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Molecular and Cellular Biology, May 2004, p. 4557-4570, Vol. 24, No. 10
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.10.4557-4570.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Tyrosine 813 Is a Site of JAK2 Autophosphorylation Critical for Activation of JAK2 by SH2-Bß

Jason H. Kurzer,1 Lawrence S. Argetsinger,2 Yong-Jie Zhou,3 Jean-Louis K. Kouadio,2,{dagger} John J. O'Shea,3 and Christin Carter-Su2*

Graduate Program in Cellular and Molecular Biology,1 Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0662,2 Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892-18203

Received 3 October 2003/ Returned for modification 2 December 2003/ Accepted 9 February 2004

The tyrosine kinase Janus kinase 2 (JAK2) binds to the majority of the known members of the cytokine family of receptors. Ligand-receptor binding leads to activation of the associated JAK2 molecules, resulting in rapid autophosphorylation of multiple tyrosines within JAK2. Phosphotyrosines can then serve as docking sites for downstream JAK2 signaling molecules. Despite the importance of these phosphotyrosines in JAK2 function, only a few sites and binding partners have been identified. Using two-dimensional phosphopeptide mapping and a phosphospecific antibody, we identified tyrosine 813 as a site of JAK2 autophosphorylation of overexpressed JAK2 and endogenous JAK2 activated by growth hormone. Tyrosine 813 is contained within a YXXL sequence motif associated with several other identified JAK2 phosphorylation sites. We show that phosphorylation of tyrosine 813 is required for the SH2 domain-containing adapter protein SH2-Bß to bind JAK2 and to enhance the activity of JAK2 and STAT5B. The homologous tyrosine in JAK3, tyrosine 785, is autophosphorylated in response to interleukin-2 stimulation and is required for SH2-Bß to bind JAK3. Taken together these data strongly suggest that tyrosine 813 is a site of autophosphorylation in JAK2 and is the SH2-Bß-binding site within JAK2 that is required for SH2-Bß to enhance activation of JAK2.

* Corresponding author. Mailing address: Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI 48109-0622. Phone: (734) 763-2561. Fax: (734) 647-9523. E-mail: cartersu{at}umich.edu.

{dagger} Present address: Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637.

Molecular and Cellular Biology, May 2004, p. 4557-4570, Vol. 24, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.10.4557-4570.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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