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J. Biol. Chem., Vol. 282, Issue 7, 4243-4252, February 16, 2007

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MNK1 and MNK2 Regulation in HER2-overexpressing Breast Cancer Lines^*

Carol A. Chrestensen¹, Jacquelyn K. Shuman, Andrew Eschenroeder, Mark Worthington², Hermann Gram^¶, and Thomas W. Sturgill³

From the Department of Pharmacology, Digestive Health Center of Excellence, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, and ^¶Arthritis and Bone Metabolism, Novartis Pharma AG, CH-4002 Basel, Switzerland

MAPK-interacting protein kinases 1 and 2 (MNK1 and MNK2) function downstream of p38 and ERK MAPK, but there are large gaps in our knowledge of how MNKs are regulated and function. As proteins activated in the HER2/Ras/Raf/ERK pathway, the MNKs are of potential interest in HER2-overexpressing cancers. We utilized a panel of breast cell lines (HCC1419, AU565, SKBR3, MCF7, and MCF10A), three of which overexpress HER2, to characterize the amounts and activation status of MNKs and other pathway enzymes (ERKs and RSKs) in these cells. We generated a phosphospecific antibody to Thr(P)-214 in the T-loop of MNKs and found that phosphorylations of both Thr-209 and Thr-214 in human MNK1 are required for activation. Increased phosphorylation and activity of the MNKs correlate with HER2 overexpression, and inhibition of the MNKs reduces colony formation in soft agar. Our work identifies the MNKs as potential therapeutic targets for breast cancer treatments.

Received for publication, August 3, 2006 , and in revised form, October 31, 2006.

^* This work was supported by National Institutes of Health Grant GM62890 (to T. W. S.) and by Department of Defense Breast Cancer Postdoctoral Award DAMD17-03-1-0555 (to C. A. C). 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 Present address: Dept. of Chemistry and Biochemistry, Kennesaw State University, Kennesaw, GA 30144.

² Present address: Division of Digestive Diseases, The Johns Hopkins Bayview Medical Center, Baltimore, MD 21224.

³ To whom correspondence should be addressed: Dept. of Pharmacology, University of Virginia School of Medicine, 1300 Jefferson Park Ave., Charlottesville, VA 22908-0735. Tel.: 434-924-9191; Fax: 434-924-5207; E-mail: Thomas_Sturgill{at}virginia.edu.

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