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MBC in Press, published online ahead of print May 25, 2005
Mol. Biol. Cell 10.1091/mbc.E04-11-1007

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Submitted on November 17, 2004
Revised on April 20, 2005
Accepted on May 17, 2005

Phosphorylation of Phosphoprotein Enriched in Astrocytes (PEA15) Regulates ERK-dependent Transcription and Cell Proliferation

Joseph Krueger,* Fan-Li Chou,* Angela Glading,* Erik Schaefer,{dagger} and Mark H. Ginsberg*

*University of California-San Diego, La Jolla, CA 92093-0726; {dagger}Biosource International, Hopkinton, MA 01748

Monitoring Editor: Martin A. Schwartz

Cell cycle progression is dependent on the nuclear localization and transcriptional effects of activated ERK1 and ERK2 MAP kinases (ERK1/2). Phosphoprotein Enriched in Astrocytes (PEA15) binds ERK1/2 and inhibits their nuclear localization, thus blocking cell proliferation. Here we report that phosphorylation of PEA15 blocks its interaction with ERK 1/2 in vitro and in vivo and that phosphorylation of both Ser104 and Ser116 is required for this effect. Using phospho-mimetic and nonphosphorylatable mutants of PEA15, we found that PEA15 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 PEA15. Additionally, we report that PEA15 phosphorylation can modulate nontranscriptional activities of ERK1/2, such as the modulation of the affinity of integrin adhesion receptors. Finally, we used a novel antiphospho-specific PEA15 antibody to establish that PEA15 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.

Address correspondence to: Mark H. Ginsberg (mhginsberg{at}ucsd.edu)




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