II pneumocytes, a cell type implicated in the development of lung adenocarcinoma. Pretreatment of the cells with wortmannin, a specific inhibitor of PI3K, or rapamycin, a specific inhibitor of mTOR kinase, prevented H 2 O 2 ‐increased mitosis. H 2 O 2 ‐induced Akt ser‐473 phosphorylation and upregulation of Ran protein were prevented by wortmannin but not by rapamycin, indicating that PI3K is upstream of Akt and mTOR is downstream from Akt. Overexpression of myr‐Akt or Ran‐wt in type II pneumocytes increased Akt ser‐473 phosphorylation and mitosis in a catalase‐dependent manner, indicating that H 2 O 2 is essential for Akt and Ran signaling. These results indicate that H 2 O 2 ‐induced mitogenic signaling in primary type II pneumocytes is mediated by PI3K, Akt, mTOR‐kinase, and Ran protein. © 2004 Wiley‐Liss, Inc.