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Vol. 16, Issue 8, 3705-3718, August 2005

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ERK Phosphorylates p66shcA on Ser36 and Subsequently Regulates p27^kip1 Expression via the Akt-FOXO3a Pathway: Implication of p27^kip1 in Cell Response to Oxidative Stress

Yuanyu Hu ^*, Xueying Wang ^*, Li Zeng ^*, De-Yu Cai ^*, Kanaga Sabapathy , Stephen P. Goff , Eduardo J. Firpo , and Baojie Li ^*

^* The Institute of Molecular and Cell Biology, Proteos, Singapore 138673, Singapore; National Cancer Centre, Singapore 169610, Singapore; Howard Hughes Medical Institute and Department of Biochemistry and Molecular Biophysics, College for Physicians and Surgeons, Columbia University, New York, NY 10032; and Howard Hughes Medical Institute and Department of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109

Submitted April 11, 2005; Accepted May 24, 2005
Monitoring Editor: Tony Hunter

Mice deficient for p66shcA represent an animal model to link oxidative stress and aging. p66shcA is implicated in oxidative stress response and mitogenic signaling. Phosphorylation of p66shcA on Ser36 is critical for its function in oxidative stress response. Here we report the identification of ERK as the kinase phosphorylating p66shcA on Ser36. Activation of ERKs was necessary and sufficient for Ser36 phosphorylation. p66shcA interacted with ERK and was demonstrated to be a substrate for ERK, with Ser36 being the major phosphorylation site. Furthermore, in response to H₂O₂, inhibition of ERK activation repressed p66shcA-dependent phosphorylation of FOXO3a and the down-regulation of its target gene p27^kip1. Down-regulation of p27 might promote cell survival, as p27 played a proapoptotic role in oxidative stress response. As a feedback regulation, Ser36 phosphorylated p66shcA attenuated H₂O₂-induced ERK activation, whereas p52/46shcA facilitated ERK activation, which required tyrosine phosphorylation of CH1 domain. p66shcA formed a complex with p52/46ShcA, which may provide a platform for efficient signal propagation. Taken together, the data suggest there exists an interplay between ERK and ShcA proteins, which modulates the expression of p27 and cell response to oxidative stress.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Baojie Li (libj{at}imcb.a-star.edu.sg).

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