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J. Biol. Chem., Vol. 282, Issue 51, 36820-36828, December 21, 2007

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Identification of in Vivo Phosphorylation Sites and Their Functional Significance in the Sodium Iodide Symporter^*

Douangsone D. Vadysirisack, Eric S.-W. Chen^¶, Zhaoxia Zhang^||, Ming-Daw Tsai^¶, Geen-Dong Chang^**, and Sissy M. Jhiang^||1

From the Integrated Biomedical Science Graduate Program, the ^||Ohio State Biochemistry Program, and the Departments of Physiology and Cell Biology and Internal Medicine, Ohio State University, Columbus, Ohio 43210, the ^¶Genomics Research Center, Academia Sinica, Taipei 115, Taiwan, and the ^**Graduate Institute of Biochemical Sciences, National Taiwan University, Taipei 106, Taiwan

The Na⁺/I^– symporter (NIS)-mediated iodide uptake activity is the basis for targeted radioiodide ablation of thyroid cancers. Although it has been shown that NIS protein is phosphorylated, neither the in vivo phosphorylation sites nor their functional significance has been reported. In this study, Ser-43, Thr-49, Ser-227, Thr-577, and Ser-581 were identified as in vivo NIS phosphorylation sites by mass spectrometry. Kinetic analysis of NIS mutants of the corresponding phosphorylated amino acid residue indicated that the velocity of iodide transport of NIS is modulated by the phosphorylation status of Ser-43 and Ser-581. We also found that the phosphorylation status of Thr-577 may be important for NIS protein stability and that the phosphorylation status of Ser-227 is functionally silent. Thr-49 appears to be critical for proper local structure/conformation of NIS because mutation of Thr-49 to alanine, aspartic acid, or serine results in reduced NIS activity without alterations in total or cell surface NIS protein levels. Taken together, we showed that NIS protein levels and functional activity could be modulated by phosphorylation through distinct mechanisms.

Received for publication, August 15, 2007 , and in revised form, September 26, 2007.

^* This work was supported in part by NIBIB Grant 1 R01 EB001876 from the National Institutes of Health (to S. M. J.) and by National Health Research Institutes Grant EX95-9508NI (to M.-D. T.). 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 To whom correspondence should be addressed: Ohio State University, 304 Hamilton Hall, 1645 Neil Ave., Columbus, OH 43210. Tel.: 614-292-4312; Fax: 614-292-4888; E-mail: jhiang.1{at}osu.edu.

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