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J. Biol. Chem., Vol. 282, Issue 42, 31019-31027, October 19, 2007

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The Long Form of the Leptin Receptor Regulates STAT5 and Ribosomal Protein S6 via Alternate Mechanisms^*

Yusong Gong¹, Ryoko Ishida-Takahashi¹, Eneida C. Villanueva, Diane C. Fingar^¶, Heike Münzberg, and Martin G. Myers, Jr.²

From the Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, and the Departments of Molecular and Integrative Physiology and ^¶Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109

The action of leptin via the long form of its receptor (LepRb) is central to the control of body energy homeostasis and neuroendocrine function, but the mechanisms by which LepRb regulates intracellular signaling have remained incompletely understood. Here we demonstrate that leptin stimulates the phosphorylation of STAT5 and ribosomal protein S6 in the hypothalamic arcuate nucleus in mice. In cultured cells, we investigate the mechanisms by which leptin regulates each of these pathways. Our analysis reveals a dominant role for LepRb Tyr¹⁰⁷⁷ (which we demonstrate to be phosphorylated during receptor activation) and a secondary role for LepRb Tyr¹¹³⁸ in the acute phosphorylation of STAT5a and STAT5b. Tyr¹¹³⁸ and STAT3 attenuate STAT5-dependent transcription over the long-term, however. In contrast, Tyr⁹⁸⁵ (the LepRb phosphorylation site required for ERK activation) mediates the phosphorylation of the ribosomal S6 kinase (RSK) and S6, as well as cap-dependent translation. Thus, these data demonstrate the phosphorylation of Tyr¹⁰⁷⁷ on LepRb during receptor activation, substantiate the hypothalamic regulation of STAT5 and S6 by leptin, and define the alternate LepRb signaling pathways that mediate each of these signals and their effects in cultured cells. Dissecting the contributions of these individual pathways to leptin action will be important for our ultimate understanding of the processes that regulate energy balance in vivo.

Received for publication, April 3, 2007 , and in revised form, August 7, 2007.

^* This work was supported by National Institutes of Health Grants R01 DK56731 and R01 DK57768 (to M. G. M.) and R01 DK78135 (to D. C. F.) and grants from the American Diabetes Association (to M. G. M. and D. C. F.), the American Heart Association (to H. M.), and core facilities of the Michigan Diabetes Research and Training Center supported by National Institutes of Health Grant DK20572 and Michigan Comprehensive Cancer Center National Institutes of Health Grant P30CA046592. 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 Both authors contributed equally.

² To whom correspondence should be addressed: 5560 MSRB II/0678, 1150 W. Medical Center Dr., Ann Arbor, MI 48109. Tel.: 734-647-9515; Fax: 734-936-6684; E-mail: mgmyers{at}umich.edu.

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