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J. Biol. Chem., Vol. 279, Issue 24, 25196-25203, June 11, 2004

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Interleukin 4 Regulates Phosphorylation of Serine 756 in the Transactivation Domain of Stat6

ROLES FOR MULTIPLE PHOSPHORYLATION SITES AND Stat6 FUNCTION^*

Yuling Wang, Maria Grazia Malabarba¶, Zsuzsanna S. Nagy, and Robert A. Kirken||

From the Department of Integrative Biology and Pharmacology, The University of Texas Medical School, Houston, Texas 77030 and the Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy

Lymphokines interleukin-4 (IL4) and IL13 exert overlapping biological activities via the shared use of the IL4 receptor -chain and signal transducer and activator of transcription 6 (Stat6). Stat6 is critical for T-helper 2 cell differentiation, B-cell Ig class switch, and allergic diseases; thus, understanding its regulation is of central importance. Phosphorylation is crucial for Stat activity. Whereas Stat6 is phosphorylated on Tyr⁶⁴¹, less is known about serine or threonine. We demonstrate in primary human T-cells (>95% CD3+) that IL4 and for the first time IL13 induce Stat6 serine but not threonine phosphorylation that closely paralleled early IL4 receptor -chain activation (10 min). Stat6 uniquely fails to share a positionally conserved Stat serine phosphorylation sequence; however, known phosphoacceptor sites are proline-flanked. Alanine substitutions of these conserved residues revealed that the transactivation domain, which localized Ser⁷⁵⁶ but not Ser⁸²⁷ or Ser¹⁷⁶, is the IL4-regulated site based on phosphoamino acid analysis. Tyr⁶⁴¹ was dispensable for IL4-mediated serine phosphorylation, suggesting that dimerization is not preconditional. Only Stat6 Y641F variant showed a significant effect on IL4-inducible C DNA-binding and reporter gene expression. Lastly, recent work has shown that protein phosphatase 2A negatively regulates Stat6 (Woetmann, A., Brockdorff, J., Lovato, P., Nielsen, M., Leick, V., Rieneck, K., Svejgaard, A., Geisler, C., and Odum, N. (2003) J. Biol. Chem. 278, 2787–2791). We propose this target residue(s) is distinct from Ser⁷⁵⁶ and may be proximal to Tyr⁶⁴¹ at Thr⁶⁴⁵, a residue conserved only among Stat6 members. The phosphomimic variants T645E or T645D ablated Stat6 activation, whereas polar uncharged substitutions (Gln or Asn) and additional mutants (Ala, Val, or Phe) showed no effect. These findings suggest that Stat6 has mechanisms of regulation distinct from other Stats.

Received for publication, December 15, 2003 , and in revised form, March 16, 2004.

^* This work was supported in part by Grants AI053566 and NIDDK 38016-12 from the American Lung Association, National Institutes of Health (to R. A. K.) and a grant from the American Heart Association, Texas Affiliate of the National Institutes of Health (to Y. W.). 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.

^¶ Present address: The Fondazione Italiana per la Ricerca sul Cancro Institute for Molecular Oncology, via Adamello 16, 20139 Milan, Italy.

^|| To whom correspondence should be addressed: Dept. of Integrative Biology and Pharmacology, University of Texas-Houston, Medical Science Bldg., Rm. 4.218, Houston, TX 77030. Tel.: 713-500-7516; Fax: 713-500-7444; E-mail: robert.a.kirken{at}uth.tmc.edu.

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