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J. Biol. Chem., Vol. 278, Issue 34, 32471-32477, August 22, 2003

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STAT4 Requires the N-terminal Domain for Efficient Phosphorylation^*

Hua-Chen Chang   ¶, Shangming Zhang  , India Oldham  , Lisa Naeger ||, Timothy Hoey || and Mark H. Kaplan   **

From the Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, the Walther Cancer Institute, Indianapolis, Indiana 46208, and ^||Tularik, Incorporated, San Francisco, California 94080

STAT4 (signal transducer and activator of transcription-4) mediates biological effects in response to interleukin-12 (IL-12). STAT4 has multiple domains that have distinct functions in signaling and gene activation. To characterize the role of the STAT4 N-terminal domain in mediating STAT4 biological function, we have generated STAT4-deficient transgenic mice that express human full-length STAT4 or an N-terminal deletion mutant (N-STAT4) lacking the N-terminal 51 amino acids. Whereas full-length STAT4 rescued IL-12 responsiveness, T lymphocytes expressing the STAT4 N-terminal mutant failed to proliferate in response to IL-12 and had limited Th1 cell development as evidenced by minimal interferon- production. Deletion of the N-terminal domain resulted in failure of STAT4 to be phosphorylated following IL-12 stimulation despite similar phosphorylation of JAK2 and TYK2 in full-length STAT4 and N-STAT4 transgenic T cells. We demonstrate that the lack of phosphorylation in cultured cells is due to reduced efficiency of phosphorylation of N-STAT4 by Janus kinases. These data support a new model wherein the N-terminal domain is required to mediate the phosphorylation of STAT4 in addition to the previously documented role in gene transactivation.

Received for publication, March 18, 2003 , and in revised form, June 6, 2003.

^* This work was supported in part by National Institutes of Health Grant AI45515 (to M. H. K.) and the Indiana Genomics Initiative of Indiana University, which is supported in part by Lilly Endowment Inc. 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.

^¶ Supported by National Institutes of Health Training Grant T32DK007519.

^** To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Walther Oncology Center, Indiana University School of Medicine, Rm. 302, 950 West Walnut St., Indianapolis, IN 46202. Tel.: 317-278-3696; Fax: 317-274-7592; E-mail: mkaplan2{at}iupui.edu.

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