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Molecular and Cellular Biology, June 2004, p. 4968-4978, Vol. 24, No. 11
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.11.4968-4978.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Tyrosine Phosphorylation of Jak2 in the JH2 Domain Inhibits Cytokine Signaling

Edward P. Feener,{dagger}* Felicia Rosario,{dagger} Sarah L. Dunn,{dagger} Zlatina Stancheva, and Martin G. Myers Jr.*

Harvard Medical School and Research Division, Joslin Diabetes Center, Boston, Massachusetts 022151

Received 4 September 2003/ Returned for modification 7 November 2003/ Accepted 9 March 2004

Jak family tyrosine kinases mediate signaling by cytokine receptors to regulate diverse biological processes. Although Jak2 and other Jak kinase family members are phosphorylated on numerous sites during cytokine signaling, the identity and function of most of these sites remains unknown. Using tandem mass spectroscopic analysis of activated Jak2 protein from intact cells, we identified Tyr221 and Tyr570 as novel sites of Jak2 phosphorylation. Phosphorylation of both sites was stimulated by cytokine treatment of cultured cells, and this stimulation required Jak2 kinase activity. While we observed no gross alteration of signaling upon mutation of Tyr221, Tyr570 lies within the inhibitory JH2 domain of Jak2, and mutation of this site (Jak2Y570F) results in constitutive Jak2-dependent signaling in the absence of cytokine stimulation and enhances and prolongs Jak2 activation during cytokine stimulation. Mutation of Tyr570 does not alter the ability of SOCS3 to bind or inhibit Jak2, however. Thus, the phosphorylation of Tyr570 in vivo inhibits Jak2-dependent signaling independently of SOCS3-mediated inhibition. This Tyr570-dependent mechanism of Jak2 inhibition likely represents an important mechanism by which cytokine function is regulated.

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

{dagger} E.P.F., F.R., and S.L.D. contributed equally to this work.

Molecular and Cellular Biology, June 2004, p. 4968-4978, Vol. 24, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.11.4968-4978.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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