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J. Biol. Chem., Vol. 283, Issue 17, 11176-11188, April 25, 2008

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Calcium-mediated Interactions Regulate the Subcellular Localization of Extracellular Signal-regulated Kinases^*

Dana Chuderland¹, Goldie Marmor¹, Alla Shainskaya, and Rony Seger²

From the Department of Biological Regulation and Mass Spectroscopy Unit, The Weizmann Institute of Science, Rehovot 76100, Israel

The subcellular localization of ERKs in cells, which is important for proper signaling, may be regulated through protein-protein interactions. We found that inactive ERK2 interacts with a large number of proteins through its cytosolic retention sequence/common docking domain, whereas the phospho-ERK2 interacts with only few substrates. Varying calcium concentrations significantly modified the repertoire of ERK2-interacting proteins, of which many were identified. The effect of calcium on ERK interactions also influenced the localization of ERKs, as calcium chelators enhanced nuclear translocation, whereas elevated calcium levels prevented it. This effect of calcium was apparent upon lysophosphatidic acid stimulation, where ERKs translocation was delayed compared with that induced by EGF in a calcium-dependent manner. In vitro translocation assay revealed that high calcium concentrations affect ERK translocation by preventing the shuttling machinery through the nuclear envelope, probably due to higher binding to nuclear pore proteins. These results are consistent with a model in which ERKs in quiescent cells are bound to several cytoplasmic proteins. Upon stimulation, ERKs are phosphorylated and released from cytoplasmic anchors to allow shuttling toward the nucleus. This translocation is delayed when calcium levels are increased, and this modifies the localization of ERKs and, therefore, also their spatiotemporal regulation. Thus, calcium regulates ERK localization, which is important for the compartmentalization of ERKs with their proper substrates and thereby their signaling specificity.

Received for publication, November 2, 2007 , and in revised form, February 8, 2008.

^* This work was supported by grants from the Israel Academy of Sciences and Humanities from the European Community's Sixth Framework Program Project IST-2004-027265-SIMAP. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors are equal contributors.

² An incumbent of the Yale Lewine and Ella Miller Lewine professorial chair for cancer research. To whom correspondence should be addressed. Tel.: 972-8-9343602; Fax: 972-8-9344116; E-mail: rony.seger{at}weizmann.ac.il.

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