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Vol. 16, Issue 8, 3552-3561, August 2005
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* University of California–San Diego, La Jolla, CA 92093-0726;
BioSource International, Hopkinton, MA 01748
Submitted November 17, 2004;
Revised April 20, 2005;
Accepted May 17, 2005
Monitoring Editor: Martin A. Schwartz
Cell cycle progression is dependent on the nuclear localization and transcriptional effects of activated extracellular signal-regulated kinase (ERK)1 and ERK2 mitogen-activated protein (MAP) kinases (ERK1/2). Phosphoprotein enriched in astrocytes (PEA-15) binds ERK1/2 and inhibits their nuclear localization, thus blocking cell proliferation. Here, we report that phosphorylation of PEA-15 blocks its interaction with ERK1/2 in vitro and in vivo and that phosphorylation of both Ser104 and Ser116 is required for this effect. Using phosphomimetic and nonphosphorylatable mutants of PEA-15, we found that PEA-15 phosphorylation abrogates its capacity to block the nuclear localization and transcriptional activities of ERK1/2; this phosphorylation therefore enables the proliferation of cells that express high levels of PEA-15. Additionally, we report that PEA-15 phosphorylation can modulate nontranscriptional activities of ERK1/2, such as the modulation of the affinity of integrin adhesion receptors. Finally, we used a novel anti-phospho-specific PEA-15 antibody to establish that PEA-15 is phosphorylated in situ in normal mammary epithelium. These results define a novel posttranslational mechanism for controlling the subcellular localization of ERK1/2 and for specifying the output of MAP kinase signaling.
Abbreviations used: DED, death effector domain; DISC, death inducing signaling complex; ERK1/2, extracellular signal-regulated kinase 1 and 2; MAP, mitogen-activated protein kinase; PEA-15, phosphoprotein enriched in astrocytes.
Address correspondence to: Mark H. Ginsberg (mhginsberg{at}ucsd.edu).
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