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Molecular and Cellular Biology, June 2006, p. 4063-4073, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.01589-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Phosphorylation of Jak2 on Ser523 Inhibits Jak2-Dependent Leptin Receptor Signaling{dagger}

Ryoko Ishida-Takahashi,1 Felicia Rosario,2 Yusong Gong,1 Keely Kopp,1 Zlatina Stancheva,1 Xiaohong Chen,2 Edward P. Feener,2* and Martin G. Myers Jr.1*

Departments of Internal Medicine and Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109,1 Research Division, Joslin Diabetes Center, Boston, Massachusetts 022152

Received 17 August 2005/ Returned for modification 20 September 2005/ Accepted 8 March 2006

The leptin receptor, LRb, and other cytokine receptors are devoid of intrinsic enzymatic activity and rely upon the activity of constitutively associated Jak family tyrosine kinases to mediate intracellular signaling. In order to clarify mechanisms by which Jak2, the cognate LRb-associated Jak kinase, is regulated and mediates downstream signaling, we employed tandem mass spectroscopic analysis to identify phosphorylation sites on Jak2. We identified Ser523 as the first-described site of Jak2 serine phosphorylation and demonstrated that this site is phosphorylated on Jak2 from intact cells and mouse spleen. Ser523 was highly phosphorylated in HEK293 cells independently of LRb-Jak2 activation, suggesting a potential role for the phosphorylation of Ser523 in the regulation of LRb by other pathways. Indeed, mutation of Ser523 sensitized and prolonged signaling by Jak2 following activation by the intracellular domain of LRb. The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition. Thus, the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling.

* Corresponding author. Mailing address for Edward P. Feener: Research Division, Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215. Phone: (617) 732-2599. Fax: (617) 732-2637. E-mail: edward.feener{at}joslin.harvard.edu. Mailing address for Martin G. Myers, Jr.: University of Michigan, Division of Metabolism, Endocrinology, and Diabetes, Departments of Internal Medicine and Molecular and Integrative Physiology, 1150 W. Medical Center Dr., 4301 MSRB III, Box 0638, Ann Arbor, MI 48109. Phone: (734) 647-9515. Fax: (734) 936-6684. E-mail: mgmyers{at}umich.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, June 2006, p. 4063-4073, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.01589-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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